apolipoprotein e genotypes and neuropsychiatric symptoms and syndromes in late-onset...
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Ageing Research Reviews 11 (2012) 87– 103
Contents lists available at ScienceDirect
Ageing Research Reviews
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polipoprotein E genotypes and neuropsychiatric symptoms and syndromes inate-onset Alzheimer’s disease
rancesco Panzaa,∗,1, Vincenza Frisardib,1, Davide Seripaa, Grazia D’Onofrioa, Andrea Santamatoc,arlo Masullod, Giancarlo Logroscinoe, Vincenzo Solfrizzib, Alberto Pilottoa
Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Foggia, ItalyDepartment of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, ItalyDepartment of Physical Medicine and Rehabilitation, University of Foggia, ItalyInstitute of Neurology, Catholic University School of Medicine, Rome, ItalyDepartment of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy
r t i c l e i n f o
rticle history:eceived 20 November 2010eceived in revised form 29 May 2011ccepted 30 June 2011vailable online 7 July 2011
eywords:europsychiatric symptomseuropsychiatric syndromeslzheimer’s diseasepolipoprotein EPOEementia
a b s t r a c t
Neuropsychiatric symptoms (NPS) in dementia, previously denominated as behavioural and psycholog-ical symptoms of dementia, are often more distressing, impairing, and costly than cognitive symptoms,representing a major health burden for older adults. These symptoms are common features of Alzheimer’sdisease (AD), and are one of the major risk factors for institutionalization. There is a high prevalenceof neuropsychiatric disturbances in patients with AD, including depression, anxiety, apathy, psychosis,aggression, and agitation. At present, the role of the apolipoprotein E (APOE) genotypes in the develop-ment of NPS or neuropsychiatric syndromes/endophenotypes in AD patients is unclear. In this article, wesummarized the findings of the studies of NPS and neuropsychiatric syndromes in AD in relation to APOEgenotypes, with special attention to the possible underlying mechanisms. While some studies failed tofind a significant association between the APOE polymorphism and NPS in late-onset AD, other studiesreported a significant association between the APOE �4 allele and an increase in agitation/aggression, hal-lucinations, delusions, and late-life depression or anxiety. However, current cumulative evidence comingfrom the few existing longitudinal studies shows no association of APOE genotypes with NPS as a wholein AD. Some negative studies that focused on the distribution of APOE genotypes between AD patientswith or without NPS further emphasized the importance of sub-grouping NPS in distinct neuropsychi-atric syndromes. Explanations for the variable findings in the existing studies included differences inpatient populations, differences in the assessment of neuropsychiatric symptomatology, possible lack of
statistical power to detect associations in the negative studies, and small sample sizes generating falsepositives that cannot be consistently replicated. Finally, many reviewed studies were cross-sectional,whereas it would be of paramount importance to evaluate the risk for incident NPS in relation to theAPOE genotype in prospectively followed cohorts of AD patients. In fact, identifying predisposing geneticrisk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromesor symptoms in AD, so optimizing possible therapeutic options.© 2011 Elsevier B.V. All rights reserved.
. Introduction
Dementia is an age-related progressive disorder with an enor-ous unmet medical need, characterized by impairments inemory and other cognitive functions that are severe enough to
∗ Corresponding author at: Geriatric Unit and Gerontology-Geriatric Researchaboratory, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013 Saniovanni Rotondo, Foggia, Italy.
E-mail addresses: [email protected], [email protected]. Panza).
1 The first two authors contributed equally to this article.
568-1637/$ – see front matter © 2011 Elsevier B.V. All rights reserved.oi:10.1016/j.arr.2011.06.005
cause significant decline from a previous level of social and occupa-tional functioning. Since population aging has become a worldwidephenomenon, the burden of age-related neurodegenerative dis-eases, particularly dementia, is expected to increase dramatically inboth developed and developing nations. Alzheimer’s disease (AD)is the most prevalent form of dementia in Western societies, affect-ing an estimated 5 million people in the United States and 17million worldwide (Ferri et al., 2005). The annual incidence world-
wide increases from 1% between the ages of 60 and 70 years to6–8% at the age of 85 years or older (Mayeux, 2003). AccurateAD epidemiological data have been recently released for the US.The 2010 figures suggested that 5.3 million Americans have AD
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Alzheimer’s Association, 2010), with >26 million patients with ADorldwide, and an expected increase to more than 106 million by
050 (Brookmeyer et al., 2007).Progressive impairment in activities of daily living, as well as
ognitive deterioration, leads to an increase in patient depen-ency. Neuropsychiatric symptoms (NPS), previously denominateds behavioural and psychological symptoms of dementia, are com-on features of AD (Mega et al., 1996; Aalten et al., 2007). NPS
n AD include psychosis (delusions and hallucinations) as wells affective and behavioural changes such as depressive mood,nxiety, irritability/lability, apathy, euphoria, disinhibition, agita-ion/aggression, aberrant motor activities, sleep disturbance andating disorder (Finkel et al., 1996; Gauthier et al., 2010). NPS are aslinically relevant as cognitive and functional impairment; impor-antly, they contribute to patient and caregiver distress (Gauthiert al., 2010), and are one of the major risk factors for institutional-zation (Steele et al., 1990), as well as for increasing costs both inSA and Western countries (Murman et al., 2002; Herrmann et al.,006).
It has been estimated that up to 80% of patients with AD showedPS in the course of the disease (Finkel et al., 1996; Lyketsos et al.,002). NPS typically increase with disease progression. In fact,PS associated with AD tend to follow a trajectory of increasing
everity over time, a feature they have in common with cogni-ive and functional decline. However, NPS may be also associatedo AD irrespective of cognitive impairment severity and may behe presenting complaint or may emerge in the course of theisease (Finkel et al., 1996). In fact, depression and anxiety are fre-uent even in the early stage of AD or mild cognitive impairmentMCI) (Beaudreau and O’Hara, 2008; Panza et al., 2010). Currentiagnostic groupings in psychiatry are predominantly developedased on similar clinical endophenotypes. Emerging diagnosticonstructs for neuropsychiatric syndromes in dementia are drawnrom and have theoretical congruence with nondementia diagnosesn psychiatry (e.g., psychotic disorders, affective disorders, etc.).ecently, the Behavioural Subgroup of the European Alzheimer’sisease Consortium (EADC) has performed a factor analysis of
he Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) in homogeneous sample of patients with AD, analyzing the largestD population ever studied for this purpose (Aalten et al., 2007).he Behavioural Subgroup of the EADC identified four separateeuropsychiatric syndromes: affective, apathetic, psychotic, andyperactive (Aalten et al., 2007), providing also evidence of the rel-tive consistency of neuropsychiatric syndromes across dementiaubtypes, age and gender (Aalten et al., 2008), and stressing themportance of thinking about neuropsychiatric syndromes insteadf separate symptoms in AD patients.
Several studies suggested that NPS may be present in AD, vas-ular dementia (VaD), and other dementia subtypes (Swearer et al.,988; Sultzer et al., 1993; Levy et al., 1996; Starkstein et al., 1996;ooi and Sachdev, 1999; Lyketsos et al., 2000; Ballard et al., 2000;haron-Peretz et al., 2000; Bathgate et al., 2001; Nyatsanza et al.,003; Kim et al., 2003; Ikeda et al., 2004; Srikanth et al., 2005;uh et al., 2005; Fernández-Martínez et al., 2008; D’Onofrio et al.,010a). In fact, while some studies have looked at differencesetween AD and fronto-temporal dementia (FTD) (Levy et al., 1996;athgate et al., 2001; Nyatsanza et al., 2003), only few studies inves-igated differences between AD and VaD, revealing inconsistentndings regarding differences in NPS (Swearer et al., 1988; Sultzert al., 1993; Starkstein et al., 1996; Looi and Sachdev, 1999; Lyketsost al., 2000; Ballard et al., 2000; Aharon-Peretz et al., 2000; Lyketsost al., 2002; Ikeda et al., 2004; Srikanth et al., 2005; Fuh et al., 2005;
ernández-Martínez et al., 2008; D’Onofrio et al., 2010a). Indeed,he clinical cognitive profile of AD and VaD often were quite sim-lar (Starkstein et al., 1996; Aharon-Peretz et al., 2000; Lyketsost al., 2002). However, a major impairment of the frontal executiveeviews 11 (2012) 87– 103
function and the relatively preservation of the verbal long-termmemory was reported in VaD (Looi and Sachdev, 1999), while sleepdisturbance, eating disorders and aberrant motor behavioural weremore prevalent and severe in AD than VaD patients (Fernández-Martínez et al., 2008). In other studies, NPS were more commonin VaD than in AD (Ballard et al., 2000; Fuh et al., 2005) and insome reports positive symptoms such as delusions and aberrantmotor behaviour were found more frequently in the AD group thanin the VaD group (Ikeda et al., 2004). In a recent study, patientswith AD had higher frequency in agitation/aggression and irri-tability/lability scores than VaD patients (D’Onofrio et al., 2010a).Furthermore, there were significant differences between AD andVaD patients with NPS, and these symptoms varied according todementia subtype and severity and induced marked disability infunctional status, increasing, prevalently, the distress of the care-givers of AD patients (D’Onofrio et al., 2010a). A better knowledgeof neuropsychiatric pattern of the different forms of demen-tia could affect significantly treatment approaches (Kim et al.,2003).
Factors that have been associated with late-onset AD includeddepressive syndromes, various vascular risk factors, level of edu-cation, head trauma, and dietary factors (Solfrizzi et al., 2008).This complexity may help to explain their high prevalence from anevolutionary perspective, but the etiologic complexity makes iden-tification of disease-related genes much more difficult (Reitz andMayeux, 2009). The “endophenotype” approach is an alternativemethod for measuring phenotypic variation that may facilitate theidentification of susceptibility genes for complexly inherited traits(Reitz and Mayeux, 2009). The majority of AD cases are sporadic(i.e., without an apparent familial patterns of inheritance) com-pared with fewer than 5% of cases that are caused by autosomaldominant inheritance of mutations in presenilin 1, presenilin 2, oramyloid precursor protein (APP) genes (Seripa et al., 2009). Severalgenes have been identified as possible risk factors for the devel-opment of sporadic late-onset AD (Seripa et al., 2009), particularlythe gene dose of apolipoprotein E (APOE) �4 alleles (Saunders et al.,1993). As recently reported (Seripa et al., 2007), the three commonvariants �2, �3, and �4 of the APOE gene are determined by three ofthe fourth haplotypes resulting from the combination of the allelesof the two SNPs rs429358 (C3937→T) and rs7412 (C4075→T) atthe APOE locus. In particular, the haplotype T3937-T4075 identifythe �2 variant, the haplotype T3937-C4075 identify the �3 vari-ant, and the haplotype C3937-C4075 identify the �4 variant. Thefourth haplotype, C3937-T4075, identify the fourth variant, named�3r (Persico et al., 2004). This fourth haplotype is rare, being previ-ously identified only in three Caucasian families from Italy (Persicoet al., 2004; Seripa et al., 2007; Murrell et al., 2006; Seripa et al.,2011) and in one Yoruba family from Ibadan (Nigeria) worldwide(Murrell et al., 2006).
Risk for late-onset AD is known to be associated with poly-morphisms of the APOE gene; people with an �4 allele have anincreased risk of both familial and sporadic forms, accounting for20–50% of the attributable risk (Seripa et al., 2009). Nonethe-less, APOE �4 allele is neither necessary nor sufficient to causeAD and this is the main reason why APOE, until now, is classi-fied as a risk factor for AD and not as a causative one. The recentgenome wide association studies (GWAS) for AD using large num-bers of cases and controls have revealed results that show modesteffect sizes with odds ratios (OR) in the range of 1.1–1.5 (Bertramet al., 2007; Reiman et al., 2007; Carrasquillo et al., 2009). Mostof these recent GWAS have only confirmed the APOE associationwith AD. Two studies have identified variants in clusterin (CLU),
phosphatidylinositol binding clathrin assembly protein (PICALM)and complement component (3b/4b) receptor 1 (CR1), but func-tional data are still lacking (Harold et al., 2009; Lambert et al.,2009). A third large GWAS confirmed these findings and reported
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wo additional loci: rs744373 near the bridging integrator 1 (BIN1)ene on chromosome 2q14.3 and rs597668 which is within 60 kbf six genes that include exocyst complex component 3-like 2EXOC3L2); biogenesis of lysosomal organelles complex 1, sub-nit 3 (BLOC1S3); and microtubule-associated protein/microtubuleffinity-regulating kinase 4 (MARK4) on chromosome 19q13.3Seshadri et al., 2010). Very recently, other two large GWAS repli-ated previous associations at CLU, PICALM, CR1, and BIN1 anduggested other new AD susceptibility loci at the membrane span-ing 4A (MS4A) gene cluster (rs610932, rs670139, rs4939338, ands4938933), at the ATP-binding cassette, sub-family A, member
(ABCA7; rs3764650), at CD33 (rs3865444), at CD2-associatedrotein (CD2AP; rs9349407), and at EPH-receptor A1 (EPHA1;s11767557) (Hollingworth et al., 2011; Naj et al., 2011). Theseery recent observations increase our understanding of the geneticrchitecture of late-onset AD and confirms the emerging consen-us that common genetic variation plays an important role in thetiology of late-onset AD, with now ten susceptibility loci in APOE,R1, CLU, PICALM, BIN1, MS4A, ABCA7, CD33, CD2AP, and EPHA1.
However, notwithstanding these genome-wide significant asso-iations at other genetic loci, very recent findings from a largease/control sample from Caucasian ancestry (7351 AD cases and0132 controls) used in a recent European AD GWAS (Lambert et al.,009) and adding two novel case/control cohorts suggested thatsing Rochester (USA) incidence (Rocca et al., 1998) at the age of5 the lifetime risk (LTR) of AD without reference to APOE geno-ype was 11% in males and 14% in females (Genin et al., 2011). At theame age, this risk ranged from 51% for APOE �4/�4 male carriers to0% for APOE �4/�4 female carriers, and from 23% for APOE �3/�4ale carriers to 30% for APOE �3/�4 female carriers, consistent with
emi-dominant inheritance of a moderately penetrant gene. UsingAQUID (France) incidence data (Letenneur et al., 1999), estimatesere globally similar except that at age 85 the LTRs reached 68
nd 35% for APOE �4/�4 and APOE �3/�4 female carriers, respec-ively (Genin et al., 2011). Clearly these values indicate that theffect of APOE on AD is more similar to the one of major genesn Mendelian diseases such as BRCA1 in breast cancer than thene of low-risk common alleles identified by recent GWASs in ADBertram et al., 2007; Reiman et al., 2007; Carrasquillo et al., 2009)nd other complex diseases. For a comparison, the LTR of breastancer in BRCA1 mutation carriers by age 70 is estimated around7% (95% CI, 47–66%), which is similar to the estimated APOE �4/�4enetrances by age 85 (Chen and Parmigiani, 2007). In conclusion,hese results urge for a shift of category of the APOE gene from “riskactor” to “major gene” with semi-dominant inheritance in AD androfound implications for patients. In fact, considering that in Cau-asian populations roughly 2% of the population bears the APOE4/�4 genotype, and the major risk conferred by this genotyperoughly 30% by age 75 and >50% by age 85), it would be appro-riate to target in priority these individuals, as well as preselininsr APP mutation carriers, in clinical trials aimed at developing novelreventive therapeutics.
Endophenotypes represent clues to genetic underpinnings ofhe disease, and diagnoses can be deconstructed in order to makehe genetic analysis more successful. The seminal finding that thePOE �4 allele is a major determinant of risk for sporadic and
ate-onset familial AD (Seripa et al., 2009) prompted investigationsf the possibility that APOE �4 allele may also constitute a riskactor for late-onset AD endophenotypes. Although APOE geno-ype is currently a non-modifiable risk factor, it has potential for
odifying the impact of other factors, in particular vascular andifestyle-related factors (Solfrizzi et al., 2008), implying that some
nterventions may perhaps best be restricted to people at geneticisk. At present, is unclear the role of the APOE genotypes in theevelopment of NPS (Levy et al., 1999; Craig et al., 2004; Pritchardt al., 2007) or neuropsychiatric syndromes/endophenotypes in ADeviews 11 (2012) 87– 103 89
patients (Borroni et al., 2006; Hollingworth et al., 2006; D’Onofrioet al., 2010b). It has been suggested that NPS in AD may be influ-enced by APOE genotype in various case–control studies (Levy et al.,1999; Craig et al., 2004; Borroni et al., 2006; Hollingworth et al.,2006), but a recent longitudinal report showed a substantial lackof association between the APOE �4 allele and NPS in AD aftercorrection for multiple testing (Pritchard et al., 2007).
In this review article, we summarized the findings of the stud-ies of NPS and neuropsychiatric syndromes/endophenotypes inAD in relation to APOE genotypes from the English literaturepublished before October 2010. We reviewed clinical and epi-demiological studies from the international literature, includingboth cross-sectional and longitudinal studies that involved sub-jects aged 65 years and older. We searched through the PubMeddatabase of NCBI (available at http://www.ncbi.nlm.nih.gov) byauthor and the following keywords: neuropsychiatric symptoms,neuropsychiatric syndromes, neuropsychiatric endophenotypes,apolipoprotein E, APOE, dementia, Alzheimer’s disease, late-lifedepression, late-life anxiety, affective syndromes, apathy, apatheticsyndrome in dementia, agitation, aggressiveness, hyperactive syn-drome in dementia, psychosis, psychotic syndrome in dementia,behavioural and psychological symptoms of dementia. In par-ticular, in organizing the contents of the present review article,we used the classification of the Behavioural Subgroup of theEADC, identifying four separate neuropsychiatric syndromes inAD: affective, apathetic, psychotic, and hyperactive (Aalten et al.,2007). Finally, special attention was paid to the possible mech-anisms linked to the development of NPS and neuropsychiatricsyndromes/endophenotypes in AD in relation to APOE genotypes.
2. APOE genotypes and affective syndromes in AD: late-lifedepression and anxiety
Among affective syndromes and symptoms in dementia,clinically significant depression is a common and important com-plication of AD that increases the suffering of patients and theirfamilies, produces excess disability, promotes institutionalization,and hastens death (Jeste et al., 2006). In adults older than age 65years, late-life depression refers to depressive syndromes encom-passing both late-onset cases as well as early-onset cases thatrecur or continue into later years of life (Potter and Steffens, 2007;Panza et al., 2010). Late-life depressive syndromes often arise inthe context of medical and neurological disorders (Alexopoulos,2005). The prevalence of major depressive disorder is about 17% inpatients with AD (Wragg and Jeste, 1989) and is even higher in thosewith subcortical dementias (Potter and Steffens, 2007; Panza et al.,2010). Furthermore, emerging research implicates also a consis-tent reciprocal relationship between late-life anxiety and cognition(Beaudreau and O’Hara, 2008; Wolitzky-Taylor et al., 2010). In fact,anxiety disorders are the most common psychiatric diagnoses inlate-life with an estimated lifetime prevalence of 15.3% in olderadults, surpassing population estimates for depressive disorders(Kessler et al., 2005) and severe cognitive impairment (Regier et al.,1988). There is evidence of more prevalent anxiety in cognitivelyimpaired older adults, elevated anxiety related to poorer cognitiveperformance, and more severe anxiety symptoms predicting futurecognitive decline (Beaudreau and O’Hara, 2008).
There is controversy as to whether the APOE �4 allele increasesthe frequency of depression in AD. Early studies examining therelationship between APOE polymorphism and depression showedthat the APOE �4 allele may be a risk factor for depressive symp-
toms in patients with AD and dementia (Ramachandran et al., 1996;Murphy et al., 1997). However, these reports were cross-sectionaland did not control for disease duration but only for severity ofdementia (Ramachandran et al., 1996) and cognitive impairment
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s 11 (2012) 87– 103
Table 1Principal studies on the association of affective (depressive and anxiety) symptoms or syndromes with apolipoprotein E (APOE) genotypes in Alzheimer’s disease (AD) patients.
Reference Study design Study sample Cognitive and neuropsychiatric assessment Principal results
Ramachandran et al. (1996) Cross-sectional 46 AD patients; 135controls, restricted toAPOE �3/3 and �3/4only
CDR, HAM-D, and SCID-DSM–III-R Depression rating greater with APOE �3/4 versus �3/3 referencegenotype. Psychosis greater with �3/4 versus �3/3 referencegenotype
Holmes et al. (1996) Cross-sectional andlongitudinal
164 AD patients BDRS APOE �2 allele significantly associated with depressive symptoms
Cacabelos et al. (1996, 1997) Cross-sectional 207 demented patients MMSE, GDS, ADAS, BCRS, FAST, BEHAVE-AD, HAM-D, HAM-A,and SDASDS
Disorientation, agitation, depression, and motor disorders wereslightly more frequent in demented patients with APOE �4/e4,while anxiety and sleep disorders appeared more frequently inAPOE �3/�4. However, these differences were not statisticallysignificant
Holmes et al. (1997) Cross-sectional 232 AD patients CAMDEX and MOUSEPAD APOE �2 allele significantly associated with depressive symptomsMurphy et al. (1997) Cross-sectional 77 AD patients MMSE, TBDQ, and ADAS non-cog APOE �4 allele associated with higher scores on TBDQCantillon et al. (1997) Cross-sectional 162 AD patients MMSE and CSDD The APOE e4 allele frequency was not increased in the late-onset
depression group among these AD patientsBallard et al. (1997) Longitudinal 51 AD patients CAMCOG, CSDD, Burns symptom checklist, and SCID-DSM-III-R Protective effect of APOE �4 allele against depression. APOE
�4-carriers more likely to have future psychotic episodeForsell et al. (1997) Cross-sectional 806 participants aged
78 years and overMMSE and CPRS Depressed and nondepressed subjects had similar APOE genotype
distributions among the demented, and among the nondemented,subjects
Lyketsos et al. (1997) Cross-sectional 120 AD patients Diagnoses for major and minor depression according toDSM-IV, and assessment of delusions or hallucinationsaccording to DSM-IV glossary definitions
There was no association between APOE genotype and thepresence of NPS or the neuropsychiatric syndromes examined.There was an interesting suggestion that the e4 allele may beprotective against the development of major depression, however,this association did not reach statistical significance
Lopez et al. (1997) Cross-sectional 194 AD patients MMSE, BRS-CERAD, and semi-structured psychiatric interviewbased on DSM-III-R
No evidence for an association of NPS, including major depression,with any specific APOE genotype in probable AD patients
Holmes et al., 1998 Cross-sectional 210 AD patients CAMDEX and MOUSEPAD APOE �2 allele significantly associated with depressive symptoms.APOE �2 allele significantly associated also with persecutorydelusions
Hirono et al. (1999) Cross-sectional 175 AD patients MMSE, CDR, and the Japanese version1of the NPI The APOE �4 allele had no effect on the manifestation of delusions,hallucinations, depression, or other NPS in AD.
Levy et al. (1999) Cross-sectional 605 AD patients MMSE and NPI Among patients with comparable disease severity, the APOE �4allele does not confer additional psychiatric morbidity
Harwood et al. (1999) Cross-sectional 501 AD patients MMSE, HAM-D, and structured interview for specific delusionsand hallucinations
Increased risk for psychosis with APOE �4 allele
Müller-Thomsen et al. (2002) Cross-sectional 137 AD patients MMSE and MADRS Overrepresentation of the APOE �4 allele in female depressed ADpatients
Liu et al. (2002) Cross-sectional 149 AD patients CASI, CDR, HAM-D, and SCID-DSM–III-R No evidence of an association between depression in AD patientsand presence or absence of the APOE �4 or �2 allele
Scarmeas et al. (2002) Longitudinal 87 AD patients MMSE, CUSPAD, BDRS, and SCID-DSM-III-R APOE �4 alleles associated with risk for incident delusions. APOE�4/�4 predicted protective effect against hallucinations
Gabryelewicz et al. (2002) Cross-sectional 139 AD patients MMSE, GDS, and BEHAVE-AD The APOE e4 allele had no effect on the behavioural changes in ADCraig et al. (2005) Cross-sectional 404 AD patients MMSE and NPI with caregiver distress The results suggested that APOE genotype created no additional
risk for depressive symptoms in ADRobertson et al. (2005) Cross-sectional 125 AD patients CSDD and NPI Greater level of anxiety in APOE �4/�4 versus �3�/3 bearers in
both genders and versus �3/�4 in males onlyBorroni et al. (2006) Cross-sectional 232 AD patients By Principal Component Analysis of NPI symptoms, four
endophenotypes were identified, these were termed“psychosis”, “moods”, “apathy”, and “frontal”
APOE genotype did not correlate with any neuropsychiatricendophenotype
Hollingworth et al. (2006) Cross-sectional 1120 AD patients By Principal Component Analysis of NPI symptoms, fourinterpretable components were identified: behaviouraldyscontrol (euphoria, disinhibition, aberrant motor behaviour,and sleep and appetite disturbances), psychosis (delusions andhallucinations), mood (depression, anxiety, and apathy), andagitation (aggression and irritability)
None of the neuropsychiatric endophenotypes identified wereassociated with age at assessment, years of education, or numberof APOE �4 alleles
F. Panza et al. / Ageing Research R
Tabl
e
1
(Con
tinu
ed)
Ref
eren
ceSt
ud
y
des
ign
Stu
dy
sam
ple
Cog
nit
ive
and
neu
rop
sych
iatr
ic
asse
ssm
ent
Prin
cip
al
resu
lts
Prit
char
d
et
al. (
2007
)
Lon
gitu
din
al
388
AD
pat
ien
ts
MM
SE
and
NPI
Prot
ecti
ve
effe
ct
of
the
APO
E
�3/
�4
gen
otyp
e
that
was
sign
ifica
ntl
yas
soci
ated
wit
h
hal
luci
nat
ion
s
sym
pto
ms.
APO
E
�3/
�4
gen
otyp
e
issi
gnifi
can
tly
asso
ciat
ed
wit
h
anxi
ety
Del
ano-
Woo
d
et
al. (
2008
)C
ross
-sec
tion
al32
3
AD
pat
ien
ts
MM
SE
and
SCID
-DSM
-III
-R
Hig
her
pre
vale
nce
rate
of
the
APO
E
�4
gen
otyp
e in
the
dep
ress
edgr
oup
com
par
ed
to
the
non
-dep
ress
ed
AD
pat
ien
ts. T
his
effe
ct
was
pri
mar
ily
acco
un
ted
for
by
wom
enC
hop
ra
et
al. (
2009
)C
ross
-sec
tion
al17
5
cogn
itiv
ely
imp
aire
d
subj
ects
, of
wh
ich
92
AD
and
80M
CI p
atie
nts
MM
SE, G
DS-
15, a
nd
NPI
The
dif
fere
nce
in
the
pro
por
tion
of
par
tici
pan
t
rep
orti
ng
‘low
ener
gy’ a
t
GD
S-15
betw
een
the
thre
e A
POE
�4
alle
le
freq
uen
cygr
oup
s
app
roac
hed
stat
isti
cal s
ign
ifica
nce
D’O
nof
rio
et
al. (
2010
b)C
ross
-sec
tion
al20
1
AD
pat
ien
ts
and
121
con
trol
sM
MSE
, AD
L,
IAD
L,
CIR
S,
and
NPI
. Fu
rth
erm
ore,
AD
pat
ien
tsw
ith
NPS
wer
e
furt
her
sub-
div
ided
in
fou
r
grou
ps
acco
rdin
g
toth
e
EAD
C
clas
sifi
cati
on
of
neu
rop
sych
iatr
ic
syn
dro
mes
in
AD
:h
yper
acti
ve, p
sych
otic
, aff
ecti
ve, a
nd
apat
het
ic
No
dif
fere
nce
in
the
dis
trib
uti
on
of
APO
E
gen
otyp
es
was
fou
nd
betw
een
AD
pat
ien
ts
wit
h
and
wit
hou
t
NPS
. In
AD
pat
ien
ts
APO
E�
4-ca
rrie
rs, t
her
e
was
an
incr
ease
d
risk
of
affe
ctiv
e
and
apat
het
icsy
nd
rom
es
CD
R
=
clin
ical
dem
enti
a
rati
ng
scal
e;
HA
M-D
=
Ham
ilto
n
rati
ng
scal
e
for d
epre
ssio
n; S
CID
-DSM
-III
-R
=
stru
ctu
red
clin
ical
inte
rvie
w
for d
iagn
osti
c
and
stat
isti
cal m
anu
al
of
men
tal d
isor
der
s-II
I-re
vise
d; B
DR
S
=
Ble
ssed
dem
enti
a
rati
ng
scal
e;
MM
SE
=
min
i
men
tal
stat
e
exam
inat
ion
;
GD
S
=
glob
al
det
erio
rati
on
scal
e;
AD
AS
=
Alz
hei
mer
’s
dis
ease
asse
ssm
ent
scal
e;
BC
RS
=
brie
f
cogn
itiv
e
rati
ng
scal
e;
FAST
= fu
nct
ion
al
asse
ssm
ent
stag
es;
BEH
AV
E-A
D
=
beh
avio
ura
lp
ath
olog
y
in
Alz
hei
mer
’s
dis
ease
rati
ng
scal
e;
HA
M-A
=
Ham
ilto
n
rati
ng
scal
e
for
anxi
ety;
SDA
SDS
=
sen
ile
dem
enti
a-as
soci
ated
slee
p
dis
ord
ers
scal
e;
CA
MD
EX
=
the
Cam
brid
ge
exam
inat
ion
for
men
tal d
isor
der
s
of
the
eld
erly
;M
OU
SEPA
D:
Man
ches
ter
and
Oxf
ord
un
iver
siti
es
scal
e
for
the
psy
chop
ath
olog
ical
asse
ssm
ent
of
dem
enti
a;
TBD
Q:
tim
e
base
d
beh
avio
ura
l dis
turb
ance
ques
tion
nai
re
(doe
s
pat
ien
t
dis
pla
y
any
of
foll
owin
g
sym
pto
ms
in
1
mon
thp
rior
to
asse
ssm
ent
(com
bati
ven
ess,
agit
atio
n, w
and
erin
g,
inco
her
ent
spee
ch, h
allu
cin
atio
ns,
con
fusi
on
and
dis
orie
nta
tion
);
AD
AS
non
-cog
=
Alz
hei
mer
’s
dis
ease
asse
ssm
ent
scal
e
non
-cog
nit
ive
subs
cale
;
CSD
D
=
Cor
nel
l
scal
efo
r
dep
ress
ion
in
dem
enti
a;
CA
MC
OG
=
Cam
brid
ge
asse
ssm
ent
for
men
tal
dis
ord
ers
in
the
eld
erly
;
CPR
S
=
com
pre
hen
sive
psy
chop
ath
olog
ical
rati
ng
scal
e;
DSM
-IV
=
dia
gnos
tic
and
stat
isti
cal
man
ual
of
men
tal
dis
ord
ers-
IV;
NPS
=
neu
rop
sych
iatr
ic
sym
pto
ms;
NPI
=
neu
rop
sych
iatr
y
inve
nto
ry;
BR
S-C
ERA
D
=
beh
avio
ur
rati
ng
scal
e
for
dem
enti
a
of
the
Con
sort
ium
to
esta
blis
h
a
regi
stry
for
Alz
hei
mer
’s
dis
ease
;
MA
DR
S
=
mon
tgom
ery-
asbe
rg
dep
ress
ion
rati
ng
scal
e;
CA
SI:
cogn
itiv
e
abil
itie
s
scre
enin
g
inst
rum
ent;
CU
SPA
D
=
Col
ombi
a
un
iver
sity
scal
e
for
psy
chop
ath
olog
y
in
AD
;
MC
I =
mil
d
cogn
itiv
e
imp
airm
ent;
GD
S-15
=
15-i
tem
geri
atri
c
dep
ress
ion
scal
e;
AD
L
=
acti
viti
es
of
dai
lyli
vin
g;
IAD
L
=
inst
rum
enta
l act
ivit
ies
of
dai
ly
livi
ng;
CIR
S
=
cum
ula
tive
illn
ess
rati
ng
scal
e;
EAD
C
=
Euro
pea
n
Alz
hei
mer
’s
Dis
ease
Con
sort
ium
.
eviews 11 (2012) 87– 103 91
(Murphy et al., 1997) (Table 1). Other investigators have demon-strated combined risks of developing AD among those with late-lifedepression and APOE �4 genotypes in nondemented geriatric pop-ulations (Krishnan et al., 1996; Steffens et al., 1997; Rigaud et al.,2001; Wilson et al., 2002). These findings were confirmed in tworecent longitudinal population-based studies (Irie et al., 2008; Kimet al., 2010). In particular, the incidence of dementia was also sig-nificantly higher in a population-based study on older Koreanswith both APOE �4 allele and depression compared to those with-out both factors, although this interaction was significant in menbut not in women, suggesting potential gender differences (Kimet al., 2010), also confirmed by other two studies on the same topic(Müller-Thomsen et al., 2002; Delano-Wood et al., 2008). In fact,the frequency of the APOE �4 allele was significantly increased indepressed women with AD but not in men (Müller-Thomsen et al.,2002). Another recent report found that depressed AD patients hada significantly higher frequency of APOE �4 genotype than non-depressed AD patients (Delano-Wood et al., 2008), so confirmingprevious studies demonstrating a relationship between APOE geno-type and depression in AD (Ramachandran et al., 1996; Murphyet al., 1997; Müller-Thomsen et al., 2002). Moreover, the higherfrequency of the APOE �4 allele in the depressed group remainedstatistical significant also after adjustment for duration of demen-tia, suggesting that the increased likelihood of depression in ADpatients with a copy of the APOE �4 allele was not due specificallyto disease severity or duration (Delano-Wood et al., 2008). Also inthis study the association between APOE genotype and depressionin AD was primarily seen in women and not men, so confirm-ing the results of a study showing an increased rate of the APOE�4 genotype in late-onset depressed women with AD relative tomen (Steffens et al., 1997). Finally, when AD patients were sub-divided according to the EADC classification of neuropsychiatricsyndromes, in APO �4-carriers there was an increased risk of affec-tive syndrome (i.e., AD patients with the NPI symptoms depressionand anxiety) (D’Onofrio et al., 2010b). These very recent resultson increased risk of an affective syndrome in AD patients APOE�4-carriers confirmed recent findings indicating that NPS in ADare not purely an epiphenomenon of cognitive impairment, butcould be attributed to specific biological brain dysfunction, sug-gesting the presence of specific AD endophenotypes (Reisberg et al.,1996; Cummings, 2000; Shinosaki et al., 2000; Borroni et al., 2006;Hollingworth et al., 2006; Reisberg et al., 1996).
Despite a relevant number of studies showed an associationbetween APOE polymorphism and depression (Ramachandranet al., 1996; Murphy et al., 1997; Müller-Thomsen et al., 2002;Delano-Wood et al., 2008; D’Onofrio et al., 2010b), several otherreports have not supported the notion that APOE �4 genotype mayinfluence depression in AD (Cantillon et al., 1997; Lopez et al., 1997;Harwood et al., 1999; Levy et al., 1999; Liu et al., 2002; Scarmeaset al., 2002; Gabryelewicz et al., 2002; Craig et al., 2004; Pritchardet al., 2007), also when specific AD endophenotypes were consid-ered (Borroni et al., 2006; Hollingworth et al., 2006) (Table 1). Somereports suggested that APOE �2-carriers may be at higher risk ofdepressive symptoms in AD (Holmes et al., 1996, 1997, 1998), thatthe APOE �4 allele may be protective against depression (Ballardet al., 1997), and there was also an interesting suggestion thatthe �4 allele may be protective against the development of majordepressive disorder (MDD) in AD, however, this association did notreach statistical significance (Lyketsos et al., 1997). Furthermore,other studies have shown trends toward association between APOEgenotype and depression but have rendered conclusions of no rela-tionship (Cacabelos et al., 1996, 1997; Forsell et al., 1997; Chopra
et al., 2009). In particular, in a small study, older subjects with APOE�4/�4 and cognitive impairment (AD or mild cognitive impairment,MCI) might experience depression with a relative paucity of depres-sive symptoms compared to those without this genotype (Chopra
9 arch R
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adapipato(d2b(tp(rivi(ooooiAfa(1mwtgildfpstM
iatdqsbw2lt(c6it
2 F. Panza et al. / Ageing Rese
t al., 2009). Hence, it is possible that the APOE �4 allele influ-nces the phenotype of depression with AD, somewhat similar to itseported influence on the pattern of cognitive impairment (Smitht al., 1998).
Among the studies supporting an association between APOE �4llele and depression in AD, only a few reports controlled for diseaseuration (Müller-Thomsen et al., 2002; Delano-Wood et al., 2008),nd other potential confounders (Müller-Thomsen et al., 2002). Inarticular, controlling for disease duration or severity is of crucial
mportance since the presence of APOE �4 allele may affect diseaserogression and the association with NPS may only be due to moredvanced disease. On the other hand, more importantly, amonghe few longitudinal studies, two reports did not support a rolef the APOE polymorphism in developing depressive symptomsScarmeas et al., 2002; Pritchard et al., 2007), also controlling forisease duration and other potential confounders (Scarmeas et al.,002), and one suggested a protective effect of the APOE e4 allele,ut in a small sample and without controlling for disease durationBallard et al., 1997). There were many possible explanations forhese contrasting findings. One reason may be the different sam-le size, with several studies including few depressed AD patientsForsell et al., 1997; Liu et al., 2002; Gabryelewicz et al., 2002), thusesulting in a different power to detect group differences. Also vary-ng schemes for diagnosing depression in AD may be a source ofariability. For example, in one study was employed a psychiatricnventory that measured only three depression-related symptomsi.e., depressed mood, change in appetite and sleep problems), twof which are vegetative symptoms and thus problematic for use inlder adult samples that frequently have somatic symptoms sec-ndary to physical comorbidity (Scarmeas et al., 2002). Similarly,ther authors utilized the NPI which contains few items pertain-ng to depressive symptoms (Levy et al., 1999; Craig et al., 2004).nother factor may be that the use of limited screening measures
or determining depression could be leading to poorer diagnosticccuracies and thus different prevalence rates of depression in ADrange 11–50% in different studies) (Forsell et al., 1997; Levy et al.,999; Delano-Wood et al., 2008). These highly variable findingsay represent significant heterogeneity within depressed groups,ith some studies with a large proportion of patients with dys-
hymic disorder in their sample (Liu et al., 2002). It appears thatreater specification of diagnostic categories is clearly needed tonspect for important subgroup differences. Thus, the bulk of pub-ished studies on possible association between APOE �4 allele andepression in AD have suffered from small sample sizes generatingalse positives that cannot be consistently replicated, low reportedrevalence rates for depression, very brief inventories of depres-ive symptoms, and/or low diagnostic rigor in the determination ofhe presence or absence of a Diagnostic and Statistical Manual of
ental Disorders (DSM)-based diagnosis of depression.In the past few years, researchers have begun to address anx-
ety symptoms in dementia (Seignourel et al., 2008; Beaudreaund O’Hara, 2008). Defining anxiety in individuals with demen-ia is complicated by the overlap among symptoms of anxiety,epression, and dementia (Seignourel et al., 2008). One importantuestion regarding anxiety symptoms in dementia is whether theyhould be considered as a separate clinical entity or as part of aroader syndrome. One possibility is that anxiety is confoundedith depression in individuals with dementia (Starkstein et al.,
007). Some authors have also suggested that there is strong over-ap between anxiety and agitation (Seignourel et al., 2008), andhat perhaps agitation may be a symptom of generalized anxietyMintzer and Brawman-Mintzer, 1996). However, anxiety is most
ommon among AD patients with a younger age at onset (under age5) (Porter et al., 2003). APOE �4 allele is a risk factor for develop-ng AD at an earlier age (Farrer et al., 1997) and might contribute tohis effect (Raber, 2007). Interestingly, APOE null mice carrying the
eviews 11 (2012) 87– 103
human �4 transgene had higher anxiety ratings than those express-ing either wild-type murine APOE or the human �3 (Robertsonet al., 2005). Very recently, these findings were also confirmed infemale APOE TR mice expressing APOE under control of the mouseAPOE promoter. APOE4 mice showed decreased activity levels andhigher measures of anxiety than mice expressing APOE2 or APOE3isoform across all ages (Siegel et al., 2010). Notwithstanding thehigher prevalence and symptom expression of anxiety disorders inlate life, not all measures of NPS in dementia reported in the lit-erature include an assessment of anxiety (Porter et al., 2003). Twostudies using cross-sectional assessments with the NPI found noassociation with anxiety (Hirono et al., 1999; Levy et al., 1999),and no association was found when assessed by the BehaviouralPathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) in across-sectional study design (Gabryelewicz et al., 2002) (Table 1).Consistent with the mouse studies (Robertson et al., 2005; Siegelet al., 2010), APOE also has isoform dependent effects on measuresof anxiety in probable AD patients (Robertson et al., 2005). In par-ticular, male APOE �4/�4 subjects had higher anxiety scores thangender-matched APOE �3/�3 subjects. In males, but not in females,subjects with APOE �4/�4 had also higher anxiety scores than thosewith APOE �3/�4 (Robertson et al., 2005), suggesting that APOE �3can antagonize the effects of APOE �4 on measures of anxiety inmale but not in female subjects. The anxiety scores did not correlatewith the mini mental state examination (MMSE) scores (Robertsonet al., 2005). Pritchard and colleagues did not support these findingsusing the same methods of analysis (Pritchard et al., 2007). How-ever, they found an association with the APOE �3/�4 genotype, butnot with the APOE �4/�4 genotype or the e4 allele (Pritchard et al.,2007), so confirming previous studies in which anxiety appearedmore frequently in APOE �3/�4 demented patients, although thisdifference was not statistically significant (Cacabelos et al., 1996,1997). Furthermore, the presence of an APOE �4 allele was a riskfactor for the EADC affective syndrome (i.e., AD patients with theNPI symptoms depression and anxiety) (D’Onofrio et al., 2010b).Therefore, notwithstanding some cross-sectional evidence of a pos-sible role of the APOE �4 allele in modulating the onset of anxietysymptoms in AD (Robertson et al., 2005; D’Onofrio et al., 2010b)(Table 1), the only longitudinal study existing did not find an asso-ciation with anxiety in AD patients APOE �4 carriers (Pritchard et al.,2007)
3. APOE genotype and apathy in AD
Apathy is one of the most frequent neuropsychiatric disordersin AD (Ishii et al., 2009), and it has been increasingly recognizedas a distinct psychiatric syndrome, and defined as a lack of moti-vation, evidenced by diminished goal-directed overt behaviour,diminished goal-directed cognition, and diminished emotionalconcomitants of goal-directed behaviour (Marin, 1991). Apathywas also considered a symptom of some other neurological orpsychiatric syndromes, including AD, if lack of motivation wasattributable to intellectual impairment, emotional distress, ordiminished level of consciousness (Ishii et al., 2009). However, thisproposed definition of apathy either as a syndrome or symptompresupposed a lack of motivation as a primary presenting fea-ture (Ishii et al., 2009). To date, there is no clear consensus asto what definition of apathy is appropriate and clinically easy tooperationalize. This lack of consensus corresponds to the DSM-lV (American Psychiatric Association, 2004) where apathy is notincluded in the glossary and mentioned merely as a nonspecific
symptom of several disorders. In particular, apathy has been tradi-tionally treated as an aspect of depression, but these two clinicalentities should be distinct (Ishii et al., 2009). In fact, depression andapathy may appear similar in some aspects among AD patients.
F. Panza et al. / Ageing Research Reviews 11 (2012) 87– 103 93
Table 2Principal studies on the association of the apathetic syndrome or the apathy symptom with apolipoprotein E (APOE) genotypes in Alzheimer’s disease (AD) patients.
Reference Study design Study sample Cognitive and neuropsychiatric assessment Principal results
Borroni et al. (2006) Cross-sectional 232 AD patients By Principal Component Analysis of NPIsymptoms, four endophenotypes wereidentified, these were termed “psychosis”,“moods”, “apathy”, and “frontal”
APOE genotype did not correlate with anyneuropsychiatric endophenotype
Hollingworth et al. (2006) Cross-sectional 1120 AD patients By Principal Component Analysis of NPIsymptoms, four interpretable componentswere identified: behavioural dyscontrol(euphoria, disinhibition, aberrant motorbehaviour, and sleep and appetitedisturbances), psychosis (delusions andhallucinations), mood (depression, anxiety,and apathy), and agitation (aggression andirritability)
None of the neuropsychiatricendophenotypes identified wereassociated with age at assessment, years ofeducation, or number of APOE �4 alleles
Monastero et al. (2006) Cross-sectional 197 AD patients MMSE and NPI The presence of apathy was significantlyassociated with the APOE �4 alleleindependently from age, education, sex,and duration of disease
van der Flier et al., 2007 Cross-sectional 110 AD patients MMSE and NPI Delusions and agitation/aggression weremore common and severer amonghomozygous APOE �4 carriers than amongheterozygous or APOE-�4 -negativepatients.
D’Onofrio et al. (2010b) Cross-sectional 201 AD patients and121 controls
MMSE, ADL, IADL, CIRS, and NPI.Furthermore, AD patients with NPS werefurther sub-divided in four groupsaccording to the EADC classification ofneuropsychiatric syndromes in AD:hyperactive, psychotic, affective, andapathetic
No difference in the distribution of APOEgenotypes was found between AD patientswith and without NPS. In AD patients APOE�4-carriers, there was an increased risk ofaffective and apathetic syndromes
N vities or se Co
Aaioif2wabrt1aarc(ANet(2astaseoeesp
PI = neuropsychiatry inventory; MMSE = mini mental state examination; ADL = actiating scale; NPS = neuropsychiatric symptoms; EADC = European Alzheimer’s Disea
pathy and depression scores were correlated in some studies,nd apathy overlaps conceptually with the anhedonia character-stic of depression (Jeste et al., 2006). Anhedonia, or loss of interestr pleasure can be used as a principal symptom to diagnose MDDnstead of or along with depressed mood. Because other criteriaor DSM-IV diagnosis of MDD (American Psychiatric Association,004) such as fatigue, hypersomnia or insomnia, loss of appetite,eight loss, and diminished ability to concentrate are prevalent
mong demented patients, a demented patient with apathy maye misdiagnosed as having MDD even in the absence of dyspho-ia (Landes et al., 2001). This diagnostic challenge stems fromhe apparent overlap between apathy and depression (Levy et al.,998). However, there is reason to believe that depressed moodnd apathy may be the predominant manifestations of distinguish-ble brain abnormalities (Starkstein et al., 2001). Different brainegions were abnormal in a functional neuroimaging study thatompared AD patients categorized as depressed versus apatheticHolthoff et al., 2005). Apathy has been reported to be common inD outpatients, and the reported prevalence for apathy using thePI was between 32.1 and 93.2% (Starkstein et al., 1996; D’Onofriot al., 2010a). Also the relationship between the APOE �4 allele andhe apathetic syndrome and/or the apathy symptom was studiedBorroni et al., 2006; Hollingworth et al., 2006; Monastero et al.,006; van der Flier et al., 2007; D’Onofrio et al., 2010b) (Table 2),lthough it has not been as thoroughly investigated as for depres-ion and psychosis. In a sample of 197 subjects with probable AD,he presence of apathy was significantly cross-sectionally associ-ted with the APOE �4 allele independently from age, education,ex, duration of disease, MMSE score and other NPS (Monasterot al., 2006). Furthermore, the recent results on an increased riskf the EADC apathetic syndrome (i.e., NPI symptoms apathy and
ating abnormalities) in AD patients APOE e4-carriers (D’Onofriot al., 2010b). In conclusion, there is some cross-sectional evidenceuggesting a relationship between the APOE �4 allele and apathy inatients with AD (Monastero et al., 2006; D’Onofrio et al., 2010b),f daily living; IADL = instrumental activities of daily living; CIRS = cumulative illnessnsortium.
also after controlling for disease duration (Monastero et al., 2006).However, no longitudinal report confirmed these suggestions, andother cross-sectional studies did not show any association of apa-thy endophenotypes (Borroni et al., 2006; Hollingworth et al., 2006)or NPI apathy symptom (van der Flier et al., 2007) with APOE geno-types (Table 2).
4. APOE genotype and psychotic symptoms and syndromesin AD
As seen above, previous studies of neuropsychiatric distur-bances in AD in relation to APOE genotype have yielded a widerange of results. However, among NPS in AD, major attention hasbeen dedicated to psychotic symptoms, that typically consist ofdelusions and/or hallucinations, and the most frequent positiveassociation has been between the APOE �4 allele and psychoticsymptoms (Zdanys et al., 2007). Although certain aspects of hallu-cinations and delusions may differ (e.g., comorbid symptoms, riskfactors, brain regions implicated), they are most often classifiedtogether (Jeste et al., 2006). The prevalence of psychosis is quitesubstantial, with estimates for delusions in AD ranging from 9.3% to63% (median 36%) and estimates for hallucinations ranging from 4%to 41% (median 18%) (Ropacki and Jeste, 2005). The wide variabil-ity in results stems, in part, from methodological inconsistencies,such as different diagnostic criteria for dementia and psychosisacross studies (Jeste et al., 2006). However, psychosis proved to bea coherent grouping of psychiatric symptoms in AD in studies usingcluster and factor analysis (Jeste et al., 2006). Therefore, it has beenreported that AD patients with psychosis (AD + psychosis, AD + P)may be clinically different from AD (Jeste and Finkel, 2000; Sweetet al., 2003; Jeste et al., 2006). Disorganized speech, disorganized
behaviour, and negative symptoms characteristic of schizophre-nia have not proved useful concepts in describing the psychosis ofAD (Jeste et al., 2006). Delusions in AD often involve theft, aban-donment, or misidentification. The delusions are also typically less
9 arch R
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4 F. Panza et al. / Ageing Rese
omplex and organized than those observed in schizophrenia (Jestet al., 2006). Likewise, hallucinatory experiences in AD are often dis-inct from those observed in schizophrenia. Visual hallucinationsredominate, in lieu of the auditory hallucinations characteristic ofchizophrenia (Jeste et al., 2006). Although the evidence concern-ng psychosis in other types of dementia is notably scarcer thanor AD, certain similarities and differences are known (Jeste et al.,006). For instance, visual hallucinations are part of the core diag-ostic construct of dementia with Lewy bodies, occurring in up to7% of patients. Delusions are also quite common, with a reportedrevalence of 46% (Del Ser et al., 2000).
Indeed, an increased familial risk for the AD + P endophenotypeas been observed (Sweet et al., 2002a), suggesting heritabilityAmerican Psychiatric Association, 2004; Bacanu et al., 2005) andhus a possible genetic component of this clinical feature. In fact,enes that have been implicated in psychosis of AD include thoseor dopamine-3 and serotonin-2A receptors (Bacanu et al., 2005).
ajor attention has been dedicated to psychotic episodes in rela-ion to APOE polymorphism, and a number of investigations havexamined whether the APOE �4 allele might contribute to theD + P endophenotype (Bacanu et al., 2005). Among initial studiesonducted in unrelated AD + P and AD without psychosis sub-ects, one large (Harwood et al., 1999) and two smaller studiesRamachandran et al., 1996; Ballard et al., 1997) have found an asso-iation of APOE �4 allele and the AD + P endophenotype. However,ost successive reports have found no association of the APOE e4
llele with AD + P (Cacabelos et al., 1996, 1997; Forsell et al., 1998;evy et al., 1999; Nacmias et al., 2001; Sweet et al., 2002b; Pritchardt al., 2007) (Table 3), suggesting that it may be necessary to oper-te a distinction among different psychotic symptoms in AD inelation to APOE polymorphism. However, also association studiesith hallucinations have been contradictory, with two copies of �4
eing reported as protective (Scarmeas et al., 2002), �4 being asso-iated with increased risk (Chang et al., 2004), and hallucinationsppeared to increase with more �4 alleles (Weiner et al., 1999) orlso, in a small longitudinal study, to decrease 1 year after diagnosisn AD patients with one �4 allele (Del Prete et al., 2009). The asso-iation of hallucinations in AD with the e3/�4 genotype (Pritchardt al., 2007), also added further inconsistencies to reported find-ngs. Hallucinations are sometimes incorporated into a measure ofsychosis, but also these studies have again been inconsistent, withignificant associations being reported for the �4 allele (Harwoodt al., 1999), and for �3/�4 versus �4/�4 carriers (Ramachandrant al., 1996). Furthermore, when the outcome was the presencef delusions in AD patients, in a longitudinal study, one �4 allelearried 2.5-fold risk whereas the presence of two �4 alleles carried.6-fold risk for development of delusions during a 9.3-year follow-p (Scarmeas et al., 2002). These findings were confirmed in otherwo longitudinal studies in which the presence of the APOE �4 allelearried a 3.4-fold risk for developing delusions (Chang et al., 2004),nd the presence of one �4 allele, 1 year after diagnosis, showed
moderate, but significant, increase in delusions (Del Prete et al.,009). Also in cross-sectional studies, the presence of the APOE �4llele was associated with increased levels of delusions within theast month from the first visit and with the presence of categoricalelusions at the early stage until the first visit (Spalletta et al., 2006),elusions appeared to increase with more �4 alleles (Weiner et al.,999) and �4/�4 genotype (van der Flier et al., 2007), and �4 wasreferentially associated with delusions also in a large sample ofD patients from US (Zdanys et al., 2007) (Table 3). However, whenD patients were sub-divided according to the EADC classificationf neuropsychiatric syndromes, for psychotic syndrome, including
D patients with delusions, hallucinations, and night-time distur-ances, no association was found between APOE polymorphismnd this neuropsychiatric syndrome (D’Onofrio et al., 2010a). Thesendings were consistent with those of a larger number of studies ineviews 11 (2012) 87– 103
which no association was found between APOE genotypes and thepsychotic endophenotype (Borroni et al., 2006; Hollingworth et al.,2006) or also single psychotic symptoms or measures incorporat-ing these symptoms, i.e. hallucinations (Lehtovirta et al., 1996a;Lopez et al., 1997; Lyketsos et al., 1997; Hirono et al., 1998, 1999;Gabryelewicz et al., 2002; Craig et al., 2004) and delusions (Lopezet al., 1997; Hirono et al., 1999) (Table 3). Sources of variationamong these studies are unclear, but may include differences inpatient populations, sample sizes (with both false positive and falsenegative findings more likely in small samples), diagnostic criteriafor psychosis, and statistical methods. In conclusion, some cross-sectional (Weiner et al., 1999; Spalletta et al., 2006; van der Flieret al., 2007; Zdanys et al., 2007) and longitudinal studies (Scarmeaset al., 2002; Chang et al., 2004; Del Prete et al., 2009) suggest thatAPOE genotype could have a role in the development of delusionsin AD patients, also after controlling for disease duration (Scarmeaset al., 2002). However, cross sectional (Cacabelos et al., 1996, 1997;Forsell et al., 1998; Levy et al., 1999; Nacmias et al., 2001) and, moreimportantly, longitudinal studies (Sweet et al., 2002b; Pritchardet al., 2007) suggest that APOE does not appear to contribute tothe risk of psychosis as a whole in AD.
5. APOE genotype, agitation/aggressiveness, andhyperactive syndrome in AD
Among NPS in AD, agitation/aggressiveness also appears to bea clinically important behavioural complication of dementia thatwarrants further study. Agitation/aggressiveness differs from psy-chosis and depression of AD in that it may be conceptualizedas a single symptom or a symptom complex (Jeste et al., 2006).The prevalence of agitation in dementia ranges from 20% to 60%,depending on diagnostic definitions used and the population stud-ied (Aalten et al., 2003). A formalized definition of agitation wasproposed as “inappropriate verbal, vocal, or motor activity thatis not judged by an outside observer to be an obvious outcomeof the needs or confusion of the individual” (Cohen-Mansfield,2001). Some subtypes of agitation that may have important clinicaldifferences were also characterized, including physical versus ver-bal and aggressive versus nonaggressive types (Cohen-Mansfield,2001). Agitation/aggressiveness in dementia often co-occurs withpsychosis and depression. There is substantial evidence that ver-bal agitation is associated with depression, and there may besome relationship to delusions (Jeste et al., 2006; Cohen-Mansfieldand Werner, 1999). Psychosis, particularly delusions, and depres-sion occur with increased frequency in aggressive patients andmay be a causative factor of agitation/aggressiveness (Deutschet al., 1991). Also the symptom complex agitation/aggressivenesshas been linked to APOE genotypes. Agitation and disorientationwere more common in demented patients �4/�4 carriers, whereasanxiety and sleep disorders were more common in �3/�4 carri-ers, although these differences were not statistically significant(Cacabelos et al., 1996, 1997). In another report, it was noted thatthe presence of the �4 allele was associated with increased com-bativeness, agitation, wandering, and confusion (Murphy et al.,1997). These findings were confirmed in two other recent cross-sectional studies in which the APOE �4 allele has been associatedwith agitation/aggressiveness using the Neuropsychiatric Inven-tory Caregiver Distress Scale (NPI-D) (Craig et al., 2004; van derFlier et al., 2007), and in a recent report in which the presenceof the APOE �4 allele increased the risk for agitated behaviour,including restlessness and vocalizations, in nursing home residents
with dementia (Woods et al., 2009) (Table 4). However, when ADpatients were sub-divided according to the EADC classification ofneuropsychiatric syndromes, for hyperactive syndrome, includingAD patients with agitation, euphoria, disinhibition, irritability, and
F. Panza et al. / Ageing Research Reviews 11 (2012) 87– 103 95
Table 3Principal studies on the association of psychotic symptoms or syndromes with apolipoprotein E (APOE) genotypes in Alzheimer’s disease (AD) patients.
Reference Study design Study sample Cognitive and neuropsychiatricassessment
Principal results
Ramachandran et al.(1996)
Cross-sectional 46 AD patients; 135controls, restricted to APOE�3/3 and �3/4 only
CDR, HAM-D, and SCID-DSM–III-R Depression rating greater with APOE �3/4versus �3/3 reference genotype. Psychosisgreater with �3/4 versus �3/3 referencegenotype
Cacabelos et al. (1996,1997)
Cross-sectional 207 demented patients MMSE, GDS, ADAS, BCRS, FAST,BEHAVE-AD, HAM-D, HAM-A, andSDASDS
Disorientation, agitation and motordisorders were slightly more frequent indemented patients with APOE �4/e4, whileanxiety and sleep disorders appeared morefrequently in APOE �3/�4. However, thesedifferences were not statisticallysignificant
Lehtovirta et al.(1996a)
Cross-sectional 58 AD patients and 16controls
MMSE, BCRS, and HAM-D; thepresence of rigidity, hypokinesia,tremor at rest, orofacial dyskinesia,myoclonus, hallucinations,delusions, and different kinds ofparesis was recorded in theneurologic examination. Theoccurrence of epileptic seizures,hallucinations, and delusions wasalso inquired from the caregivers
Cognitive and neuropsychiatric symptomsand signs were not related to the APOEgenotype
Ballard et al. (1997) Longitudinal 51 AD patients CAMCOG, CSDD, Burns symptomchecklist, and SCID-DSM-III-R
Protective effect of APOE �4 allele againstdepression. APOE �4-carriers more likelyto have future psychotic episode
Lopez et al. (1997) Cross-sectional 194 AD patients MMSE, BRS-CERAD, andsemi-structured psychiatricinterview based on DSM-III-R
No evidence for an association of NPS,including psychosis (delusions andhallucinations), with any specific APOEgenotype in probable AD patients
Lyketsos et al. (1997) Cross-sectional 120 AD patients Diagnoses for major and minordepression according to DSM-IV,and assessment of delusions orhallucinations according to DSM-IVglossary definitions
There was no association between APOEgenotype and the presence of NPS or theneuropsychiatric syndromes examined.There was an interesting suggestion thatthe e4 allele may be protective against thedevelopment of major depression,however, this association did not reachstatistical significance
Forsell et al. (1998) Cross-sectional 668 participants aged 75years and over
Dementia was diagnosed using theDSM-III-R criteria Psychoticsymptoms were defined accordingto DSM-IV criteria
There was no statistical significantdifference in APOE genotype betweensubjects with and without psychoticsymptoms, stratified by dementiadiagnosis
Hirono et al. (1998) Cross-sectional 228 AD patients MMSE, BEHAVE-AD, and NPI The presence of NPS were not significantlyrelated to APOE genotype
Hirono et al. (1999) Cross-sectional 175 AD patients MMSE, CDR, and the Japaneseversion of the NPI
The APOE �4 allele had no effect on themanifestation of delusions, hallucinations,depression, or other NPS in AD.
Weiner et al. (1999) Cross-sectional 97clinically diagnosed ADpatients and 61neuropathologicallyconfirmed cases of AD
MMSE and BDRS A marginal association between delusionsand hallucinations and increasing numbersof �4 alleles was found
Levy et al. (1999) Cross-sectional 605 AD patients MMSE and NPI Among patients with comparable diseaseseverity, the APOE �4 allele does not conferadditional psychiatric morbidity
Harwood et al. (1999) Cross-sectional 501 AD patients MMSE, HAM-D, and structuredinterview for specific delusionsand hallucinations
Increased risk for psychosis with APOE �4allele
Nacmias et al. (2001) Cross-sectional 275 AD patients A semi-structured psychiatricinterview
No correlation between APOE genotypesand the presence of psychotic symptoms inAD patients
Gabryelewicz et al.(2002)
Cross-sectional 139 AD patients MMSE, GDS, and BEHAVE-AD The APOE e4 allele had no effect on thebehavioural changes in AD
Sweet et al. (2002b) Longitudinal 316 AD patients MMSE, BRS-CERAD, andSCID-DSM–III-R
There was no significant associations ofAPOE genotype with time to psychosisonset and no significant interaction of thisgenotypes with time to psychosis onset
Scarmeas et al. (2002) Longitudinal 87 AD patients MMSE, CUSPAD, BDRS, andSCID-DSM-III-R
APOE �4 alleles associated with risk forincident delusions. APOE �4/�4 predictedprotective effect against hallucinations
Chang et al. (2004) Longitudinal 135 AD patients CASI, CDR, and SCID-DSM-III-R APOE �4 significantly associated withhallucinations and delusions
Borroni et al. (2006) Cross-sectional 232 AD patients By Principal Component Analysisof NPI symptoms, fourendophenotypes were identified,these were termed “psychosis”,“moods”, “apathy”, and “frontal”
APOE genotype did not correlate with anyneuropsychiatric endophenotype
96 F. Panza et al. / Ageing Research Reviews 11 (2012) 87– 103
Table 3 (Continued)
Reference Study design Study sample Cognitive and neuropsychiatricassessment
Principal results
Hollingworth et al.(2006)
Cross-sectional 1120 AD patients By Principal Component Analysisof NPI symptoms, fourinterpretable components wereidentified: behavioural dyscontrol(euphoria, disinhibition, aberrantmotor behaviour, and sleep andappetite disturbances), psychosis(delusions and hallucinations),mood (depression, anxiety, andapathy), and agitation (aggressionand irritability)
None of the neuropsychiatricendophenotypes identified wereassociated with age at assessment, years ofeducation, or number of APOE �4 alleles
Spalletta et al. (2006) Cross-sectional 171 AD patients MMSE and NPI The association between NPS and APOE �4allele in AD was confirmed for delusionsonly
Pritchard et al. (2007) Longitudinal 388 AD patients MMSE and NPI Protective effect of the APOE �3/�4genotype that was significantly associatedwith hallucinations symptoms. APOE �3/�4genotype is significantly associated withanxiety
van der Flier et al.(2007)
Cross-sectional 110 AD patients MMSE and NPI Delusions and agitation/aggression weremore common and severer amonghomozygous APOE �4 carriers than amongheterozygous or APOE-�4 -negativepatients.
Zdanys et al. (2007) Cross-sectional 266 AD patients MMSE, ADL, IADL, and NPI APOE �4 was significantly associated withpsychotic symptoms, adjusting for age, sex,education, and MMSE score
Del Prete et al. (2009) Longitudinal 53 AD patients MMSE and NPI Patients with APOE 4 allele showed a widerrange of NPS when compared tonon-carriers and higher scores forhallucinations and aberrant motorbehaviours. Over time, �4 carriers showedan increase/delayed onset in somesymptoms and a parallel decrease inothers, while non-carriers presented anundifferentiated worsening ofsymptomatology
D’Onofrio et al. (2010b) Cross-sectional 201 AD patients and 121controls
MMSE, ADL, IADL, CIRS, and NPI.Furthermore, AD patients with NPSwere further sub-divided in fourgroups according to the EADCclassification of neuropsychiatricsyndromes in AD: hyperactive,psychotic, affective, and apathetic
No difference in the distribution of APOEgenotypes was found between AD patientswith and without NPS. In AD patients APOE�4-carriers, there was an increased risk ofaffective and apathetic syndromes
CDR = clinical dementia rating scale; HAM-D = Hamilton rating scale for depression; SCID-DSM-III-R = structured clinical interview for diagnostic and statistical manual ofmental disorders-III-revised; BDRS = Blessed dementia rating scale; MMSE = mini mental state examination; GDS = global deterioration scale; ADAS = Alzheimer’s diseaseassessment scale; BCRS = brief cognitive rating scale; FAST = functional assessment stages; BEHAVE-AD = behavioural pathology in Alzheimer’s disease rating scale; HAM-A = Hamilton rating scale for anxiety; SDASDS = senile dementia-associated sleep disorders scale; CAMCOG = Cambridge assessment for mental disorders in the elderly;CSDD = Cornell scale for depression in dementia; BRS-CERAD = behaviour rating scale for dementia of the Consortium to establish a registry for Alzheimer’s disease;NPS = neuropsychiatric symptoms; DSM-IV = diagnostic and statistical manual of mental disorders-IV; NPI = neuropsychiatry inventory; CUSPAD = Colombia university scalef vities
D
ag2sn(uctIAAi2ont
or psychopathology in AD; ADL = activities of daily living; IADL = instrumental actiisease Consortium
berrant motor behaviour, no association was found between APOEenotype and this neuropsychiatric syndrome (D’Onofrio et al.,010a). These findings on the EADC hyperactive syndrome wereimilar to previous negative cross-sectional results with endophe-otype (Hollingworth et al., 2006) and single symptom approachHirono et al., 1999; Levy et al., 1999), and from two studies eval-ating risk for incident NPS symptoms in a prospectively followedohorts (Scarmeas et al., 2002; Pritchard et al., 2007), also after con-rolling for the duration of disease (Scarmeas et al., 2002) (Table 4).nterestingly, a recent study that found no association betweenPOE �4 genotype and NPS in AD did report an association betweenPOE �4 and aggression in patients with FTD, and with delusions
n patients with dementia with Lewy bodies (Engelborghs et al.,
006). Therefore, notwithstanding some cross-sectional findingsn increased agitation in APOE �4-carriers, these suggestions wereot confirmed in longitudinal studies, and the current evidence isoo limited to draw definitive conclusions.of daily living; CIRS = cumulative illness rating scale; EADC = European Alzheimer’s
6. Mechanisms linking neuropsychiatric symptoms andsyndromes with APO genotypes in AD
A relevant number of studies suggested a possible role ofthe APOE genotypes on the development of NPS in AD patients,confirming that genetic factors may account for some of the neu-ropsychiatric heterogeneity associated with AD (DeMichele-Sweetand Sweet, 2010; Borroni et al., 2010). There are several possiblepathways by which this genetic factor may lead to the developmentof single NPS or different neuropsychiatric syndromes in AD. Therole of APOE genotype in AD-related depression, for example, is stillcontroversial and additional research is needed (López-León et al.,2008). However, recent evidence has been accumulating to suggest
that APOE may be linked to vascular risk factors in late life and, inturn, may be associated with depression. Indeed, it has been positedthat the �4 allele may be a predisposing genetic marker for ischemiccerebrovascular disease (CVD) (McCarron et al., 1999) given its
F. Panza et al. / Ageing Research Reviews 11 (2012) 87– 103 97
Table 4Principal studies on the association of the agitation/aggressiveness symptom or hyperactive syndrome with apolipoprotein E (APOE) genotypes in Alzheimer’s disease (AD)patients.
Reference Reference Study sample Cognitive and neuropsychiatric assessment Principal results
Cacabelos et al.(1996, 1997)
Cross-sectional 207 demented patients MMSE, GDS, ADAS, BCRS, FAST, BEHAVE-AD,HAM-D, HAM-A, and SDASDS
Disorientation, agitation and motordisorders were slightly more frequentin demented patients with APOE �4/e4,while anxiety and sleep disordersappeared more frequently in APOE�3/�4. However, these differenceswere not statistically significant
Murphy et al.(1997)
Cross-sectional 77 AD patients MMSE, TBDQ, and ADAS non-cog APOE �4 allele associated with higherscores on TBDQ
Levy et al. (1999) Cross-sectional 605 AD patients MMSE and NPI Among patients with comparabledisease severity, the APOE �4 alleledoes not confer additional psychiatricmorbidity
Scarmeas et al.(2002)
Longitudinal 87 AD patients MMSE, CUSPAD, BDRS, and SCID-DSM-III-R APOE �4 alleles associated with risk forincident delusions. APOE �4/�4predicted protective effect againsthallucinations
Craig et al. (2004) Cross-sectional 400 AD patients NPI with caregiver distress Increase in agitation/aggression inpatients with the APOE �4 allele
Hollingworth et al.(2006)
Cross-sectional 1120 AD patients By Principal Component Analysis of NPIsymptoms, four interpretable componentswere identified: behavioural dyscontrol(euphoria, disinhibition, aberrant motorbehaviour, and sleep and appetitedisturbances), psychosis (delusions andhallucinations), mood (depression, anxiety,and apathy), and agitation (aggression andirritability)
None of the neuropsychiatricendophenotypes identified wereassociated with age at assessment,years of education, or number of APOE�4 alleles
Pritchard et al.(2007)
Longitudinal 388 AD patients MMSE and NPI Protective effect of the APOE �3/�4genotype that was significantlyassociated with hallucinationssymptoms. APOE �3/�4 genotype issignificantly associated with anxiety
van der Flier et al.(2007)
Cross-sectional 110 AD patients MMSE and NPI Delusions and agitation/aggressionwere more common and severeramong homozygous APOE �4 carriersthan among heterozygous or APOE-�4-negative patients.
Woods et al. (2009) Cross-sectional 36 demented patients MMSE and mABRS Patients with an APOE �4 allele had asignificant increase in their observedNPS, including restlessness andvocalizations, compared to those whodid not have an APOE �4 allele present
D’Onofrio et al.(2010b)
Cross-sectional 201 AD patients and121 controls
MMSE, ADL, IADL, CIRS, and NPI.Furthermore, AD patients with NPS werefurther sub-divided in four groups accordingto the EADC classification of neuropsychiatricsyndromes in AD: hyperactive, psychotic,affective, and apathetic
No difference in the distribution ofAPOE genotypes was found betweenAD patients with and without NPS. InAD patients APOE �4-carriers, therewas an increased risk of affective andapathetic syndromes
MMSE = mini mental state examination; GDS = global deterioration scale; ADAS = Alzheimer’s disease assessment scale; BCRS = brief cognitive rating scale; FAST = functionalassessment stages; BEHAVE-AD = behavioural pathology in Alzheimer’s disease rating scale; HAM-A = Hamilton rating scale for anxiety; SDASDS = senile dementia-associatedsleep disorders scale; TBDQ: time based behavioural disturbance questionnaire (does patient display any of following symptoms in 1 month prior to assessment (combative-ness, agitation, wandering, incoherent speech, hallucinations, confusion and disorientation); ADAS non-cog = Alzheimer’s disease assessment scale non-cognitive subscale;N tholoi ; mABA umula
ar2ecaiIchcaoh
PI = neuropsychiatry inventory; CUSPAD = Colombia university scale for psychopacal interview for diagnostic and statistical manual of mental disorders-III-revisedDL = activities of daily living; IADL = instrumental activities of daily living; CIRS = c
ssociation with hyperlipidemia (Sawada et al., 2000), atheroscle-osis (Davignon et al., 1999), myocardial infarction (Brscic et al.,000), and subcortical white matter lesion pathology (de Leeuwt al., 2004). Current etiological models of late-life depression andognitive decline focus on the potential role of vascular risk factors,nd suggested possible opportunities for specific prevention andntervention strategies in high-risk populations (Panza et al., 2005).n fact, some late-life depressive syndromes might predispose, pre-ipitate, or perpetuate by CVD, the so called “vascular depression”ypothesis (Alexopoulos et al., 1997). This notion is based on the
omorbidity of depressive syndromes with cerebrovascular lesionsnd cerebrovascular risk factors and on the fact that depressionften develops after a stroke (Alexopoulos et al., 2005). In fact, aistory of stroke was associated with a 3–4-fold increased risk ofgy in AD; BDRS = blessed dementia rating scale; SCID-DSM-III-R = structured clin-RS = modified agitated behaviour rating scale; NPS = neuropsychiatric symptoms;tive illness rating scale; EADC = European Alzheimer’s Disease Consortium.
apathy and depression in AD (Treiber et al., 2008). CVD has pre-viously been linked to depression in several studies of individualswith dementia (O’Brien et al., 2000). In addition, the APOE �4 allelemay increase the odds that older depressed patients develop MCI(Geda et al., 2006). Finally, it has been proposed that, for thosecarrying a copy of the �4 allele, the destructive effect of subtle,underlying vascular risk factors may be enhanced (de Leeuw et al.,2004). Therefore, future studies should examine a broader rangeof patients to determine the relative contributions of CVD risk todepression in AD. Furthermore, the APOE �4 allele appears to be
less efficient than other isoforms at inducing cholesterol trans-port (Michikawa et al., 2000), which may have an important rolein maintaining the integrity of membranes, and in synaptic plas-ticity. Thus, it appears that the APOE �4 allele is associated with
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mpaired response to cerebral damage and diminished capacity foreuronal repair (Arendt et al., 1997; Crawford et al., 2002), and thathis poorer neuronal reparative capacity may be implicated in theevelopment of cognitive decline and depression in older adultsith the APOE �4 genotype. Some studies demonstrated that the
ssociation between APOE genotype and depression in AD was pri-arily seen in women and not men (Müller-Thomsen et al., 2002;elano-Wood et al., 2008). Recent research has shown that womenemonstrate higher rates of vascular risk factors (i.e., hyperlipi-emia) compared to men (Hippisley-Cox et al., 2001; de Leeuwt al., 2004) and depressed women have been shown to be overlyepresented in diffuse neurological disease such as AD (Okiishi et al.,001). Thus, it may be important to consider potential sex differ-nces in the risk for depression for AD patients possessing the APOE4 allele. Indeed, sex effects have not been taken into account inany of the previous studies that have demonstrated negative find-
ngs (Table 1). Therefore, it is unclear to what extent the lack ofeasurement for sex differences may have contributed to a lack of
ssociation reported in previous studies.Furthermore, for affective syndromes and/or symptoms in
D, also the mechanisms underlying the suggested associationetween late-life anxiety and APOE genotypes in AD are, at present,ot completely understood (Robertson et al., 2005; Raber, 2007;iegel et al., 2010). Interestingly, higher measures of anxiety wereeported in male mice lacking murine APOE (APOE-/−) than in sex-atched wild type controls (Robertson et al., 2005; Raber, 2007).
here were isoform-dependent effects of APOE on measures ofnxiety in male APOE−/− and APOE3 and APOE4 mice express-ng human APOE in neurons under control of the neuron-specificnolase (NSE) promoter or in astrocytes under control of the glialbrillary acidic protein (GFAP) promoter (Robertson et al., 2005;aber, 2007). APOE−/− and APOE4 male mice showed increasedeasures of anxiety, whereas APOE3 mice behaved like wild type
ontrols (Robertson et al., 2005; Raber, 2007). These differentialffects were age-dependent, as they were not seen in younger maleice (Robertson et al., 2005; Raber, 2007). Very recently, these find-
ngs were also confirmed in female APOE TR mice expressing APOEnder control of the mouse APOE promoter. APOE4 mice showedecreased activity levels and higher measures of anxiety than micexpressing APOE2 or APOE3 isoform across all ages (Siegel et al.,010).
The association of CVD with apathy may reflect stroke-relatedamage to areas of the prefrontal cortex or related neural pathways,
nvolved in the planning and execution of goal-directed behaviourCraig et al., 1996). In fact, apathy is associated with frontal andubcortical pathology (Migneco et al., 2001; Tekin et al., 2001), andore severe apathy has been related with a severe impairment
f frontal executive functions (McPherson et al., 2002). Functionalmaging studies revealed that apathy in AD is related to dysfunc-ion of the right temporo-parietal and anterior cingulate corticesCraig et al., 1996; Migneco et al., 2001), regions involved in frontal-ubcortical networks. A recent neuropathological study reported aignificant relationship between chronic apathy and anterior cingu-ated cortex tangle pathology (Tekin et al., 2001). Apathetic patients
ith AD treated with cholinesterase inhibitors showed a signifi-ant reduction in apathy (Boyle and Malloy, 2004). This is probablyelated to loss of nucleus basalis of Meynert cholinergic input torefrontal and subcortical regions (Craig et al., 1996). Interestingly,iochemical and neuropathological data suggested an associationetween the APOE gene and frontal dysfunction. In fact, the APOE4 allele has been associated with a severe loss of cholinergic activ-
ty in the frontal cortex (Soininen et al., 1995), and with enhanced
-amyloid (A�) deposition in the frontal region of non-dementedresenile subjects (Yamaguchi et al., 2001).The mechanism by which APOE �4 may increase the risk for psy-hotic symptoms in AD is unclear. Although the �4 allele has been
eviews 11 (2012) 87– 103
shown to promote the neuropathological features of AD, includingA� deposition (Schmechel et al., 1993; Gomez-Isla et al., 1996) andneurofibrillary tangle formation (Schmechel et al., 1993; Gomez-Isla et al., 1996), attempts to relate these features to psychoticsymptoms in AD have yielded conflicting results (Zubenko et al.,1991; Sweet et al., 2000). Therefore, neuropsychiatric symptoma-tology could be associated with more severe neuropathologicalchanges, although there is no clear consensus on this. Furthermore,the �4 allele has been associated with more profound deficits incholinergic neurons, in particular in the frontal cortex (Soininenet al., 1995) and medial temporal lobe (Poirier et al., 1995), whereasthe development of NPS in AD appears to be related to specificneurotransmitter imbalances, notably acetylcholine (Cummingsand Kaufer, 1996). Consequently, the presence of the �4 allelecould favor a preferential pathologic involvement of the choliner-gic system, which in turn might result in more frequent psychoticmanifestations. Neuroimaging studies may shed additional light onthe association between APOE �4 and psychotic symptoms in AD.Psychotic manifestations in AD have been associated with pathol-ogy in the temporal lobe and hippocampus (Zubenko et al., 1991;Forstl et al., 1994). One single photon emission computed tomog-raphy (SPECT) study has suggested that delusions in AD may beassociated with hypoperfusion in the temporal lobes (Starksteinet al., 1994), and some (Lee et al., 2003) but not all (van Dycket al., 1998) functional imaging studies have shown that AD patientswho carry the �4 allele have reduced temporal lobe function.The structural MRI literature is more unified in showing greatermedial temporal lobe atrophy in association with the e4 allele inAD (Lehtovirta et al., 1996b; Hashimoto et al., 2001; Basso et al.,2006). It is conceivable that the detected association between APOEgenotype and psychotic symptom, particularly delusions, mightreflect neuropathology more heavily concentrated in the temporallobe.
Finally, also the mechanisms of the possible association betweenAPOE genotype and aggressive/agitated behaviour in AD areunclear. APOE is associated with more rapid progression as mea-sured by SPECT and higher tangle burden in the brain (Gomez-Islaet al., 1996; van Dyck et al., 1998; Kanai et al., 1999; McNamaraet al., 1998). The accepted spread of neuropathological damageseen in AD, from the hippocampus to frontal–temporal–parietalregions, may encourage the development of those behaviouralsymptoms that not only localize regionally within the brain but aredependent on progressive neuronal loss and amyloid depositionaway from the mesial temporal lobe. Frontal involvement is thebest neuroanatomical correlate for aggression and agitation withsecondary disruption of the serotonergic and dopaminergic sys-tems (Reinikainen et al., 1990; Lawlor, 1990; Hirono et al., 2000;Tekin et al., 2001). High agitation scores correlate with bilateralorbitofrontal and left anterior cingulated tangle burden (Tekin et al.,2001), and with left fronto-temporal hypoperfusion on SPECT scan-ning (Hirono et al., 2000).
7. Conclusions
The association of APOE genotypes with NPS or neuropsy-chiatric syndromes in AD appeared to be still unclear. NPS indifferent times could coexist in a single patient showing a verycomplex psychological profile. However, current cumulative evi-dence coming from the few existing longitudinal studies showsno association of APOE genotypes with NPS as a whole in AD.The discrepancy in dementia syndromes between the occurrence
of NPS from rather linear cognitive decline implies indepen-dent pathophysiological pathways between these symptoms. Inparticular, contrasting findings existed on the possible associa-tion between affective symptoms or syndromes in AD and APOE
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enotype, with studies with measures of late-life depressive syn-romes and symptoms more frequent than studies that focusedn late-life anxiety. At present, there is only limited evidence ofn increased risk of apathy or agitated behaviour linked to theresence of APOE �4 allele in AD patients, and no longitudinaleport confirmed these suggestions. Furthermore, some studiesave found an association between APOE �4 allele and the ADlus psychosis endophenotype, with several studies suggesting aossible role of this polymorphism when the outcome was theresence of delusions in AD patients rather than of hallucina-ions. As a whole, however, APOE genotype does not appear toontribute to the risk of psychosis in AD. The fact that some stud-es assessing NPS in relation to APOE status often analyzed theichotomized APOE �4 status rather than the number of APOE4 alleles may partially account for these contrasting findings,uggesting a methodological limit for the correct evaluation ofredisposing factors and the pathogenetic basis of NPS in AD.iscrepant findings may be due also to other factors includ-
ng small sample sizes generating false positives that cannot beonsistently replicated, differences in sample compositions (e.g.,eneral “dementia” groups versus strictly diagnosed patients withprobable AD”, with some of the studies including patients withementia with Lewy bodies), the use of very brief, wide-ranging,r unstructured psychopathology inventories, and possible lackf statistical power to detect associations in the negative studies.urthermore, some negative studies that focused on the distribu-ion of APOE genotypes between AD patients with or without NPSurther emphasized the importance of sub-grouping NPS in dis-inct neuropsychiatric syndromes, suggesting also genetic basis forndividual NPS. In fact, despite many efforts to highlight associa-ions between APOE genotypes and individual NPS, a syndromalpproach might be of interest. In addition, many of the abovetudies did not control for potential confounding variables, par-icularly for disease duration. Importantly, many reviewed studiesere cross-sectional, whereas it would be of paramount impor-
ance to evaluate the risk for incident NPS in relation to thePOE genotype in prospectively followed cohorts of AD patients.
n fact, cross-sectional studies have limitations in interpretinghe causal relationship between APOE genotypes and NPS oreuropsychiatric syndromes/endophenotypes. Further longitudi-al studies on larger sample of patients are needed to clarify theossible role of this polymorphism in NPS or neuropsychiatric syn-romes/endophenotypes in AD. In fact, identifying valid clustersf NPS in AD and the related predisposing genetic risk factors,ay allow us to understand the pathophysiological features of
europsychiatric syndromes or symptoms in AD, so optimizingossible treatment approaches.
cknowledgement
This work was fully supported by “Ministero della Salute”, IRCCSesearch Program, Ricerca Corrente 2009–2011, Linea n. 2 “Malat-ie complesse”.
eferences
alten, P., de Vugt, M.E., Lousberg, R., Korten, E., Jaspers, N., Senden, B., Jolles, J.,Verhey, F.R., 2003. Behavioral problems in dementia: a factor analysis of theneuropsychiatric inventory. Dement. Geriatr. Cogn. Disord. 15, 99–105.
alten, P., Verhey, F.R., Boziki, M., Bullock, R., Byrne, E.J., Camus, V., Caputo, M.,Collins, D., De Deyn, P.P., Elina, K., Frisoni, G., Girtler, N., Holmes, C., Hurt, C.,Marriott, A., Mecocci, P., Nobili, F., Ousset, P.J., Reynish, E., Salmon, E., Tsolaki, M.,Vellas, B., Robert, P.H., 2007. Neuropsychiatric syndromes in dementia. Resultsfrom the European Alzheimer Disease Consortium: part I. Dement. Geriatr. Cogn.
Disord. 24, 457–463.alten, P., Verhey, F.R., Boziki, M., Brugnolo, A., Bullock, R., Byrne, E.J., Camus, V.,Caputo, M., Collins, D., De Deyn, P.P., Elina, K., Frisoni, G., Holmes, C., Hurt, C.,Marriott, A., Mecocci, P., Nobili, F., Ousset, P.J., Reynish, E., Salmon, E., Tsolaki, M.,Vellas, B., Robert, P.H., 2008. Consistency of neuropsychiatric syndromes across
eviews 11 (2012) 87– 103 99
dementias: results from the European Alzheimer Disease Consortium: part II.Dement. Geriatr. Cogn. Disord. 25, 1–8.
Aharon-Peretz, J., Kliot, D., Tomer, R., 2000. Behavioral differences between whitematter lacunar dementia and Alzheimer’s disease: a comparison on the neu-ropsychiatric inventory. Dement. Geriatr. Cogn. Disord. 11, 294–298.
Alexopoulos, G.S., Meyers, B.S., Young, R.C., Kakuma, T., Silbersweig, D., Charlson, M.,1997. Clinically defined vascular depression. Am. J. Psychiatry 154, 562–565.
Alexopoulos, G.S., 2005. Depression in the elderly. Lancet 365, 1961–1970.Alexopoulos, G.S., Schultz, S.K., Lebowitz, B.D., 2005. Late-life depression: a model
for medical classification. Biol. Psychiatry 58, 283–289.Alzheimer’s Association, 2010. Alzheimer’s disease facts and figures. Alzheimers
Dement. 6, 158–194.American Psychiatric Association, 2004. Diagnostic and Statistical Manual of Mental
Disorders, fourth edition. American Psychiatric Publishing, Inc., Arlington, VA.Arendt, T., Schindler, C., Brückner, M.K., Eschrich, K., Bigl, V., Zedlick, D., Marcova,
L., 1997. Plastic neuronal remodelling is impaired in patients with Alzheimer’sdisease carrying apolipoprotein epsilon 4 allele. J. Neurosci. 17, 516–529.
Bacanu, S.A., Devlin, B., Chowdari, K.V., DeKosky, S.T., Nimgaonkar, V.L., Sweet, R.A.,2005. Heritability of psychosis in Alzheimer disease. Am. J. Geriatr. Psychiatry13, 624–627.
Ballard, C., Massey, H., Lamb, H., Morris, C., 1997. Apolipoprotein E: non-cognitivesymptoms and cognitive decline in late onset Alzheimer’s disease. J. Neurol.Neurosurg. Psychiatry 63, 273.
Ballard, C., Neill, D., O’Brien, J., McKeith, I.G., Ince, P., Perry, R., 2000. Anxiety, depres-sion and psychosis in vascular dementia: prevalence and associations. J. Affect.Disord. 59, 97–106.
Basso, M., Gelernter, J., Yang, J., MacAvoy, M.G., Varma, P., Bronen, R.A., van Dyck,C.H., 2006. Apolipoprotein E epsilon4 is associated with atrophy of the amygdalain Alzheimer’s disease. Neurobiol. Aging 27, 1416–1424.
Bathgate, D., Snowden, J.S., Varma, A., Blackshaw, A., Neary, D., 2001. Behaviourin frontotemporal dementia. Alzheimer’s disease and vascular dementia. ActaNeurol. Scand. 103, 367–378.
Beaudreau, S.A., O’Hara, R., 2008. Late-life anxiety and cognitive impairment: areview. Am. J. Geriatr. Psychiatry 16, 790–803.
Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., Tanzi, R.E., 2007. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.Nat. Genet. 39, 17–23.
Borroni, B., Grassi, M., Agosti, C., Costanzi, C., Archetti, S., Franzoni, S., Caltagirone,C., Di Luca, M., Caimi, L., Padovani, A., 2006. Genetic correlates of behavioralendophenotypes in Alzheimer disease: role of COMT, 5-HTTLPR and APOE poly-morphisms. Neurobiol. Aging 27, 1595–1603.
Borroni, B., Costanzi, C., Padovani, A., 2010. Genetic susceptibility to behavioural andpsychological symptoms in Alzheimer disease. Curr. Alzheimer Res. 7, 158–164.
Boyle, P.A., Malloy, P.F., 2004. Treating apathy in Alzheimer’s disease. Dement. Geri-atr. Cogn. Disord. 17, 91–99.
Brscic, E., Bergerone, S., Gagnor, A., Colajanni, E., Matullo, G., Scaglione, L., Cassader,M., Gaschino, G., Di Leo, M., Brusca, A., Pagano, G.F., Piazza, A., Trevi, G.P., 2000.Acute myocardial infarction in young adults: prognostic role of angiotensin-converting enzyme angiotensin II type I receptor apolipoprotein E endothelialconstitutive nitric oxide synthase and glycoprotein IIIa genetic polymorphismsat medium-term follow-up. Am. Heart J. 139, 979–984.
Brookmeyer, R., Johnson, E., Ziegler-Graham, K., Arrighi, H.M., 2007. Forecasting theglobal burden of Alzheimer’s disease. Alzheimers Dement. 3, 186–191.
Cacabelos, R., Rodríguez, B., Carrera, C., Caamano, J., Beyer, K., Lao, J.I., Sellers,M.A., 1996. APOE-related frequency of cognitive and noncognitive symptomsin dementia. Methods Find. Exp. Clin. Pharmacol. 18, 693–706.
Cacabelos, R., Rodríguez, B., Carrera, C., Beyer, K., Lao, J.I., Sellers, M.A., 1997. Behav-ioral changes associated with different apolipoprotein E genotypes in dementia.Alzheimer Dis. Assoc. Disord. 11 (Suppl. 4), S27–S34.
Cantillon, M., Harwood, D., Barker, W., St George-Hyslop, P., Tsuda, T., Ekatarina, R.,Duara, R., 1997. No association between apolipoprotein E genotype and late-onset depression in Alzheimer’s disease. Biol. Psychiatry 41, 246–248.
Carrasquillo, M.M., Zou, F., Pankratz, V.S., Wilcox, S.L., Ma, L., Walker, L.P., Younkin,S.G., Younkin, C.S., Younkin, L.H., Bisceglio, G.D., Ertekin-Taner, N., Crook, J.E.,Dickson, D.W., Petersen, R.C., Graff-Radford, N.R., Younkin, S.G., 2009. Geneticvariation in PCDH11X is associated with susceptibility to late-onset Alzheimer’sdisease. Nat. Genet. 41, 192–198.
Chang, J.B., Wang, P.N., Chen, W.T., Liu, C.Y., Hong, C.J., Lin, K.N., Liu, T.Y., Chi, C.W.,Liu, H.C., 2004. ApoE epsilon4 allele is associated with incidental hallucinationsand delusions in patients with AD. Neurology 63, 1105–1107.
Chen, S., Parmigiani, G., 2007. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin.Oncol. 25, 1329–1333.
Chopra, M.P., Landes, R.D., Jones, R.A., Feldman, Z.L., Beck, C., Griffin, S.T., 2009. Doesthe apolipoprotein E epsilon 4 genotype influence the expression of depressionwith cognitive impairment? Int. J. Geriatr. Psychiatry 24, 650–652.
Cohen-Mansfield, J., 2001. Nonpharmacologic interventions for inappropriatebehaviors in dementia: a review and critique. Am. J. Geriatr. Psychiatry 9,361–381.
Cohen-Mansfield, L., Werner, P., 1999. Longitudinal predictors of nonaggressivebehaviors in the elderly. Int. J. Geriatr. Psychiatry 14, 831–844.
Craig, A.H., Cummings, J.L., Fairbanks, L., Itti, L., Miller, B.L., Li, J., Mena, I., 1996.
Cerebral blood flow correlates of apathy in Alzheimer disease. Arch. Neurol. 53,1116–1120.Craig, D., Hart, D.J., McCool, K., McIlroy, S.P., Passmore, A.P., 2004. ApolipoproteinE �4 allele influences aggressive behaviour in Alzheimer’s disease. J. Neurol.Neurosurg. Psychiatry 75, 1327–1330.
1 arch R
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00 F. Panza et al. / Ageing Rese
raig, D., Hart, D.J., McIlroy, S.P., Passmore, A.P., 2005. Association analysis ofapolipoprotein E genotype and risk of depressive symptoms in Alzheimer’sdisease. Dement. Geriatr. Cogn. Disord. 19, 154–157.
rawford, F.C., Vanderploeg, R.D., Freeman, M.J., Singh, S., Waisman, M., Michaels,L., 2002. APOE genotype influences acquisition and recall following traumaticbrain injury. Neurology 58, 1115–1118.
ummings, J.L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D.A., Gorn-bein, J., 1994. The Neuropsychiatric Inventory: comprehensive assessment ofpsychopathology in dementia. Neurology 44, 2308–2314.
ummings, J.L., Kaufer, D., 1996. Neuropsychiatric aspects of Alzheimer’s disease:the cholinergic hypothesis revisited. Neurology 47, 876–883.
ummings, J.L., 2000. Cognitive and behavioral heterogeneity in Alzheimer’s dis-ease: seeking the neurobiological basis. Neurobiol. Aging 21, 845–861.
avignon, J., Cohn, J.S., Mabile, L., Bernier, L., 1999. Apolipoprotein E and atheroscle-rosis: insight from animal and human studies. Clin. Chim. Acta 286, 115–143.
elano-Wood, L., Houston, W.S., Emond, J.A., Marchant, N.L., Salmon, D.P., Jeste,D.V., Thal, L.J., Bondi, M.W., 2008. APOE genotype predicts depression in womenwith Alzheimer’s disease: a retrospective study. Int. J. Geriatr. Psychiatry 23,632–636.
el Prete, M., Spaccavento, S., Craca, A., Fiore, P., Angelelli, P., 2009. Neuropsychi-atric symptoms and the APOE genotype in Alzheimer’s disease. Neurol. Sci. 30,367–373.
el Ser, T., McKeith, I., Anand, R., Cicin-Sain, A., Ferrara, R., Spiegel, R., 2000. Demen-tia with Lewy bodies: findings from an international multicentre study. Int. J.Geriatr. Psychiatry 15, 1034–1045.
e Leeuw, F.E., Richard, F., de Groot, J.C., van Duijn, C.M., Hofman, A., Van Gijn,J., Breteler, M.M., 2004. Interaction between hypertension, apoE, and cerebralwhite matter lesions. Stroke 35, 1057–1060.
eMichele-Sweet, M.A., Sweet, R.A., 2010. Genetics of psychosis in Alzheimer’s dis-ease: a review. J. Alzheimers Dis. 7, 158–164.
eutsch, L.H., Bylsma, F.W., Rovner, B.W., Steele, C., Folstein, M.F., 1991. Psychosisand physical aggression in probable Alzheimer’s disease. Am. J. Psychiatry 148,1159–1163.
’Onofrio, G., Sancarlo, D., Panza, F., Copetti, M., Cascavilla, L., Paris, F., Seripa, D.,Matera, M.G., Solfrizzi, V., Pellegrini, F., Pilotto, A., 2010a. Neuropsychiatricsymptoms in patients with Alzheimer’s disease and vascular dementia. Curr.Alzheimer Res., in press.
’Onofrio, G., Panza, F., Seripa, D., Sancarlo, D., Paris, F., Cascavilla, L., Urbano, M.,Gravina, C., Fontana, A., Solfrizzi, V., Pellegrini, F., Pilotto, A., 2010b. The APOEpolymorphism in Alzheimer’s disease patients with neuropsychiatric symptomsand syndromes. Int. J. Geriatr. Psychiatry, doi:10.1002/gps.2644 (epub ahead ofprint).
ngelborghs, S., Dermaut, B., Marien, P., Symons, A., Vloeberghs, E., Maertens, K.,Somers, N., Goeman, J., Rademakers, R., Van den Broeck, M., Pickut, B., Cruts,M., Van Broeckhoven, C., De Deyn, P.P., 2006. Dose dependent effect of APOEe4 on behavioral symptoms in frontal lobe dementia. Neurobiol. Aging 27,285–292.
arrer, L.A., Cupples, L.A., Haines, J.L., Hyman, B., Kukull, W.A., Mayeux, R., Myers,R.H., Pericak-Vance, M.A., Risch, N., van Duijn, C.M., 1997. Effects of age, sex, andethnicity on the association between apolipoprotein E genotype and Alzheimerdisease: a meta-analysis. JAMA 278, 1349–1356.
ernández-Martínez, M., Castro, J., Molano, A., Zarranz, J.J., Rodrigo, R.M., Ortega,R., 2008. Prevalence of neuropsychiatric symptoms in Alzheimer’s disease andvascular dementia. Curr. Alzheimer Res. 5, 61–69.
erri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K.,Hasegawa, K., Hendrie, H., Huang, Y., Jorm, A., Mathers, C., Menezes, P.R., Rimmer,E., Scazufca, M., Alzheimer’s Disease International, 2005. Global prevalence ofdementia: a Delphi consensus study. Lancet 366, 2112–2117.
inkel, S.I., Costa e Silva, J., Cohen, G., Miller, S., Sartorius, N., 1996. Behavioral andpsychological signs and symptoms of dementia: a consensus statement on cur-rent knowledge and implications for research and treatment. Int. Psychogeriatr.8 (Suppl. 3), 497–500.
orsell, Y., Corder, E.H., Basun, H., Lannfelt, L., Viitanen, M., Winblad, B., 1997. Depres-sion and dementia in relation to apolipoprotein E polymorphism in a populationsample age 75+. Biol. Psychiatry 42, 898–903.
orsell, Y., Basun, H., Corder, E.H., Lannfelt, L., Winblad, B., 1998. Psychotic symptomsand apolipoprotein E genotypes in an elderly population. Biol. Psychiatry 44,139–140.
orstl, H., Burns, A., Levy, R., Cairns, N., 1994. Neuropathological correlates of psy-chotic phenomena in confirmed Alzheimer’s disease. Br. J. Psychiatry 165, 53–59.
uh, J.L., Wang, S.J., Cummings, J.L., 2005. Neuropsychiatric profiles in patients withAlzheimer’s disease and vascular dementia. J. Neurol. Neurosurg. Psychiatry 76,1337–1341.
abryelewicz, T., Religa, D., Styczynska, M., Peplonska, B., Pfeffer, A., Wasiak, B.,Luczywek, E., Golebiowski, M., Androsiuk, W., Czyzewski, K., Przekop, I., Bar-cikowska, M., 2002. Behavioural pathology in Alzheimer’s disease with specialreference to apolipoprotein E genotype. Dement. Geriatr. Cogn. Disord. 14,208–212.
authier, S., Cummings, J., Ballard, C., Brodaty, H., Grossberg, G., Robert, P., Lyket-sos, C., 2010. Management of behavioral problems in Alzheimer’s disease. Int.
Psychogeriatr. 22, 346–372.eda, Y.E., Knopman, D.S., Mrazek, D.A., Jicha, G.A., Smith, G.E., Negash, S., Boeve,B.F., Ivnik, R.J., Petersen, R.C., Pankratz, V.S., Rocca, W.A., 2006. Depression,apolipoprotein E genotype, and the incidence of mild cognitive impairment:a prospective cohort study. Arch. Neurol. 63, 435–440.
eviews 11 (2012) 87– 103
Genin, E., Hannequin, D., Wallon, D., Sleegers, K., Hiltunen, M., Combarros, O., Bul-lido, M.J., Engelborghs, S., De Deyn, P., Berr, C., Pasquier, F., Dubois, B., Tognoni,G., Fiévet, N., Brouwers, N., Bettens, K., Arosio, B., Coto, E., Del Zompo, M., Mateo,I., Epelbaum, J., Frank-Garcia, A., Helisalmi, S., Porcellini, E., Pilotto, A., Forti, P.,Ferri, R., Scarpini, E., Siciliano, G., Solfrizzi, V., Sorbi, S., Spalletta, G., Valdivieso, F.,Vepsäläinen, S., Alvarez, V., Bosco, P., Mancuso, M., Panza, F., Nacmias, B., Bossù,P., Hanon, O., Piccardi, P., Annoni, G., Seripa, D., Galimberti, D., Licastro, F., Soini-nen, H., Dartigues, J.F., Kamboh, M.I., Van Broeckhoven, C., Lambert, J.C., Amouyel,P., Campion, D., 2011. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry, doi:10.1038/mp.2011.52 (epub ahead ofprint).
Gomez-Isla, T., West, H.L., Rebeck, G.W., Harr, S.D., Growdon, J.H., Locascio, J.J.,Perls, T.T., Lipsitz, L.A., Hyman, B.T., 1996. Clinical and pathological correlatesof apolipoprotein E e4 in Alzheimer’s disease. Ann. Neurol. 39, 62–70.
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M.L., Pahwa,J.S., Moskvina, V., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A.,Morgan, A.R., Lovestone, S., Powell, J., Proitsi, P., Lupton, M.K., Brayne, C., Rubin-sztein, D.C., Gill, M., Lawlor, B., Lynch, A., Morgan, K., Brown, K.S., Passmore, P.A.,Craig, D., McGuinness, B., Todd, S., Holmes, C., Mann, D., Smith, A.D., Love, S.,Kehoe, P.G., Hardy, J., Mead, S., Fox, N., Rossor, M., Collinge, J., Maier, W., Jessen,F., Schürmann, B., van den Bussche, H., Heuser, I., Kornhuber, J., Wiltfang, J., Dich-gans, M., Frölich, L., Hampel, H., Hüll, M., Rujescu, D., Goate, A.M., Kauwe, J.S.,Cruchaga, C., Nowotny, P., Morris, J.C., Mayo, K., Sleegers, K., Bettens, K., Engel-borghs, S., De Deyn, P.P., Van Broeckhoven, C., Livingston, G., Bass, N.J., Gurling,H., McQuillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw, C.E., Tsolaki, M.,Singleton, A.B., Guerreiro, R., Mühleisen, T.W., Nöthen, M.M., Moebus, S., Jöckel,K.H., Klopp, N., Wichmann, H.E., Carrasquillo, M.M., Pankratz, V.S., Younkin, S.G.,Holmans, P.A., O’Donovan, M., Owen, M.J., Williams, J., 2009. Genome-wide asso-ciation study identifies variants at CLU and PICALM associated with Alzheimer’sdisease. Nat. Genet. 41, 1088–1093.
Harwood, D.G., Barker, W.W., Ownby, R.L., St George-Hyslop, P., Duara, R., 1999.Apolipoprotein-E (APO-E) genotype and symptoms of psychosis in Alzheimer’sdisease. Am. J. Geriatr. Psychiatry 7, 119–123.
Hashimoto, M., Yasuda, M., Tanimukai, S., Matsui, M., Hirono, N., Kazui, H., Mori, E.,2001. Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy inAlzheimer’s disease. Neurology 57, 1461–1466.
Herrmann, N., Lanctôt, K.L., Sambrook, R., Lesnikova, N., Hébert, R., McCracken, P.,Robillard, A., Nguyen, E., 2006. The contribution of neuropsychiatric symptomsto the cost of dementia care. Int. J. Geriatr. Psychiatry 21, 972–976.
Hippisley-Cox, J., Pringle, M., Crown, N., Meal, A., Wynn, A., 2001. Sex inequalitiesin ischaemic heart disease in general practice: cross sectional survey. BMJ 322,832–835.
Hirono, N., Mori, E., Yasuda, M., Ikejiri, Y., Imamura, T., Shimomura, T., Ikeda, M.,Hashimoto, M., Yamashita, H., 1998. Factors associated with psychotic symp-toms in Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 64, 648–652.
Hirono, N., Mori, E., Yasuda, M., Imamura, T., Shimomura, T., Hashimoto, M., Tan-imukai, S., Kazui, H., Yamashita, H., 1999. Lack of effect of apolipoprotein E E4allele on neuropsychiatric manifestations in Alzheimer’s disease. J. Neuropsy-chiatry Clin. Neurosci. 11, 66–70.
Hirono, N., Mega, M.S., Dinov, I.D., Mishkin, F., Cummings, J.L., 2000. Left frontotem-poral hypoperfusion is associated with aggression in patients with dementia.Arch. Neurol. 57, 861–866.
Hollingworth, P., Hamshere, M.L., Moskvina, V., Dowzell, K., Moore, P.J., Foy, C.,Archer, N., Lynch, A., Lovestone, S., Brayne, C., Rubinsztein, D.C., Lawlor, B., Gill,M., Owen, M.J., Williams, J., 2006. Four components describe behavioral symp-toms in 1,120 individuals with late-onset Alzheimer’s disease. J. Am. Geriatr.Soc. 54, 1348–1354.
Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, J.C., Carrasquillo, M.M.,Abraham, R., Hamshere, M.L., Pahwa, J.S., Moskvina, V., Dowzell, K., Jones, N.,Stretton, A., Thomas, C., Richards, A., Ivanov, D., Widdowson, C., Chapman, J.,Lovestone, S., Powell, J., Proitsi, P., Lupton, M.K., Brayne, C., Rubinsztein, D.C.,Gill, M., Lawlor, B., Lynch, A., Brown, K.S., Passmore, P.A., Craig, D., McGuinness,B., Todd, S., Holmes, C., Mann, D., Smith, A.D., Beaumont, H., Warden, D., Wilcock,G., Love, S., Kehoe, P.G., Hooper, N.M., Vardy, E.R., Hardy, J., Mead, S., Fox, N.C.,Rossor, M., Collinge, J., Maier, W., Jessen, F., Rüther, E., Schürmann, B., Heun, R.,Kölsch, H., van den Bussche, H., Heuser, I., Kornhuber, J., Wiltfang, J., Dichgans, M.,Frölich, L., Hampel, H., Gallacher, J., Hüll, M., Rujescu, D., Giegling, I., Goate, A.M.,Kauwe, J.S., Cruchaga, C., Nowotny, P., Morris, J.C., Mayo, K., Sleegers, K., Bet-tens, K., Engelborghs, S., De Deyn, P.P., Van Broeckhoven, C., Livingston, G., Bass,N.J., Gurling, H., McQuillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw,C.E., Tsolaki, M., Singleton, A.B., Guerreiro, R., Mühleisen, T.W., Nöthen, M.M.,Moebus, S., Jöckel, K.H., Klopp, N., Wichmann, H.E., Pankratz, V.S., Sando, S.B.,Aasly, J.O., Barcikowska, M., Wszolek, Z.K., Dickson, D.W., Graff-Radford, N.R.,Petersen, R.C., the Alzheimer’s Disease Neuroimaging Initiative, van Duijn, C.M.,Breteler, M.M., Ikram, M.A., Destefano, A.L., Fitzpatrick, A.L., Lopez, O., Launer,L.J., Seshadri, S., CHARGE Consortium, Berr, C., Campion, D., Epelbaum, J., Dar-tigues, J.F., Tzourio, C., Alpérovitch, A., Lathrop, M., EADI1 Consortium, Feulner,T.M., Friedrich, P., Riehle, C., Krawczak, M., Schreiber, S., Mayhaus, M., Nicol-haus, S., Wagenpfeil, S., Steinberg, S., Stefansson, H., Stefansson, K., Snædal, J.,Björnsson, S., Jonsson, P.V., Chouraki, V., Genier-Boley, B., Hiltunen, M., Soininen,H., Combarros, O., Zelenika, D., Delepine, M., Bullido, M.J., Pasquier, F., Mateo, I.,
Frank-Garcia, A., Porcellini, E., Hanon, O., Coto, E., Alvarez, V., Bosco, P., Siciliano,G., Mancuso, M., Panza, F., Solfrizzi, V., Nacmias, B., Sorbi, S., Bossù, P., Piccardi, P.,Arosio, B., Annoni, G., Seripa, D., Pilotto, A., Scarpini, E,. Galimberti, D., Brice, A.,Hannequin, D., Licastro, F., Jones, L., Holmans, P.A., Jonsson, T., Riemenschneider,M., Morgan, K., Younkin, S.G., Owen, M.J., O’Donovan, M., Amouyel, P., Williams,
arch R
H
H
H
H
I
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J
J
K
K
K
K
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L
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L
L
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L
F. Panza et al. / Ageing Rese
J., 2011. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2APare associated with Alzheimer’s disease. Nat. Genet. 43, 429–435.
olmes, C., Levy, R., McLoughlin, D.M., Powell, J.F., Lovestone, S., 1996. Apolipopro-tein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer’sdisease. J. Neurol. Neurosurg. Psychiatry 61, 580–583.
olmes, C., McLoughlin, D.M., Powell, J., Lovestone, S., 1997. Reply. J. Neurol. Neu-rosurg. Psychiatry 63, 273–274.
olmes, C., Russ, C., Kirov, G., Aitchison, K.J., Powell, J.F., Collier, D.A., Love-stone, S., 1998. Apolipoprotein E: depressive illness, depressive symptoms andAlzheimer’s disease. Biol. Psychiatry 43, 159–164.
olthoff, V.A., Beuthien-Baumann, B., Kalbe, E., Lüdecke, S., Lenz, O., Zündorf, G.,Spirling, S., Schierz, K., Winiecki, P., Sorbi, S., Herholz, K., 2005. Regional cerebralmetabolism in early Alzheimer’s disease with clinically significant apathy ordepression. Biol. Psychiatry 57, 412–421.
keda, M., Fukuhara, R., Shigenobu, K., Hokoishi, K., Maki, N., Nebu, A., Komori, K.,Tanabe, H., 2004. Dementia associated mental and behavioral disturbances inelderly people in the community: finding from the first Nakayama study. J.Neurol. Neurosurg. Psychiatry 75, 146–148.
rie, F., Masaki, K.H., Petrovitch, H., Abbott, R.D., Ross, G.W., Taaffe, D.R., Launer, L.J.,White, L.R., 2008. Apolipoprotein E epsilon4 allele genotype and the effect ofdepressive symptoms on the risk of dementia in men: the Honolulu-Asia AgingStudy. Arch. Gen. Psychiatry 65, 906–912.
shii, S., Weintraub, N., Mervis, J.R., 2009. Apathy: a common psychiatric syndromein the elderly. J. Am. Med. Dir. Assoc. 10, 381–393.
este, D.V., Finkel, S.I., 2000. Psychosis of Alzheimer’s disease and related dementias.Diagnostic criteria for a distinct syndrome. Am. J. Geriatr. Psychiatry 8, 29–34.
este, D.V., Meeks, T.W., Kim, D.S., Zubenko, G.S., 2006. Research agenda for DSM-V:diagnostic categories and criteria for neuropsychiatric syndromes in dementia.J. Geriatr. Psychiatry Neurol. 19, 160–171.
anai, M., Shizuka, M., Urakami, K., Matsubara, E., Harigaya, Y., Okamoto, K., Shoji,M., 1999. Apolipoprotein E4 accelerates dementia and increases cerebrospinalfluid tau levels in Alzheimer’s disease. Neurosci. Lett. 267, 65–68.
essler, R.C., Berglund, P., Demler, O., Jin, R., Merikangas, K.R., Walters, E.E.,2005. Lifetime prevalence and age-of-onset distributions of DSM–IV disor-ders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62,593–602.
im, J.M., Lyons, D., Shin, I.S., Yoon, J.S., 2003. Differences in behavioral and psycho-logical symptoms between Alzheimer’s disease and vascular dementia: are thedifferent pharmacologic treatment strategies justifiable? Hum. Psychopharma-col. 18, 215–220.
im, J.M., Kim, S.Y., Bae, K.Y., Kim, S.W., Shin, I.S., Yang, S.J., Song, Y.H., Yoon, J.S.,2010. Apolipoprotein e4 genotype and depressive symptoms as risk factors fordementia in an older korean population. Psychiatry Investig. 7, 135–140.
rishnan, K.R., Tupler, L.A., Ritchie Jr., J.C., McDonald, W.M., Knight, D.L., Nemeroff,C.B., Carroll, B.J., 1996. Apolipoprotein E-�4 frequency in geriatric depression.Biol. Psychiatry 40, 69–71.
ambert, J.C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros,O., Zelenika, D., Bullido, M.J., Tavernier, B., Letenneur, L., Bettens, K., Berr, C.,Pasquier, F., Fiévet, N., Barberger-Gateau, P., Engelborghs, S., De Deyn, P., Mateo,I., Franck, A., Helisalmi, S., Porcellini, E., Hanon, O., European Alzheimer’s DiseaseInitiative Investigators, de Pancorbo, M.M., Lendon, C., Dufouil, C., Jaillard, C.,Leveillard, T., Alvarez, V., Bosco, P., Mancuso, M., Panza, F., Nacmias, B., Bossù,P., Piccardi, P., Annoni, G., Seripa, D., Galimberti, D., Hannequin, D., Licastro,F., Soininen, H., Ritchie, K., Blanché, H., Dartigues, J.F., Tzourio, C., Gut, I., VanBroeckhoven, C., Alpérovitch, A., Lathrop, M., Amouyel, P., 2009. Genome-wideassociation study identifies variants at CLU and CR1 associated with Alzheimer’sdisease. Nat. Genet. 41, 1094–1099.
andes, A.M., Sperry, S.D., Strauss, M.E., Geldmacher, D.S., 2001. Apathy inAlzheimer’s disease. J. Am. Geriatr. Soc. 49, 1700–1707.
awlor, B., 1990. Serotonin and Alzheimer’s disease. Psychiatric Ann. 20, 567–570.ee, K.U., Lee, J.S., Kim, K.W., Jhoo, J.H., Lee, D.Y., Yoon, J.C., Lee, J.H., Lee, D.S., Lee, M.C.,
Woo, J.I., 2003. Influence of the apolipoprotein E type 4 allele on cerebral glucosemetabolism in Alzheimer’s disease patients. J. Neuropsychiatry Clin. Neurosci.15, 78–83.
ehtovirta, M., Soininen, H., Helisalmi, S., Mannermaa, A., Helkala, E.L., Har-tikainen, P., Hänninen, T., Ryynänen, M., Riekkinen, P.J., 1996a. Clinicaland neuropsychological characteristics in familial and sporadic Alzheimer’sdisease: relation to apolipoprotein E polymorphism. Neurology 46, 413–419.
ehtovirta, M., Soininen, H., Laakso, M.P., Partanen, K., Helisalmi, S., Mannermaa, A.,Ryynänen, M., Kuikka, J., Hartikainen, P., Riekkinen Sr., P.J., 1996b. SPECT and MRIanalysis in Alzheimer’s disease: relation to apolipoprotein E e4 allele. J. Neurol.Neurosurg. Psychiatry 60, 644–649.
evy, M.L., Miller, B.L., Cummings, J.L., Fairbanks, L.A., Craig, A., 1996. Alzheimerdisease and frontotemporal dementias. Behavioral distinctions. Arch. Neurol.53, 687–690.
evy, M.L., Cummings, J.L., Fairbanks, L.A., Masterman, D., Miller, B.L., Craig, A.H.,Paulsen, J.S., Litvan, I., 1998. Apathy is not depression. J. Neuropsychiatry Clin.Neurosci. 10, 314–319.
evy, M.L., Cummings, J.L., Fairbanks, L.A., Sultzer, D.L., Small, G.W., 1999.Apolipoprotein E genotype and noncognitive symptoms in Alzheimer’s disease.
Biol. Psychiatry 45, 422–425.etenneur, L., Gilleron, V., Commenges, D., Helmer, C., Orgogozo, J.M., Dartigues,J.F., 1999. Are sex and educational level independent predictors of dementiaand Alzheimer’s disease? Incidence data from the PAQUID project. J. Neurol.Neurosurg. Psychiatry 66, 177–183.
eviews 11 (2012) 87– 103 101
Liu, C.Y., Hong, C.J., Liu, T.Y., Lin, K.N., Wang, P.N., Chi, C.W., Chuang, Y.Y., Liu,H.C., 2002. Lack of association between the ApoE genotype and depression inAlzheimer’s disease. J. Geriatr. Psychiatry Neurol. 15, 20–23.
Looi, J.C., Sachdev, P.S., 1999. Differentiation of vascular dementia from AD on neu-ropsychological tests. Neurology 53, 670–678.
Lopez, O.L., Kamboh, M.I., Becker, J.T., Kaufer, D.I., Dekosky, S.T., 1997. Theapolipoprotein E epsilon 4 allele is not associated with psychotic symptoms orextrapyramidal signs in probable Alzheimer’s disease. Neurology 49, 794–797.
López-León, S., Janssens, A.C., González-Zuloeta Ladd, A.M., Del-Favero, J., Claes, S.J.,Oostra, B.A., van Duijn, C.M., 2008. Meta-analyses of genetic studies on majordepressive disorder. Mol. Psychiatry 13, 772–785.
Lyketsos, C.G., Baker, L., Warren, A., Steele, C., Brandt, J., Steinberg, M., Kopunek, S.,Baker, A., 1997. Depression, delusions, and hallucinations in Alzheimer’s disease:no relationship to apolipoprotein E genotype. J. Neuropsychiatry Clin. Neurosci.9, 64–67.
Lyketsos, C.G., Steinberg, M., Tschanz, J.T., Norton, M.C., Steffens, D.C., Breitner, J.C.,2000. Mental and behavioral disturbances in dementia: findings from the CacheCounty Study on Memory in Aging. Am. J. Psychiatry 157, 708–714.
Lyketsos, C.G., Lopez, O., Jones, B., Fitzpatrick, A.L., Breitner, J., DeKosky, S.,2002. Prevalence of neuropsychiatric symptoms in dementia and mild cog-nitive impairment: results from the cardiovascular health study. JAMA 288,1475–1483.
Marin, R.S., 1991. Apathy: a neuropsychiatric syndrome. J. Neuropsychiatry Clin.Neurosci. 3, 243–254.
Mayeux, R., 2003. Epidemiology of neurodegeneration. Annu. Rev. Neurosci. 26,81–104.
McCarron, M.O., Delong, D., Alberts, M.J., 1999. APOE genotype as a risk factor forischemic cerebrovascular disease. Neurology 53, 1308–1311.
McNamara, M.J., Gomez-Isla, T., Hyman, B.T., 1998. Apolipoprotein E genotype anddeposits of Ab40 and Ab42 in Alzheimer disease. Arch. Neurol. 55, 1001–1004.
McPherson, S., Fairbanks, L., Tiken, S., Cummings, J.L., Back-Madruga, C., 2002. Apa-thy and executive function in Alzheimer’s disease. J. Int. Neuropsychol. Soc. 8,373–381.
Mega, M.S., Cummings, J.L., Fiorello, T., Gornbein, J., 1996. The spectrum of behavioralchanges in Alzheimer’s disease. Neurology 46, 130–135.
Michikawa, M., Fan, Q.W., Isobe, I., Yanagisawa, K., 2000. Apolipoprotein E exhibitsisoform-specific promotion of lipid efflux from astrocytes and neurons in cul-ture. J. Neurochem. 74, 1008–1016.
Migneco, O., Benoit, M., Koulibaly, P.M., Dygai, I., Bertogliati, C., Desvignes, P., Robert,P.H., Malandain, G., Bussiere, F., Darcourt, J., 2001. Perfusion brain SPECT andstatistical parametric mapping analysis indicate that apathy is a cingulate syn-drome: a study in Alzheimer’s disease and nondemented patients. Neuroimage13, 896–902.
Mintzer, J.E., Brawman-Mintzer, O., 1996. Agitation as a possible expression of gen-eralized anxiety disorder in demented elderly patients: toward a treatmentapproach. J. Clin. Psychiatry 57 (Suppl. 7), 55–63.
Monastero, R., Mariani, E., Camarda, C., Ingegni, T., Averna, M.R., Senin, U., Camarda,R., Mecocci, P., 2006. Association between apolipoprotein E epsilon4 allele andapathy in probable Alzheimer’s disease. Acta Psychiatr. Scand. 3, 59–63.
Murman, D.L., Chen, Q., Powell, M.C., Kuo, S.B., Bradley, C.J., Colenda, C.C., 2002. Theincremental direct costs associated with behavioral symptoms in AD. Neurology59, 1721–1729.
Müller-Thomsen, T., Arlt, S., Ganzer, S., Mann, U., Mass, R., Naber, D., Beisiegel, U.,2002. Depression in Alzheimer’s disease might be associated with apolipopro-tein E e4 allele: frequency in women but not in men. Dement. Geriatr. Cogn.Disord. 14, 59–63.
Murphy Jr., G.M., Taylor, J., Tinklenberg, J.R., Yesavage, J.A., 1997. The apolipopro-tein E epsilon 4 allele is associated with increased behavioral disturbance inAlzheimer’s disease. Am. J. Geriatr. Psychiatry 5, 88–89.
Murrell, J.R., Price, B.M., Baiyewu, O., Gureje, O., Deeg, M., Hendrie, H., Ogun-niyi, A., Hall, K., 2006. The fourth apolipoprotein E haplotype found inthe Yoruba of Ibadan. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 141B,426–427.
Nacmias, B., Tedde, A., Forleo, P., Piacentini, S., Guarnieri, B.M., Bartoli, A., Ortenzi, L.,Petruzzi, C., Serio, A., Marcon, G., Sorbi, S., 2001. Association between 5-HT(2A)receptor polymorphism and psychotic symptoms in Alzheimer’s disease. Biol.Psychiatry 50, 472–475.
Naj, A.C., Jun, G., Beecham, G.W., Wang, L.S., Vardarajan, B.N., Buros, J., Gallins,P.J., Buxbaum, J.D., Jarvik, G.P., Crane, P.K., Larson, E.B., Bird, T.D., Boeve, B.F.,Graff-Radford, N.R., De Jager, P.L., Evans, D., Schneider, J.A., Carrasquillo, M.M.,Ertekin-Taner, N., Younkin, S.G., Cruchaga, C., Kauwe, J.S., Nowotny, P., Kramer,P., Hardy, J., Huentelman, M.J., Myers, A.J., Barmada, M.M., Demirci, F.Y., Baldwin,C.T., Green, R.C., Rogaeva, E., George-Hyslop, P.S., Arnold, S.E., Barber, R., Beach,T., Bigio, E.H., Bowen, J.D., Boxer, A., Burke, J.R., Cairns, N.J., Carlson, C.S., Carney,R.M., Carroll, S.L., Chui, H.C., Clark, D.G., Corneveaux, J., Cotman, C.W., Cummings,J.L., Decarli, C., Dekosky, S.T., Diaz-Arrastia, R., Dick, M., Dickson, D.W., Ellis, W.G.,Faber, K.M., Fallon, K.B., Farlow, M.R., Ferris, S., Frosch, M.P., Galasko, D.R., Gan-guli, M., Gearing, M., Geschwind, D.H., Ghetti, B., Gilbert, J.R., Gilman, S., Giordani,B., Glass, J.D., Growdon, J.H., Hamilton, R.L., Harrell, L.E., Head, E., Honig, L.S.,Hulette, C.M., Hyman, B.T., Jicha, G.A., Jin, L.W., Johnson, N., Karlawish, J., Kary-das, A., Kaye, J.A., Kim, R., Koo, E.H., Kowall, N.W., Lah, J.J., Levey, A.I., Lieberman,
A.P., Lopez, O.L., Mack, W.J., Marson, D.C., Martiniuk, F., Mash, D.C., Masliah,E., McCormick, W.C., McCurry, S.M., McDavid, A.N., McKee, A.C., Mesulam, M.,Miller, B.L., Miller, C.A., Miller, J.W., Parisi, J.E., Perl, D.P., Peskind, E., Petersen,R.C., Poon, W.W., Quinn, J.F., Rajbhandary, R.A., Raskind, M., Reisberg, B., Ring-man, J.M., Roberson, E.D., Rosenberg, R.N., Sano, M., Schneider, L.S., Seeley, W.,
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02 F. Panza et al. / Ageing Rese
Shelanski, M.L., Slifer, M.A., Smith, C.D., Sonnen, J.A., Spina, S., Stern, R.A., Tanzi,R.E., Trojanowski, J.Q., Troncoso, J.C., Van Deerlin, V.M., Vinters, H.V., Vonsattel,J.P., Weintraub, S., Welsh-Bohmer, K.A., Williamson, J., Woltjer, R.L., Cantwell,L.B., Dombroski, B.A., Beekly, D., Lunetta, K.L., Martin, E.R., Kamboh, M.I., Saykin,A.J., Reiman, E.M., Bennett, D.A., Morris, J.C., Montine, T.J., Goate, A.M., Blacker,D., Tsuang, D.W., Hakonarson, H., Kukull, W.A., Foroud, T.M., Haines, J.L., Mayeux,R., Pericak-Vance, M.A., Farrer, L.A., Schellenberg, G.D., 2011. Common variantsat MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onsetAlzheimer’s disease. Nat. Genet. 43, 436–441.
yatsanza, S., Shetty, T., Gregory, C., Lough, S., Dawson, K., Hodges, J.R., 2003. A studyof stereotypic behaviours in Alzheimer’s disease and frontal and temporal vari-ant frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 74, 1398–1402.
’Brien, J., Perry, R., Barber, R., Gholkar, A., Thomas, A., 2000. The association betweenwhite matter lesions on magnetic resonance imaging and noncognitive symp-toms. Ann. N. Y. Acad. Sci. 903, 482–489.
kiishi, C.G., Paradiso, S., Robinson, R.G., 2001. Gender differences in depres-sion associated with neurologic illness: clinical correlates and pharmacologicalresponse. J. Gender Specific Med. 4, 65–72.
anza, F., D’Introno, A., Colacicco, A.M., Capurso, C., Del Parigi, A., Capurso, S.A.,Caselli, R.J., Pilotto, A., Scafato, E., Capurso, A., Solfrizzi, V., 2005. Cognitive frailty:predementia syndrome and vascular risk factors. Neurobiol. Aging 27, 933–940.
anza, F., Frisardi, V., Capurso, C., D’Introno, A., Colacicco, A.M., Imbimbo, B.P., San-tamato, A., Vendemiale, G., Seripa, D., Pilotto, A., Capurso, A., Solfrizzi, V., 2010.Late-life depression, mild cognitive impairment, and dementia: possible con-tinuum? Am. J. Geriatr. Psychiatry 18, 98–116.
ersico, A.M., D’Agruma, L., Zelante, L., Militerni, R., Bravaccio, C., Schneider, C.,Melmed, R., Trillo, S., Montecchi, F., Elia, M., Palermo, M., Rabinowitz, D., Pascucci,T., Puglisi-Allegra, S., Reichelt, K.L., Muscarella, L., Guarnieri, V., Melgari, J.M.,Conciatori, M., Keller, F., 2004. Enhanced APOE2 transmission rates in familieswith autistic probands. Psychiatr. Genet. 14, 73–82.
oirier, J., Delisle, M.C., Quirion, R., Aubert, I., Farlow, M., Lahiri, D., Hui, S., Bertrand,P., Nalbantoglu, J., Gilfix, B.M., Gauthier, S., 1995. Apolipoprotein E4 allele as apredictor of cholinergic deficits and treatment outcome in Alzheimer’s disease.Proc. Natl. Acad. Sci. U.S.A. 92, 12260–12264.
orter, V.R., Buxton, W.G., Fairbanks, L.A., Strickland, T., O’Connor, S.M., Rosenberg-Thompson, S., Cummings, J.L., 2003. Frequency and characteristics of anxietyamong patients with Alzheimer’s disease and related dementias. J. Neuropsy-chiatry Clin. Neurosci. 15, 180–186.
otter, G.G., Steffens, D.C., 2007. Contribution of depression to cognitive impairmentand dementia in older adults. Neurologist 13, 105–117.
ritchard, A.L., Harris, J., Pritchard, C.W., Coates, J., Haque, S., Holder, R., Bentham, P.,Lendon, C.L., 2007. The effect of the apolipoprotein E gene polymorphisms andhaplotypes on behavioural and psychological symptoms in probable Alzheimer’sdisease. J. Neurol. Neurosurg. Psychiatry 78, 123–126.
aber, J., 2007. Role of apolipoprotein E in anxiety. Neural. Plast. 2007, 91236.amachandran, G., Marder, K., Tang, M., Schofield, P.W., Chun, M.R., Devanand,
D.P., Stern, Y., Mayeux, R., 1996. A preliminary study of apolipoprotein Egenotype and psychiatric manifestations of Alzheimer’s disease. Neurology 47,256–259.
egier, D.A., Boyd, J.H., Burke Jr., J.D., Rae, D.S., Myers, J.K., Kramer, M., Robins, L.N.,George, L.K., Karno, M., Locke, B.Z., 1988. One-month prevalence of mental dis-orders in the United States. Based on five epidemiologic catchment area sites.Arch. Gen. Psychiatry 45, 977–986.
eiman, E.M., Webster, J.A., Myers, A.J., Hardy, J., Dunckley, T., Zismann, V.L.,Joshipura, K.D., Pearson, J.V., Hu-Lince, D., Huentelman, M.J., Craig, D.W., Coon,K.D., Liang, W.S., Herbert, R.H., Beach, T., Rohrer, K.C., Zhao, A.S., Leung, D., Bry-den, L., Marlowe, L., Kaleem, M., Mastroeni, D., Grover, A., Heward, C.B., Ravid,R., Rogers, J., Hutton, M.L., Melquist, S., Petersen, R.C., Alexander, G.E., Caselli,R.J., Kukull, W., Papassotiropoulos, A., Stephan, D.A., 2007. GAB2 alleles modifyAlzheimer’s risk in APOE epsilon4 carriers. Neuron 54, 713–720.
einikainen, K.J., Soininen, H., Reikkinen, P.J., 1990. Neurotransmitter changes inAlzheimer’s dementia and agitation. J. Neurosci. Res. 27, 576–586.
eisberg, B., Auer, S.R., Monteiro, I.M., 1996. Behavioral pathology in Alzheimer’sDisease (BEHAVE-AD) Rating Scale. Int. Psychogeriatr. 8 (Suppl. 3), 301–308.
eitz, C., Mayeux, R., 2009. Endophenotypes in normal brain morphology andAlzheimer’s disease: a review. Neuroscience 164, 174–190.
igaud, A.S., Traykov, L., Caputo, L., Coste, J., Latour, F., Couderc, R., Moulin, F., Boller,F., Forette, F., 2001. Association of the apolipoprotein E 4 allele with late-onsetdepression. Neuroepidemiology 20, 268–272.
obertson, J., Curley, J., Kaye, J., Quinn, J., Pfankuch, T., Raber, J., 2005. APOE isoformsand measures of anxiety in probable AD patients and apoe −/− mice. Neurobiol.Aging 26, 637–643.
occa, W.A., Cha, R.H., Waring, S.C., Kokmen, E., 1998. Incidence of dementia andAlzheimer’s disease: a reanalysis of data from Rochester, Minnesota, 1975–1984.Am. J. Epidemiol. 148, 51–62.
opacki, S.A., Jeste, D.V., 2005. Epidemiology of and risk factors for psychosis ofAlzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am. J.Psychiatr. 162, 160–171.
aunders, A.M., Strittmatter, W.J., Schmechel, D., George-Hyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper-MacLachlan, D.R., Alberts,M.J., 1993. Association of apolipoprotein E allele epsilon 4 with late-onset famil-
ial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472.awada, H., Udaka, F., Izumi, Y., Nishinaka, K., Kawakami, H., Nakamura, S.,Kameyama, M., 2000. Cerebral white matter lesions are not associated withapoE genotype but with age and female sex in Alzheimer’s disease. J. Neurol.Neurosurg. Psychiatry 68, 653–656.
eviews 11 (2012) 87– 103
Scarmeas, N., Brandt, J., Albert, M., Devanand, D.P., Marder, K., Bell, K., Ciappa,A., Tycko, B., Stern, Y., 2002. Association between the APOE genotype andpsychopathologic symptoms in Alzheimer’s disease. Neurology 58, 1182–1188.
Schmechel, D.E., Saunders, A.M., Strittmatter, W.J., Crain, B.J., Hulette, C.M., Joo,S.H., Pericak-Vance, M.A., Goldgaber, D., Roses, A.D., 1993. Increased amyloid �-peptide deposition as a consequence of apolipoprotein E genotype in late-onsetAlzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 90, 9649–9653.
Seignourel, P.J., Kunik, M.E., Snow, L., Wilson, N., Stanley, M., 2008. Anxiety in demen-tia: a critical review. Clin. Psychol. Rev. 28, 1071–1082.
Seripa, D., Matera, M.G., Daniele, A., Bizzarro, A., Rinaldi, M., Gravina, C., Bisceglia,L., Corbo, R.M., Panza, F., Solfrizzi, V., Fazio, V.M., Forno, G.D., Masullo, C., Dal-lapiccola, B., Pilotto, A., 2007. The missing ApoE allele. Ann. Hum. Genet. 71,496–500.
Seripa, D., Panza, F., Franceschi, M., D’Onofrio, G., Solfrizzi, V., Dallapiccola, B.,Pilotto, A., 2009. Non-apolipoprotein E and apolipoprotein E genetics of sporadicAlzheimer’s disease. Ageing Res. Rev. 8, 214–236.
Seripa, D., D’Onofrio, G., Panza, F., Cascavilla, L., Masullo, C., Pilotto, A., 2011. Thegenetics of the human APOE polymorphism. Rejuvenation Res., in press.
Seshadri, S., Fitzpatrick, A.L., Ikram, M.A., DeStefano, A.L., Gudnason, V., Boada, M.,Bis, J.C., Smith, A.V., Carassquillo, M.M., Lambert, J.C., Harold, D., Schrijvers, E.M.,Ramirez-Lorca, R., Debette, S., Longstreth Jr., W.T., Janssens, A.C., Pankratz, V.S.,Dartigues, J.F., Hollingworth, P., Aspelund, T., Hernandez, I., Beiser, A., Kuller, L.H.,Koudstaal, P.J., Dickson, D.W., Tzourio, C., Abraham, R., Antunez, C., Du, Y., Rotter,J.I., Aulchenko, Y.S., Harris, T.B., Petersen, R.C., Berr, C., Owen, M.J., Lopez-Arrieta,J., Varadarajan, B.N., Becker, J.T., Rivadeneira, F., Nalls, M.A., Graff-Radford, N.R.,Campion, D., Auerbach, S., Rice, K., Hofman, A., Jonsson, P.V., Schmidt, H., Lathrop,M., Mosley, T.H., Au, R., Psaty, B.M., Uitterlinden, A.G., Farrer, L.A., Lumley, T.,Ruiz, A., Williams, J., Amouyel, P., Younkin, S.G., Wolf, P.A., Launer, L.J., Lopez,O.L., van Duijn, C.M., Breteler, M.M., CHARGE Consortium, GERAD1 Consortium,EADI1 Consortium, 2010. Genome-wide analysis of genetic loci associated withAlzheimer disease. JAMA 303, 1832–1840.
Shinosaki, K., Nishikawa, T., Takeda, M., 2000. Neurobiological basis of behavioraland psychological symptoms in dementia of the Alzheimer type. Psychiatry Clin.Neurosci. 54, 611–620.
Siegel, J.A., Haley, G.E., Raber, J., 2010. Apolipoprotein E isoform-dependenteffects on anxiety and cognition in female TR mice. Neurobiol. Aging, 2010,doi:10.1016/j.neurobiolaging.2010.03.002.
Smith, G.E., Bohac, D.L., Waring, S.C., Kokmen, E., Tangalos, E.G., Ivnik, R.J., Petersen,R.C., 1998. Apolipoprotein E genotype influences cognitive ‘phenotype’ inpatients with Alzheimer’s disease but not in healthy control subjects. Neurology50, 355–362.
Soininen, H., Kosunen, O., Helisalmi, S., Mannermaa, A., Paljärvi, L., Talasniemi, S.,Ryynänen, M., Riekkinen Sr., P., 1995. A severe loss of choline acetyltransferasein the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon 4allele. Neurosci. Lett. 187, 79–82.
Solfrizzi, V., Capurso, C., D’Introno, A., Colacicco, A.M., Santamato, A., Ranieri, M.,Fiore, P., Capurso, A., Panza, F., 2008. Lifestyle-related factors in predementiaand dementia syndromes. Expert Rev. Neurother. 8, 133–158.
Spalletta, G., Bernardini, S., Bellincampi, L., Federici, G., Trequattrini, A., Calta-girone, C., 2006. Delusion symptoms are associated with APOE �4 allelic variantat the early stage of Alzheimer’s disease with late onset. Eur. J. Neurol. 13,176–182.
Srikanth, S., Nagaraja, A.V., Ratnavalli, E., 2005. Neuropsychiatric symptoms indementia-frequency, relationship to dementia severity and comparison inAlzheimer’s disease, vascular dementia and frontotemporal dementia. J. Neurol.Sci. 236, 43–48.
Starkstein, S.E., Vázquez, S., Petracca, G., Sabe, L., Migliorelli, R., Tesón, A., Leiguarda,R., 1994. A SPECT study of delusions in Alzheimer’s disease. Neurology 44,2055–2059.
Starkstein, S.E., Sabe, L., Vazquez, S., Teson, A., Petracca, G., Chemerinski, E., DiLorenzo, G., Leiguarda, R., 1996. Neuropsychological, psychiatric, and cerebralblood flow findings in vascular dementia and Alzheimer’s disease. Stroke 27,408–414.
Starkstein, S.E., Petracca, G., Chemerinski, E., Kremer, J., 2001. Syndromic validity ofapathy in Alzheimer’s disease. Am. J. Psychiatry 158, 872–877.
Starkstein, S.E., Jorge, R., Petracca, G., Robinson, R.G., 2007. The construct of gen-eralized anxiety disorder in Alzheimer disease. Am. J. Geriatr. Psychiatry 15,42–49.
Steele, C., Rovner, B., Chase, G.A., Folstein, M., 1990. Psychiatric symptoms and nurs-ing home placement of patients with Alzheimer’s disease. Am. J. Psychiatry 147,1049–1051.
Steffens, D.C., Plassman, B.L., Helms, M.J., Welsh-Bohmer, K.A., Saunders, A.M.,Breithner, J.C., 1997. A twin study of late-onset depression and apolipopro-tein E epsilon 4 as risk factors for Alzheimer’s disease. Biol. Psychiatry 41,851–856.
Sultzer, D.L., Levin, H.S., Mahler, M.E., High, W.M., Cummings, J.L., 1993. A compari-son of psychiatric symptoms in vascular dementia and Alzheimer’s disease. Am.J. Psychiatry 150, 1806–1812.
Swearer, J.M., Drachman, D.A., O’Donnell, B.F., Mitchell, A.L., 1988. Troublesome anddisruptive behaviors in dementia: relationship to diagnosis and disease severity.
J. Am. Geriatr. Soc. 36, 784–790.Sweet, R.A., Hamilton, R.L., Lopez, O.L., Klunk, W.E., Wisniewski, S.R., Kaufer, D.I.,Healy, M.T., DeKosky, S.T., 2000. Psychotic symptoms in Alzheimer’s disease arenot associated with more severe neuropathologic features. Int. Psychogeriatr.12, 547–558.
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F. Panza et al. / Ageing Rese
weet, R.A., Nimgaonkar, V.L., Devlin, B., Lopez, O.L., DeKosky, S.T., 2002a. Increasedfamilial risk of the psychotic phenotype of Alzheimer disease. Neurology 58,907–911.
weet, R.A., Kamboh, M.I., Wisniewski, S.R., Lopez, O.L., Klunk, W.E., Kaufer, D.I.,DeKosky, S.T., 2002b. Apolipoprotein E and alpha-1-antichymotrypsin geno-types do not predict time to psychosis in Alzheimer’s disease. J. Geriatr.Psychiatry Neurol. 15, 24–30.
weet, R.A., Nimgaonkar, V.L., Devlin, B., Jeste, D.V., 2003. Psychotic symptomsin Alzheimer disease: evidence for a distinct phenotype. Mol. Psychiatry 8,383–392.
ekin, S., Mega, M.S., Masterman, D.M., Chow, T., Garakian, J., Vinters, H.V., Cum-mings, J.L., 2001. Orbitofrontal and anterior cingulate cortex neurofibrillarytangle burden is associated with agitation in Alzheimer disease. Ann. Neurol.49, 355–361.
reiber, K.A., Lyketsos, C.G., Corcoran, C., Steinberg, M., Norton, M., Green, R.C.,Rabins, P., Stein, D.M., Welsh-Bohmer, K.A., Breitner, J.C., Tschanz, J.T., 2008.Vascular factors and risk for neuropsychiatric symptoms in Alzheimer’s disease:the Cache County Study. Int. Psychogeriatr. 20, 538–553.
an Dyck, C.H., Gelernter, J., MacAvoy, M.G., Avery, R.A., Criden, M., Okereke, O.,Varma, P., Seibyl, J.P., Hoffer, P.B., 1998. The absence of an apolipoprotein Ee4 allele is associated with increased parietal rCBF asymmetry in Alzheimer’s
disease. Arch. Neurol. 55, 1460–1466.an der Flier, W.M., Staekenborg, S., Pijnenburg, Y.A., Gillissen, F., Romkes, R., Kok,A., Bouwman, F.H., Scheltens, P., 2007. Apolipoprotein E genotype influencespresence and severity of delusions and aggressive behavior in Alzheimer disease.Dement. Geriatr. Cogn. Disord. 23, 42–46.
eviews 11 (2012) 87– 103 103
Weiner, M.F., Vega, G., Risser, R.C., Honig, L.S., Cullum, C.M., Crumpacker, D., Rosen-berg, R.N., 1999. Apolipoprotein E epsilon 4, other risk factors, and course ofAlzheimer’s disease. Biol. Psychiatry 45, 633–638.
Wilson, R.S., Barnes, L.L., Mendes de Leon, C.F., Aggarwal, N.T., Schneider, J.S., Bach,J., Pilat, J., Beckett, L.A., Arnold, S.E., Evans, D.A., Bennett, D.A., 2002. Depres-sive symptoms, cognitive decline and risk of AD in older persons. Neurology 59,364–370.
Wolitzky-Taylor, K.B., Castriotta, N., Lenze, E.J., Stanley, M.A., Craske, M.G., 2010.Anxiety disorders in older adults: a comprehensive review. Depress. Anxiety27, 190–211.
Woods, D.L., Bushnell, B., Kim, H., Geschwind, D., Cummings, J., 2009. Apolipopro-tein epsilon4 status is associated with behavioral symptoms in nursing homeresidents with dementia. Int. Psychogeriatr. 21 (Suppl. 4), 722–728.
Wragg, R.E., Jeste, D.V., 1989. Overview of depression and psychosis in Alzheimer’sdisease. Am. J. Psychiatry 146, 577–589.
Yamaguchi, H., Sugihara, S., Ogawa, A., Oshima, N., Ihara, Y., 2001. Alzheimer betaamyloid deposition enhanced by apoE epsilon4 gene precedes neurofibrillarypathology in the frontal association cortex of nondemented senior subjects. J.Neuropathol. Exp. Neurol. 60, 731–739.
Zdanys, K.F., Kleiman, T.G., MacAvoy, M.G., Black, B.T., Rightmer, T.E., Grey, M.,Garman, K.S., Tampi, R.R., Gelernter, J., van Dyck, C.H., 2007. Apolipoprotein E
epsilon4 allele increases risk for psychotic symptoms in Alzheimer’s disease.Neuropsychopharmacology 32, 171–179.Zubenko, G.S., Moossy, J., Martinez, A.J., Rao, G., Claassen, D., Rosen, J., Kopp, U.,1991. Neuropathologic and neurochemical correlates of psychosis in primarydementia. Arch. Neurol. 48, 619–624.