preventing and treating alzheimer’s disease: strategies and prospects

5
Editorial David A Drachman, MD Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA [email protected] © Future Drugs Ltd. All rights reserved. ISSN 1473-7175 565 Preventing and treating Alzheimer’s disease: strategies and prospects ‘Despite the many thousands of studies of AD, only a few of the observations have provided clinically meaningful handholds which have advanced our grasp of AD sufficiently to contribute to its prevention and/or treatment.’ Expert Rev. Neurotherapeutics 3(5), 565–569 (2003) In 1976, the scientific enterprise for finding the cause and cure for Alzheimer’s disease (AD) was first seriously engaged following an influential editorial in Archives of Neurology by Robert Katzman [1]. Katzman argued persua- sively that AD and senile dementia were the same disease due to the similarity of clinical manifestations and identical pathological brain changes. With the stroke of a pen, AD began a transition from an obscure cause of early-onset dementia to one of the most widely prevalent and feared diseases of humankind the fourth major killer in the developed world. During the next dec- ade, AD was inten- tionally reified from a common concomitant of age to a named and terrifying illness, due to the efforts of a group of physicians, scien- tists and laymen [2]. As it was now an identi- fied disease, the scientific community began a crescendo effort to understand the cause and develop a means of preventing or treating AD [3]. A mere 98 medical or scientific articles on AD had been published between 1965 and 1976, when Katzman’s seminal editorial appeared. By mid-2003 more than 31,500 additional articles have been published in the scientific literature, with the number growing daily. The dual goals of identifying the precise etiology of AD and developing effective pre- vention and/or treatment have remained elu- sive despite this effort but considerable progress has been made. How far have we come and where are we headed? In the early 1970s, AD was largely a descrip- tive entity – an imperfectly defined and little- recognized clinical condition, with an estab- lished post mortem constellation of senile plaques and neurofibrillary tangles. The clini- cal picture was poorly codified, epidemiology and genetics uncer- tain, neurotransmit- ter and biochemical changes unknown, focal and widespread losses of neurons and synapses unrevealed, and no treatment with even a minimal degree of efficacy had been developed. No specific social support for patients and their families existed; and grants for scientific investigation were sparse. Pros- pects for a medical conquest of the disorder appeared poor to nonexistent. To develop a means of prevention, cure or treatment for this cryptic degenerative disease, three approaches could bear fruit: finding its underlying etiology(ies); examining the mech- anism(s) by which the disorder causes degener- ation in the brain; or making serendipitous or epidemiologic observations of what might The dual goals of identifying the precise etiology of AD and developing effective prevention and/or treatment have remained elusive despite this effort but considerable progress has been made. For reprint orders, please contact [email protected]

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Editorial

David A Drachman, MDDepartment of Neurology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655, USA [email protected]

© Future Drugs Ltd. All rights reserved. ISSN 1473-7175 565

Preventing and treating Alzheimer’s disease: strategies and prospects‘Despite the many thousands of studies of AD, onlya few of the observations have provided clinically meaningful handholds which have advanced our grasp of AD sufficiently to contribute to its prevention and/or treatment.’Expert Rev. Neurotherapeutics 3(5), 565–569 (2003)

In 1976, the scientific enterprise for findingthe cause and cure for Alzheimer’s disease(AD) was first seriously engaged following aninfluential editorial in Archives of Neurology byRobert Katzman [1]. Katzman argued persua-sively that AD and senile dementia were thesame disease due to the similarity of clinicalmanifestations and identical pathological brainchanges. With the stroke of a pen, AD began atransition from an obscure cause of early-onsetdementia to one of the most widely prevalentand feared diseases ofhumankind – thefourth major killer inthe developed world.During the next dec-ade, AD was inten-tionally reified from acommon concomitantof age to a named andterrifying illness, dueto the efforts of a group of physicians, scien-tists and laymen [2]. As it was now an identi-fied disease, the scientific community began acrescendo effort to understand the cause anddevelop a means of preventing or treating AD[3]. A mere 98 medical or scientific articles onAD had been published between 1965 and1976, when Katzman’s seminal editorialappeared. By mid-2003 more than 31,500additional articles have been published in thescientific literature, with the number growingdaily. The dual goals of identifying the precise

etiology of AD and developing effective pre-vention and/or treatment have remained elu-sive despite this effort but considerableprogress has been made. How far have wecome and where are we headed?

In the early 1970s, AD was largely a descrip-tive entity – an imperfectly defined and little-recognized clinical condition, with an estab-lished post mortem constellation of senileplaques and neurofibrillary tangles. The clini-cal picture was poorly codified, epidemiology

and genetics uncer-tain, neurotransmit-ter and biochemicalchanges unknown,focal and widespreadlosses of neurons andsynapses unrevealed,and no treatmentwith even a minimaldegree of efficacy had

been developed. No specific social support forpatients and their families existed; and grantsfor scientific investigation were sparse. Pros-pects for a medical conquest of the disorderappeared poor to nonexistent.

To develop a means of prevention, cure ortreatment for this cryptic degenerative disease,three approaches could bear fruit: finding itsunderlying etiology(ies); examining the mech-anism(s) by which the disorder causes degener-ation in the brain; or making serendipitous orepidemiologic observations of what might

‘The dual goals of identifying the precise etiology of AD and

developing effective prevention and/or treatment have

remained elusive despite this effort but considerable progress

has been made.’

For reprint orders, please contact [email protected]

Drachman

566 Expert Rev. Neurotherapeutics 3(5), (2003)

increase or decrease the occurrence of AD. Despite the manythousands of studies of AD, only a few of the observations haveprovided clinically meaningful handholds which have advancedour grasp of AD sufficiently to contribute to its preventionand/or treatment (BOX 1).

These advances and others derived from them, have resultedin five major strategies for the treatment and prevention of AD:

• Increase of cholinergic function

• Alteration of amyloid formation

• Genetic modifications

• Lipid-altering strategies

• Methods of altering age-related changes

Each of these strategies derives from a concept of the etiologyof AD; the mechanism by which it produces the neuropathologicand cognitive changes; or serendipitous and/or epidemiologicassociations between AD or its absence and other factors.

Cholinergic strategyThe cholinergic strategy was conceptually similar to the use oflevodopa for the treatment of Parkinson’s disease (i.e., derivedfrom the idea that relatively specific loss of structure or func-tion in a neurotransmitter system may be the mechanism caus-ing the clinical neurologic deficits) [4]. Disorders of the cholin-ergic system were related to cognitive impairment in aging and

dementia when it was observed that cholinergic blockade pro-duced by the parental administration of scopolamine to normalyoung subjects produced cognitive deficits similar to those seenin elderly and demented individuals [5]. Subsequent biochemi-cal studies revealed that choline acetyl transferase, the rate-lim-iting enzyme for the synthesis of acetylcholine in the brain, wasdecreased in AD; and that this was due to the loss of the cells oforigin of cholinergic fibers in the substantia innominata [6–10].Although initial studies with cholinergic agonists, anti-cholinesterases and precursors were unimpressive, an article bySummers describing dramatic improvements in patients withAD treated with tacrine (Cognex®, Warner-Lambert, Canada),led to further studies [11]. Large-scale, multicenter, double-blindparallel-group clinical trials demonstrated a small but statisti-cally significant benefit with improvement of cognitive func-tions [12]. While tacrine is no longer in general use, three othercentrally active anticholinesterase medications (donepezil [Ari-cept®, Eisai Co. Ltd, Tokyo, Japan], galantamine [Reminyl®,Janssen Pharmaceuticals, NJ, USA] and rivastigmine [Exelon®,Novartis Pharmaceuticals Corp., NJ, USA]) are the only drugscurrently approved in the USA for the treatment of AD. Sincecognitive impairment in AD is due to considerably more exten-sive loss of neurons than just the cholinergic system, however,this therapeutic strategy has been of limited benefit [13].

Amyloid approachThe presence of amyloid in senile plaques and in cerebral bloodvessels (amyloid angiopathy), has long been pathologically rec-ognized. In 1984, Glenner and Wong first sequenced thedeposits, showing them to be β-pleated sheets of amyloid (Aβ)[14]. Amyloid deposits were shown to be derived from the deg-radation of the amyloid precursor protein (APP) – a transmem-brane protein of variable length and unknown function, codedon chromosome 21. The association of neuropathologicchanges of AD in patients with Down’s syndrome (trisomy 21)and in patients with the early-onset, dominantly inherited(EODI) forms of familial AD has suggested an etiologic rela-tionship between Aβ and AD. Despite extensive studies thathave been performed to determine the precise relationshipbetween amyloid deposits in the brain and the neuronal andcognitive deficits seen in AD, however, no direct causal rela-tionship has been established. The accumulation of senileplaques and considerable burdens of amyloid occur in cogni-tively normal elderly individual. In patients with AD, thedegree of dementia does not correlate with the number ofplaques. Various theories have suggested that circulating amy-loid, vascular amyloid, fibrillar deposits of amyloid and morerecently, soluble oligomeric species of amyloid, may be reponsi-ble for the cognitive impairment and neural degeneration inAD [15,16].

Despite these uncertainties regarding the potential etiologicrelationship of Aβ to AD, there has been much work attempt-ing to interrupt the enzymatic degradation of APP by which Aβis produced, or to remove the Aβ deposits by other means. Themost active studies target two strategies for the reduction of

Box 1. Major advances in Alzheimer's disease.

Alois Alzheimer's identification of neurofibrillary tangles

Editorial linking AD and senile dementia

EM recognition of paired helical filaments

Cholinergic deficits in brain

Sequencing of ß-amyloid in plaque cores

NINDS-ADRDA criteria for AD

Phosphorylated tau chemistry of NFTs

Age-related changes

APOEε4 risk factor for AD

Recognition of neuronal losses in hippocampus, ERC

Recognition of synaptic losses in dentate gyrus, cortex

Familial AD – dominant APP mutation

Familial AD – Presenilins

Development of transgenic mouse model

Experimental study of amyloid vaccine

Epidemiologic studies of statins; lipids

AD: Alzheimer’s disease; ADRDA: Alzheimer Disease and Related Disorders Association; APOE: Apolipoprotein; APP: β-amyloid precurser protein;EM: Electron microscope; ERC: Entorhinal cortex; NFT: Neurofibrillary tangle; NINDS: National Institute of Neurological Diseases and Stroke.

Preventing and treating AD

www.future-drugs.com 567

amyloid. The first employs interference with the β- and γ-secre-tase enzymes, which cleave the APP molecule to release the Aβfragment [17]. The second utilizes active or passive immuniza-tion against Aβ, which is presumed to help remove the amyloidfrom the brain by a sink mechanism [18].

The role of Aβ in causation of AD is still unclear. If the pro-duction or accumulation of amyloid is the primary factor inproducing AD, it could then be viewed as a specific metabolicdisorder. Alternatively, Aβ may be a secondary factor, resultingfrom a different initial insult but acting as a harmful elementin a cascade of degenerative biochemical events. Finally, it maybe a highly visible marker of other etiologic processes and oflesser importance.

It is likely that abnormalities of APP processing or Aβ metab-olism are the primary disorders in the EODI Familial forms ofAD. Several observations raise questions over the precise role ofAβ itself in the causation of AD. In the transgenic mice carryingboth APP and Presenilin mutations responsible for Familial AD(FAD), there is little or no loss of neurons, despite a heavy accu-mulation of Aβ. As noted, the burden of Aβ and plaques corre-lates poorly with the extent of dementia in elderly humans.Recently, studies have reported that in tissue culture, neuronsrequire Aβ and die in the absence of Aβ1–40, when β- or γ-secre-tase are inhibited, or antibodies to Aβ introduced; while Aβ1–42is less effective in supporting neuronal survival [19].

Genetic modificationsA number of genetic abnormalities have been clearly associatedwith AD. The first of these was Down’s syndrome, where theunderlying 21-trisomy was associated with consistent patho-logic changes typical of AD, usually by the age of 35, althoughfewer than half of the patients withthis pathology had progressive cog-nitive decline indicating a dement-ing process [20,21]. Subsequently,Goate and colleagues demonstratedthat a few rare families with muta-tions in the APP gene on chromosome 21 had an early-onset,dominantly inherited form of familial AD [22]. In 1992, Hyslopand colleagues demonstrated that mutations in the Presenilin-1gene on chromosome 14 were the most common cause ofEODI FAD; and later studies showed a similar abnormality onchromosome 1, involving the similar Presenilin-2 gene [23].While in total, the APP and Presenilin gene mutations accountfor 5–10% of all AD, these mutations have pointed to theimportance of abnormalities of Aβ metabolism in producingthe pathology of AD. APP is the precursor protein from whichAβ arises and the Presenilins have been shown to be importantcomponents of the γ-secretase enzyme involved in the finalcleavage of the precursor of Aβ.

In 1993, Roses and colleagues found that the ε4 allele ofapolipoprotein (APOEε4) was associated with a significantincrease in the occurrence of late-onset sporadic AD [24]. Themechanism by which this increases the risk of developing AD,or accelerates its onset, is presently unknown.

To date, no methods of genetic alteration to reduce the riskof AD in either the EODI FAD or APOEε4-induced formincreased risk of AD have been attempted. Genetic analysis hasbeen selectively used in EODI FAD to confirm the presence orabsence of the known genetic abnormalities involving thepresenilin or APP mutations, however, approximately one-thirdof families do not have any of the known dominantly-inheritedmutations. APOEε4 analysis has been of little diagnostic use,since many individuals with the allele are not affected with ADand many without, are affected [25].

The major use of these mutations has, so far, been the pro-duction of transgenic mice to serve as models of the domi-nantly-inherited form of AD [26]. While transgenic mice withone or more of the EODI mutations develop neuropathologicalchanges similar to AD, with amyloid-containing neuriticplaques, they do not develop neurofibrillary tangles, neuronalloss, or in many studies, any impairment of behavior [27]. Thus,the transgenic mouse model has been of potential use todevelop treatments that reduce the amyloid burden in EODIFAD; the validity of this model for sporadic AD is uncertain.

Lipid-altering strategiesA number of clues have pointed to the potential role of lipids,or lipid metabolism, in the pathogenesis of AD. In 1990,Sparks and colleagues discovered that AD was more prevalentin patients with cardiovascular disease [28]. The observation byRoses and colleagues of the relationship between APOEε4 andlate-onset sporadic AD suggested another link, although themechanism was unclear [29]. In 2000, two observational studieswere published showing that patients who received statins (3-Hydroxy-3-Methylglutaryl-CoA reductase inhibitors) were

almost 70% less likely to developAD or dementia than control sub-jects [30,31]. Subsequently, anumber of other epidemiologicalstudies have supported these find-ings, although clinical trials remain

to be performed [32]. Experimental studies have shown that intissue culture and transgenic animals, lowering cholesterol andadministering statins reduce the production of Aβ [33,34].

It is not clear as yet whether lipid metabolism is directly relatedto the development of AD; whether statins are protective and/ortherapeutic for AD; and if so, what the mechanism may be. Ofinterest is that statins reduced the risk of AD in comparison withother subjects who had normal lipid levels, and the use of nonsta-tin lipid-lowering agents did not have a similar effect [30]. It seemslikely that the putative effect of statins may have been unrelatedto the lipid-lowering properties and instead related to their othereffects via inhibition of the mevalonate pathway – the increase inendothelial nitrous oxide synthase, reduction in endothelin-1,anti-inflammatory or neuroprotective effects.

Altering age-related changesWhile amyloid accumulation, the formation of neurofibrillarytangles, genetic mutations, APOE alleles, lipid abnormalities

‘It is likely that AD is more than one disease – due to multiple etiologies, with similar clinical and pathological

final common pathways.’

Drachman

568 Expert Rev. Neurotherapeutics 3(5), (2003)

and a host of other changes (BOX 2) have been associated withAD, it is clear that the most important risk factor for thedevelopment of AD is age. The risk of developing AD at 85 isapproximately 30-fold greater than at the age of 60; and afterthe age of 60, the risk doubles every 5 years [35]. Among theage-related changes (ARCs) that may play a role in the occur-rence of AD are: the accumulation of free oxygen radicals;conformational changes in proteins; loss of energy productionin mitochondria; impairment of the chaperone functions;accumulation of errors in DNA replication; decreased cellulardivision due to loss of telomeres; accumulation of advancedglycation end products; cross-linking of proteins; lack of nervegrowth factors; hormonal declines; vascular impairment;deregulation of apoptosis; and many more [36].

Imposing as this list of ARCs may be, it is likely that one, or afew, of these changes are key factors in the initiation of AD. Thedecrease of mitochondrial energy production, for example, islinked with many of the other ARCs; and decline in the integ-rity of brain microvascular endothelial function may also beresponsible for a cascade of subsequent degenerative events[37–39]. Careful identification of the locus minoris resistentiae mayyield a strategy capable of delaying or avoiding the developmentof the changes resulting in AD.

ConclusionsIn 2003, more than 20 years after the beginning of the mod-ern era of research on AD, the only accepted treatments in theUSA are presently the anticholinesterases. These drugs –derived from serendipitous observations a quarter of a centuryago on the relation of cholinergic blockade to the cognitiveeffects of aging and dementia – merely marginally reduce thedisease manifestations without altering its course or affectingits etiology.

It is likely that AD is more than one disease – due to multi-ple etiologies, with similar clinical and pathological final com-mon pathways. Age is the most important risk factor for AD;and the array of ARCs are most likely the triggers that initiatea cascade of events resulting in neuronal and synaptic loss,dementia and the hallmark pathologic changes. Yet, despitethe fact that we cannot prevent the “flight of the arrow oftime,” and avoid the risk of ARCs, it is also likely that one, ora very few, of the ARCs are the changes that initiate the cas-cade resulting in AD in the large majority of elderly individu-als. By discovering these critical initiating events, we will havethe opportunity to intervene in effective ways to prevent AD.Perhaps interrupting the production or accumulation of Aβwill result in preventing or slowing the course of AD. Alterna-tively, an earlier or later process causing the loss of function-ing neurons and their connections must be modified. Regard-less, the scientific basis for understanding the etiology of ADand preventing its occurrence is far closer than it was a fewdecades ago.

Box 2. Observations associated withAlzheimer's disease.

Monoamine oxidase A (↑ ) and B (↓ )

Insulin degrading enzyme polymorphisms

LDL receptor polymorphisms

Activated brain complement

Neocortical metal ion abnormalities (Zn, Cu, Fe)

Increased matrix metalloproteinase-9

Androgen receptor CAG repeat polymorphisms

Humoral immune reaction to Ab

Free oxygen radicals

Down-regulation of neprilysin

Proapoptotic mechanisms

TGF-β-1 effect on amyloid

Breakdown of blood–brain barrier

LDL: Low-density lipoprotein; TGF: Tumor growth factor.

References

1 Katzman R. The prevalence and malignancy of Alzheimer’s disease. Arch. Neurol. 33, 217 (1976).

2 Katzman R, Bick K. Alzheimer’s Disease: the Changing View. New York Academic Press, NY, USA (2000).

3 Pollen DA. Hannah’s Heirs: the Quest For the Genetic Origins of Alzheimer’s Disease. Oxford University Press, NY, USA (1993).

4 Bernheimer H, Hornykiewicz, O. Decreased homovanillic acid concentration in the brain in parkinsonian subjects as an expression of a disorder of central dopamine metabolism. Klin. Wochenschr. 43, 711–715 (1965).

5 Drachman D, Leavitt J. Human memory and the cholinergic system: a relationship to aging? Arch Neurol. 30,113–121 (1974).

6 Bowen DM, Smith CB, White P, Davison AN. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99(3),459–496 (1976).

7 White P, Hiley CR, Goodhardt MJ et al. Neocortical cholinergic neurons in elderly people. Lancet 1(8013), 668–671 (1977).

8 Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2(8000), 1403 (1976).

9 Davies P, Verth AH. Regional distribution of muscarinic acetylcholine receptor in normal and Alzheimer’s-type dementia brains. Brain Res. 138(2), 385–392 (1977).

10 Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer’s disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann. Neurol. 10(2), 122–126 (1981).

11 Summers WK, Viesselman JO, Marsh GM, Candelora K. Use of THA in treatment of Alzheimer-like dementia: pilot study in twelve patients. Biol. Psych. 16(2), 145–153 (1981).

Preventing and treating AD

www.future-drugs.com 569

12 Davis KL, Thal LJ, Gamzu ER et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. The Tacrine Collaborative Study Group. N. Engl. J. Med. 327(18), 1253–1259 (1992).

13 Francis PT, Palmer AM, Sims NR et al. Neurochemical studies of early-onset Alzheimer’s disease. Possible influence on treatment. N. Engl. J. Med. 313(1), 7–11 (1985).

14 Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Com. 120(3), 885–890 (1984).

15 Selkoe DJ. Toward a comprehensive theory for Alzheimer’s disease. Hypothesis: Alzheimer’s disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann. NY Acad. Sci. 924, 17–25 (2000).

16 Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 298(5594), 789–791 (2002).

17 Selkoe DJ, Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Ann. Rev. Pharmacol. Toxicol. 43, 545–584 (2003).

18 Schenk D, Seubert P, Ciccarelli RB. Immunotherapy with β-amyloid for Alzheimer’s disease: a new frontier. DNA Cell. Biol. 20(11), 679–681 (2001).

19 Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA. The production of amyloid β peptide is a critical requirement for the viability of central neurons. J. Neurosci. 23(13), 5531–5535 (2003).

20 Price DL, Whitehouse PJ, Struble RG et al. Alzheimer’s disease and Down’s syndrome. Ann. NY Acad. Sci. 396, 145–164 (1982).

21 Wisniewski HM, Rabe A. Discrepancy between Alzheimer-type neuropathology and dementia in persons with Down’s syndrome. Ann. NY Acad. Sci. 477, 247–260 (1986).

22 Goate A. Molecular genetics of Alzheimer’s disease. Geriatrics 52(Suppl. 2), S9–S12 (1997).

23 St George-Hyslop P, Haines J et al. Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14. Nature Gen. 2(4), 330–334 (1992).

24 Saunders A, Strittmatter W, Schmechel D et al. Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43, 1467–1472 (1993).

25 Mayeux R, Saunders A, Shea S et al. Utility of apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. N. Engl. J. Med. 338, (1998).

26 Duff K, Eckman C, Zehr C et al. Increased amyloid-β 42(43) in brains of mice expressing mutant presenilin 1. Nature 383(6602), 710–713 (1996).

27 Savonenko AV, Xu GM, Price DL, Borchelt DR, Markowska AL. Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE. Neurobiol. Dis. 12(3), 194–211 (2003).

28 Refolo LM, Pappolla MA, LaFrancois J et al. A cholesterol-lowering drug reduces β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 8(5), 890–899 (2001).

29 Seshadri S, Drachman D, Lippa C. Apolipoprotein E e4 allele and the lifetime risk of Alzheimer’s disease: what physicians know and what they should know. Arch. Neurol. 52, 1074–1080 (1995).

30 Drachman D. Aging and the brain: a new frontier. Ann. Neurol. 42, 819–828 (1997).

31 Beal M. Aging, energy and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38, 357–366 (1995).

32 Wei Y-H, Kao S-H, Lee H-C. Simultaneous increase of mitochondrial DNA delections and lipid peroxidation in human aging. In: Pharmacological Intervention in Aging and

Age-Associated Disorders. Kitani K, Aoba A, Goto S (Eds). New York Academy of Sciences, NY, USA, 24–43 (1996).

33 Buee L, Hof PR, Bouras C et al. Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathologica 87(5), 469–480 (1994).

34 Sparks DL, Hunsaker JC 3rd, Scheff SW, Kryscio RJ, Henson JL, Markesbery WR. Cortical senile plaques in coronary artery disease, aging and Alzheimer’s disease. Neurobiol. Aging 11(6), 601–607 (1990).

35 Strittmatter W, Saunders A, Schmechel D et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of Type 4 allele in late-onset familial Alzheimer’s disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).

36 Jick H, Zornberg G, Jick S, Seshadri S, Drachman D. Statins and the risk of dementia. Lancet 356, 1627–1631 (2000).

37 Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57(10), 1439–1443 (2000).

38 Rockwood K, Kirkland S, Hogan DB et al. Use of lipid-lowering agents, indication bias and the risk of dementia in community-dwelling elderly people. Arch. Neurol. 59(2), 223–227 (2002).

39 Fassbender K, Simons M, Bergmann C et al. Simvastatin strongly reduces levels of Alzheimer’s disease β-amyloid peptides Aβ 42 and Aβ 40 in vitro and in vivo. Proc. Natl Acad. Sci. USA 98(10), 5856–5861 (2001).

Affiliation• David A Drachman, MD, Professor and

Chairman Emeritus, Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655 USA, [email protected]