Age at Onset, Survival Duration,and Cognitive Performance inProbable Alzheinler's Disease

Asenath La Rue, Ph.D., Susan McPherson, Ph.D.Herb Robinson, Ph.D., Ruby Takushi, Ph.D.

Steven S. Matsuyama, Ph.D., Lissy F. Jarvik, M.D., Ph.D.

The relative importance ofage at onset, survival duration pasttesting, symptom duration, and education as predictors ofcognitivepeiformance was assessed in 50patients with moder­ately severe dementia ofthe Alzheimertype. Survivalpast testingand duration ofsymptoms prior to assessment emerged as thestrongest predictors of cognitive peiformance, and educationeffects were noted for several verbal tests. A robust associationemerged between cognitive impairment and nearness to death.This association, first noted in studies of "nannal" aging, re­quires further exploration. Age-at-onset effects, with poorerperformance in early-onset disease, were obseroed onlyfor a fewmeasures.

I n recent years, there has been renewedinterest in examining the role of age at

onset in the pathogenesis and clinical ex­pression of dementia of the Alzheimer type(DAT). However, studies that compare neu­ropsychological test performance in early­and late-onset DAT have produced conflict­ing results. Some studies have reportedmore severe cognitive deficits in early onsetthan in late-onset DAT,t~ but others havefound negligible differences.7

-11 Among

studies with significant outcomes, somehave found differences between onsetgroups in several areas of cognitive func-

tion,1.4,6 whereas others suggest a selectiveleft-hemisphere or language impairment inearly-onset disease.3,5

Limitations in design and analysis strat­egies may have contributed to these out­comes. Many studiesl -6 have treated age atonset as a categorical variable, separatingsamples into onset groups based on anarbitrary age (e.g., 65 years); typically, thishas been done without indication of bimo­dality in the age-at-onset distribution. Inaddition, although attempts have beenmade to control for severity of illness in thecomparison of age-at-onset groups, the

Received May 27 t 1992; revised January 6. 1993; accepted January II, 1993. From the Department of Psychiatry andBiobehavioral Sciences t Neuropsychiatric InsUtute, University of California, Los Angeles, and the West Los AngelesVA Medical Center, Brentwood, CA. Address reprint requests to Dr. McPherson, Department of Psychiatry andBiobehavioral Sciences. Neuropsychiatric Institute, UCLA, 760 Westwood Plaza, Los Angeles, CA 90024-1759.

Copyright © 1993 American Association for Geriatric Psychiatry

THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY 221

Age at Onset

measures used to index severity have beenlimited. Selecting groups with similar scoreson mental status exams2

,4 may obscure indi­vidual differences in premorbid abilities andwould tend to decrease the odds of observ­ing differences on neuropsychological tests.Equating groups on estimated duration ofillness is another common approach,2-5 al­though this overlooks the possibility of vari­ations in rates of decline.

Survival duration past testing (near­ness to death) has not been covaried orcontrolled in the research assessing age­at-onset effects on cognition. However, acase can be made that the time remainingto an individual with DAT may be a betterindicator of disease progression than timeelapsed. In normal aging, the phenome­non of "terminal decline" (Le., accelera­tion in the rate of cognitive decline in theyears near death) has been documented inseveral studies,12,13 and this relationship ap­pears to hold for patients with OAT aswell. 14-17

The aim of our investigation, whichfocused on patients with moderately severeDAT, was to examine the combined effectsof age at onset of illness, duration of symp­toms, and sUlVival duration past testing aspredictors of cognitive perfonnance, whilecontrolling for possible effects of educationand age at the time of testing.

MEmODS

Subjects

The sample consisted of 50 patientswith a clinical diagnosis of DAT who wereparticipating in the UCWWest Los AngelesVA Family Study of Dementia. Most wereenrolled by family members who re­sponded to descriptions of the project inlocal newspapers, but a few were recruitedfrom the clinical services of university-affil­iated hospitals. Informed consent was ob­tained from both patients and relatives.

Table 1 provides descriptive informa­tion about the sample as a whole (16 men,34 women), as well as the subsample of 31participants who were deceased at the timeof this report (14 men, 17 women). Age atonset of dementia spanned a relativelybroad range (49--84 years); for 16 subjectsor 32% of the sample, the illness reportedlybegan at or before age 60, whereas for 9subjects (18%), initial symptoms were notobserved until age 75 or older. An adequaterange of variation was also noted for educa­tion, duration of symptoms, and years ofsurvival past testing. There were no signifi­cant differences between deceased and liv­ing subjects on demographic variables,duration of symptoms, or performance on

TABLE 1. Characterisdcs of two groups of patients with DAT

Measure

Age at testingEducationAge at onsetDuration of symptoms

Age at testingEducationAge at onsetDuration of symptomsSUlVival past testing

Note: Values other than n are years.

334 women; 16 menbI7 women; 14 men

222

" Means±SD Range

Complete Samplea

50 71.8 ± 8.8 52-9147 12.2±3.9 3-2050 65.6±8.7 49-8450 6.2± 2.8 1-14

Deceased Subjectsb

31 72.0±7.2 59-9129 12.0 ± 4.4 3-2031 6S.6±7.5 52-8431 6.4 ± 3.0 2-1431 4.1 ± 2.3 Q-8

VOLUME 1 • NUMBER 3 • SUMMER 1993

any of the cognitive tests.The diagnosis of DAT was based on

DSM-III criteria for primary degenerativedementia18 supplemented by National Insti­tute of Neurological Diseases and Commu­nicative Disorders and Stroke-Alzheimer'sDisease and Related Disorders Associationcriteria for possible and probable OAT. 19

Psychiatric, medical, and neurological ex­aminations and clinical laboratory tests(complete blood count and differential,blood chemistries, folate, B12, thyroid, andurinalysis) were performed on all subjects,with computerized tomography, electroen­cephalogram, and other studies obtained asneeded to rule out specific causes. Therewas a low level of depressive symptoms inthis sample (mean score on Hamilton RatingScale for Depression20 = 5.75 ±4.64) and amoderately severe level of cognitive impair­ment (mean errors on the Mental StatusQuestionnaire21 = 6.71 ± 2.71).

To date, autopsies have been obtainedfor 11 of the SO patients, and results haveconfirmed the clinical diagnosis of DAT inall cases.

Neuropsychological Battery

The cognitive battery consisted of sev­eral subtests (Digit Span, Vocabulary, Simi­larities, Block Design, and Digit Symbol) ofthe Wechsler Adult Intelligence Scale22

(WAIS), three tests of learning and memory(the Visual Retention Test23 [VRTl, the Ob­ject Memory Evaluation24 [OME], and thePaired Associate Learning Test25), and twotests of visuQspatial and executive functions(the Visual Organization Test,26 ColouredProgressive Matrices27

).

For memory tests, the measures in­cluded in analyses were the following: thetotal number of designs correctly repro­duced on the Visual Retention Test (maxi­mum = 10), the number of correctresponses on five learning trials from thePaired Associate Learning Test (pairs withintermediate associative strength; maximum= 15), and the number of items correctly

THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY

La Rueetal.

recalled on the first trial of the OME retrieval(maximum = 10). A measure of retrievalfrom semantic memory (semantic retrieval),consisting of the number of first names ofthe subject's gender that could be generatedin 60 seconds, was provided by the firstdistraction trial of the OME.24 For Raven'sMatrices, the dependent measure used inanalyses was the number of correct re­sponses on series A (maximum = 12).

Determination ofAge at Onset

Information about early symptoms ofillness in patients was obtained from eachrelative participating in the study, either ininitial screening or during the psychiatricintelView. In addition, follow-up telephoneinterviews were conducted with patients'spouses and additional relatives to resolveany discrepancies in estimated age at onset.These interviews probed for specific earlysymptoms, including memory loss, lan­guage changes, topographic disorientation,difficulties in financial management, andchanges in behavior or personality, andasked the relative to estimate when specificsymptoms had first been observed. Otherstudies28

,29 using similar methods suggestthat reports of age at onset from familymembers are reliable across multiple inter­views (Kendall coefficient of concordance =

0.96) and that agreement among multiple fam­ily infonnants is quite high (intraclass r= 0.91).

Statistical Analyses

Table 2 provides descriptive statisticsfor performance on each of the cognitivemeasures for the complete sample, andTable 3 provides descriptive statistics for thesubsample of deceased subjects. Prelimi­nary examination of test score distributionsshowed that for Similarities, Digit Symbol,Block Design, OME retrieval, Paired Associ­ates, and Visual Retention, a sizable propor­tion of subjects obtained zero scores (Tables2 and 3). For each of these measures, per­formance distributions were converted to a

223

Age at Onset

binary classification (zero vs. non-zeroscore; Tables 2 and 3), and effects of predic­tors were examined by logistic regressionanalysis. For the remaining measures (Vo­cabulary, Digit Span, Semantic Retrieval,Raven's Matrices, and Visual Organization),multiple regression analyses were per­formed.

Two sets of logistic and multiple regres­sion analyses were conducted. For the com-

plete sample of patients, age at onset, yearsof education, and estimated duration ofsymptoms (in years) were entered simulta­neously as independent variables for eachcognitive dependent measure. In a secondseries of analyses, survival duration pasttesting (in years) was added to the list ofindependent variables for the subset of 31patients who had died.

Before multivariate analyses were per-

TABLE 2. Performance on various cognitive measures: romplete sample

Continuous Variablesn Means ±SD Range

WAlS VocabularyWAIS Digit SpanSemantic RetrievalRaven's MatricesVisual Organization Test

4949453740

B.Bt 3.47.9±3.86.2 ±4.76.2 ± 3.2

11.7 ±6.5

2-160-140-181-120-23

Dichotomous Variables," (°/0)Zero Non-ZeroScore SCore

WAIS SimilaritiesWAIS Digit SymbolWAIS Block DesignOME RetrievalPaired AssociatesVisual Retention

11 (240/0)22 (480/0)25 C57°A.)18 (44%)9 (24°A.)

19 (460/0)

35 (76%)24 (520/0)19 (43%)23 (560/0)28 (76%)22 (54%)

Note: WAIS = Wechsler Adult Intelligence Scale; OME = Object Memory Evaluation; values for WAIS measuresare age-scaled scores.

TABLE 3. Performance on various cognitive measures: deceased subjects

Continuous Variablesn Means ± SD Range

WAlS VocabularyWAIS Digit SpanSemantic RetrievalRaven's MatricesVisual Organization Test

3030292325

8.8± 3.87.4 ± 4.26.1 ± 4.66.4 ±3.5

11.8±7.3

2-160-140-171-120-23

Dichotomous Variables, n (%)Zero Non-ZeroScore SCore

WAIS SimilaritiesWAIS Digit SymbolWAIS Block DesignOME RetrievalPaired AssociatesVisual Retention

5 (18%)16 (57%)16 (57%)10 (38%)4 (18%)

12 (48%)

23 (82%)12 (430/0)12 (43%)16 (620/0)18 (82%)13 (520/0)

Note; WAIS::z: Wechsler Adult Intelligence Scale; OME :: Object Mernol)' Evaluation; values for WAlS measuresare age-scaled scores.

224 VOLUME 1 • NUMBER 3 • SUMMER 1993

formed, associations between independentvariables were examined as a check formulticollinearity. As would be expected,age at onset of illness and age at time oftesting were highly intercorrelated (r=0.95). To determine which of these variableswould be most appropriate to enter in mul­tivariate analyses, zero-order correlationswere computed between each age-relatedpredictor and the cognitive measures. Forage at the time of testing, no significantassociations were noted, and the directionof correlations was inconsistent across thecognitive tests (positive for 5 measures, neg­ative for 6). By contrast, there was a signif­icant association between age at onset ofillness and Digit Span (r= 0.30, P= 0.04),and the direction of correlations across thefull range of tests (positive for 8 of 11measures). In addition, in a preliminaryseries of regression analyses in which bothage at testing and age at onset were enteredas predictors, age at the time of testingfailed to meet default criteria for entry intoprediction equations for any of the cogni­tive variables. Therefore, age at onset)rather than age at testing, was selected forentry as an independent variable in subse­quent multivariate analyses.

Other associations among the indepen­dent variables were small in magnitude.Zero-order correlations between age atonset and duration of symptoms (r= -0.11)

LaRueetal.

and survival past testing (r= -0.04) werenonsignificant, as was the association be­tween duration of symptoms and survivalpast testing (r= 0.16). There was a negativecorrelation between age at onset and edu­cation (r= -0.44, P< 0.05), for the sampleas a whole, and between education andsurvival past testing in the subgroup ofdeceased subjects (r= -0.41, P< 0.05).However, none of these associations was ofsufficient strength to pose a problem withinterdependence of predictors in regressionanalyses.

RESULTS

Tables 4 and 5 present the results ofanalysesfor the complete sample, with Table 4 pre­senting multiple regression analyses, andTable 5, logistic regression analyses. Sum­mary statistics from the regression analysesare provided in the tables for each cognitivevariable; for those with outcomes significantat the 0.05 level or better, partial correlations(from multiple regression analyses) and Rvalues (from logistic regression analyses)are listed to provide estimates ofthe strengthof individual predictors. The combined setof predictors accounted for a significantproportion of variance on Vocabulary, Se­mantic Retrieval, and Paired Associate learn­ing. Age at onset contributed significantly

TABLE 4. Predictors of cognitive performance: multiple regression analysis for the complete sample

Age at onsetof dementia

Education

Duration ofsymptoms

Adjusted R 2

WAISVocabulary

r

-0.27

WAISDIgit Span

r

0.07

SemanticRetrieval

r

0.21

0.02

-0.37·

0.11·

Raven'sMatrices

r

-0.06

VisualOrganization

r

-0.04

Nole: Partial correlations for individual variables are reported for those variables with overall outcomes at theP = 0.05 level or lessj r::: the partial correlation between the dependent and independent variable.• p~ 0.05; •• P-5: 0.01.

TIlE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY 225

Age at Onset

for Vocabulary, with earlier onset associatedwith lower test scores, and duration ofsymptoms contributed significantly for Se­mantic Retrieval. For a majority of measures,however, the overall percentage of varianceexplained by the predictors was quite small.In the multiple regression analyses, therange of adjusted R 2 values was 0.07 to 0.17,and in the logistic regression analyses, only63% to 78% of subjects were correctly clas­sified.

Tables 6 and 7 present the results ofanalyses for the subsample of deceasedpatients, with Table 6 presenting multiple

regression, and Table 7, logistic regressionanalyses. For several measures, the additionof survival past testing as a predictor sub­stantially increased the amount of varianceexplained by the combined list of indepen­dent variables. On Digit Span, for example,the adjusted R 2 increased from 0.07 in thefirst analysis (for the complete sample) to0.35 (for the deceased subsample); similarimprovements in fit were noted for Vocab­ulary, Semantic Retrieval, Similarities, DigitSymbol, and Block Design. Age at onsetwas a significant predictor for Vocabularyand Digit Span, in combination witll other

TABLE 5. Predictors of cognitive performance: logistic regression analysis for the complete sample

WAIS WAIS WAIS OME Paired VisualSimilarities Digit Symbol Block Design Retrieval Associates Retention

R R R R R R

Age at onset 0.00of dementia

Education 0.27·

Duration of 0.00symptoms

Model chi-square

(df=3) 5.72 6.38 4.14 5.82 8.58 3.51Classified correctly, % 76 65 64 68 78 63

Note: The R statistic in logistic regression is analogous to the partial correlation between the dependent andindependent variable (cf. SPSS Advanced Statistics Manual, 199033).• p SO.OS;·· PSO.Ol.

TABLE 6. Predictors of cognitive perfonnance: multiple regression analysis for deceased subjects only

WAfS WAIS semanticVocabulary Digit Span Retrieval

r r r

Age at onset 0.49..

0.53·· 0.34of dementia

Education 0.61-· a .39* a .41·

Duration of -0.38 -0.39* -0.51··symptoms

Survival past 0,45· 0.56·· 0.62··testing

Adjusted R 2 0.30·· 0.35-· 0.35··

Raven'sMatrices

r

0.13

VisualOrganization

r

-0.05

Note: Partial correlations for individual variables are reported for those variables with overall outcomes at thep= 0.05 level or better; r= the partial correlation between the dependent and independent variable.• PS 0.05; •• PS 0.01.

226 VOLUME 1 • NUMBER 3 • SUMMER 1993

variables. By contrast, performance on Se­mantic Retrieval, Similarities, Digit Symboland Block Design was more closely relatedto education, duration of symptoms, or sur­vival past testing than to age at onset. Forother measures (Raven's Matrices, VisualOrganization, OME retrieval, Paired Associ­ates, and Visual Retention), there were nosignificant relationships between perfor­mance and the independent variables.

DISCUSSION

Others, as well as our group, have pointedto the heterogeneity that exists among pa­tients with OAT, phenotypically and genet­ically.3O-32 The present findings illustrate theimportance of adopting a multivariate ap­proach in the assessment of individual dif­ferences and in the search for possibleclinical subgroups.

Perhaps the most important outcomewas the relatively strong connection ob­served between cognitive performance andnearness to death. When data on nearnessto death were lacking (Table 4), there wassubstantial unexplained variance for mostcognitive measures. By contrast, in the anal-

La Rueet al.

yses for deceased subjects, the percentageof variance explained (adjusted for multiplepredictors) increased substantially for sev­eral measures (Table 5). Among the six testsfor which the overall regression analysiswas statistically significant, for the deceasedsubsample, suxvival past testing ranked asthe strongest predictor for two (Digit Spanand Semantic Retrieval) and as a significantbut secondary predictor for three others(Vocabulary, Digit Symbol, and Block De­sign). These findings suggest that nearnessto death is an important parameter to con­sider in judging disease severity, especiallyfor conditions such as DAT, in which thecauses of death (e.g., pneumonia) are oftenlinked to the general debilitation that occursin later stages of the disease. Therefore,other longitudinal or retrospective studiesmay benefit from controlling for nearness todeath when individual differences in clini­cal features are being examined. The pres­ent findings also suggest that severity ofcognitive loss may be useful in predictingsurvival duration for patients with moder­ately severe dementia. In an ancillary re­gression analyses, relating cognitive tests asindependent variables to survival past test­ing as the dependent variable, a combina-

TABLE 7. Predictors of cognitive performance: logistic regression analysis for deceased subjects only

WAIS WAIS WAIS OME Paired VisualSimilarities Digit Symbol Block Design Retrieval Associates Retendon

R R R R R R

Age at onset 0.00 0.00 0.00of dementia

Education 0.28- 0.05 0.00

Duration of -0.17 -0.25' -0.34"symptoms

SUlVival past 0.24 0.26' 0.24'testing

Model chi-square11.3-(df= 4) 11.9' 13.0" 4.65 8.16 5.72

Classified correctly t °Al 89 79 82 65 86 72

Note: The R statistic in logistic regression is analogous to the partial correlation between the dependent andindependent variable (cf. SPSS Advanced Statistics Manual, 199033).• P S 0.05,0 -- P S 0.01.

THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY 227

Age at Onset

tion of three measures (Digit Span) Vocabu­lary, and Semantic Retrieval) was found toaccount for a significant portion of the sur­vival duration variance (adjusted R 2 = 0.44,p= 0.01) in the present sample.

Other studiesl5-17 have also obsetved

associations between performance on lan­guage or memory tests and survival in de­mented patients) but, to our knowledge, thisis the first study to document this relation­ship in a non-institutionalized sample witha relatively long survival duration. The rela­tionship between cognitive decline andmortality, first noted in "normal" aging12

,13 isin need of further exploration.

In our sample) duration of symptomsprior to testing and subsequent sUlVival pastassessment were not significantly corre..Jated; therefore, each made a separate con­tribution to prediction of cognitiveperformance. Among dementia patients ingeneral, it is likely that these two variableswould be related to some degree; however,unless the obselVed correlation is very high,joint consideration of both parameters islikely to yield the best estimate of the effectsof disease severity. The present results alsodemonstrate the importance of controllingfor education effects in studies of dementia;that is, despite the relatively severe impair­ment level noted in this sample, perfor­mance on several verbal measures(Vocabulary, Similarities, Semantic Re­trieval, and Paired Associates) still showeda residual benefit from more extensive edu­cation.

When other factors that might affectperformance were statistically controlled,age at onset was found to be a significantpredictor for only one aspect of cognitivefunctioning (Vocabulary) in the completesample, and two measures (Vocabulary andDigit Span) in deceased subjects. On bothof these verbal tests, patients with youngerages at onset were more severely impaired.There were no significant age-at-onset ef­fects on tests of visuospatial or executivefunctions (Block Design, Digit Symbol, Pro­gressive Matrices, and Visual Organization)

228

or on measures of secondary memory (Vi­sual Retention, OME retrieval, and PairedAssociates). The finding of a selective pat­tern of age-at-onset effects, with significantoutcomes confined to certain verbally basedfunctions, might be viewed as added sup­port for the hypothesis of preferential left­hemisphere involvement in early onsetDAT.315 However, because this effect wasnot consistent across all verbal tests, andbecause floor effects were noted on manymeasures, our results offer little support forspecific intertest patterns.

The fact that age at onset of illness wascorrelated in this sample with age at thetime of testing raises the possibility that thesmall obsetved age-at-onset effects weresimply due to chronological aging. How­ever, the direction of the association be­tween age at onset and cognitiveperformance was opposite to what is typi­cally obsetved in cognitive aging research;that is, subjects who had a later onset ofillness (and hence, were older at time oftesting) performed better on the cognitivetests. It is also worth noting that patientswith late-onset illness had less education onthe average than those with early onsetdisease. Therefore, it appears that neitherchronological age per se nor differences ineducation can account for the observedage-at-onset effects. Other factors (e.g., dif­ferences in premorbid abilities, occupa­tional background, etc.) may have beenconfounded with age at onset, but largersample sizes would be needed to addressthese possibilities.

Overall, this study selVes to illustratethe multiplicity of factors that influence cog­nitive performance in DAT, even in laterstages of the disease. Survival past testingand duration of symptoms had the mostpervasive effect on cognitive performance,and an improved fit to the data was ob­tained when both of these variables wereincluded in prediction equations. Educationinfluenced performance on several verbaltests, despite the relatively advanced stageof the illness. Age-at-onset effects were of

VOLUME 1 • NUMBER 3 • SUMMER 1993

modest strength and confined to only twocognitive measures. Longitudinal analyseswould be helpful in delineating the impor­Stance of these and other individual-differ­ence parameters and in determiningwhether the salience of these parametersshifts with disease progression.

The authors are grateful to thefamilies andpatients who generously contributed theirtime. The authors also thank the colleaguesand staffwho assisted with thisproject, espe-

laRue etal.

cially Elisabeth Clark, Ph.D., for participa­tion in age-at-onset determinations, and EdListon, M.D., for diagnostic review. The opin­ions expressed here are those ofthe authorsand do not represent those of the VeteransAdministration.

This study was supported in part by theDepartment ofHealth Seroices, State ofCal­ifornia, the Medical Research Service oftheDepartment of Veterans Affairs, and Na­tional Institute of Mental Health GrantMH36205.

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