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The Apolipoprotein E  4 Allele and Decline in Different Cognitive Systems During a 6-Year Period
Robert S. Wilson, PhD;
Julie A. Schneider, MD;
Lisa L. Barnes, PhD;
Laurel A. Beckett, PhD;
Neelum T. Aggarwal, MD;
Elizabeth J. Cochran, MD;
Elizabeth Berry-Kravis, MD, PhD;
Julie Bach;
Jacob H. Fox, MD;
Denis A. Evans, MD;
David A. Bennett, MD
Arch Neurol. 2002;59:1154-1160.
ABSTRACT
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Context Impairment of episodic memory is an early and defining feature of Alzheimer
disease (AD). The apolipoprotein E (APOE)  4 allele is known to influence
risk of AD but it has been difficult to establish whether it affects episodic
memory differently from other cognitive functions.
Objective To examine the association of 4 with decline in different cognitive
systems.
Design Longitudinal cohort study.
Setting More than 40 groups of Catholic clergy from across the United States.
Participants Older Catholic clergy members without clinical evidence of dementia
at baseline underwent annual clinical evaluations for up to 6 years. Of 624
persons eligible for follow-up, 611 (98%) participated, of whom 161 (26%)
had at least 1 4 allele. They completed an average of 5.5 evaluations
(range, 2-7).
Main Outcome Measures Incident AD and annual rates of change in episodic memory, semantic
memory, working memory, perceptual speed, and visuospatial ability.
Results The presence of 4 was associated with risk of developing AD on
follow-up (relative risk, 1.92; 95% confidence interval, 1.27-2.89). In a
series of random effects models, 4 was associated with impaired baseline
function in episodic memory and visuospatial ability and with more rapid decline
in all domains. The effect of 4 on annual decline in episodic memory
(>3-fold increase) was significantly stronger than its effect on decline in
other cognitive systems (P<.01), and at baseline,
its effect on episodic memory was marginally stronger than its effect on other
cognitive domains (P = .06).
Conclusion The results suggest that the APOE 4 allele influences risk of
AD by a relatively selective effect on episodic memory.
INTRODUCTION
POSSESSION OF 1 or more copies of the apolipoprotein E (APOE) 4
allele is associated with an increased risk of Alzheimer disease (AD)1-2 but the mechanism underlying this association
is unclear. Since a defining feature of AD is progressive loss of episodic
memory, several researchers have hypothesized that the 4 allele is selectively
associated with episodic memory decline in older persons.3-5
Support for this hypothesis has been mixed, however. The 4 allele has
been associated with episodic memory impairment in some cross-sectional studies3, 6-7 and with more global
cognitive impairment in others.8-10
Although several longitudinal studies have examined the relationship of the 4
allele to cognitive decline,4, 11-20
few have assessed multiple cognitive systems4, 13-14,17-19
and most of these have been based on only 2 observations during periods of
3 years or less and have conducted analyses on individual tests, which are
subject to floor and ceiling effects. In addition, no previous longitudinal
study has directly tested whether the association of 4 with change in
measures of episodic memory differs from its association with change in other
cognitive measures.
We used data from the Religious Orders Study, an ongoing clinicopathological
study of aging and AD in older Catholic clergy members, to investigate the
differential effects of the APOE 4 allele on change in episodic memory
and other cognitive abilities. At baseline, participants were 65 years and
older and free of clinical evidence of AD. They underwent annual clinical
evaluations for up to 6 years, including detailed cognitive function testing
and clinical classification of AD, with follow-up participation in survivors
exceeding 95%. Composite measures of episodic memory, semantic memory, working
memory, perceptual speed, and visuospatial ability, each based on 2 or more
individual tests, were the main outcomes. In analyses, we first assessed the
association of the 4 allele with risk of developing AD. We then used
a growth curve approach to estimate the association of 4 with the baseline
level of and annual rate of change in each cognitive system and to test whether
the effects on any 1 system differed from the average effects on the other
systems.
SUBJECTS AND METHODS
SUBJECTS
Subjects are participants in the Religious Orders Study, a longitudinal
clinicopathological study of aging and AD in older Catholic nuns, priests,
and brothers recruited from about 40 groups across the United States. Eligibility
required age of 65 years or older, absence of a clinical diagnosis of dementia,
and consent to annual clinical evaluations and to brain donation at death.
The study was approved by the institutional review board of Rush-Presbyterian–St
Luke's Medical Center (Chicago, Ill).
Participants enrolled in the Religious Orders Study by October 2000
were eligible for analyses in this study if they had a valid APOE genotype,
did not meet criteria for dementia at baseline, and survived to the first
follow-up date. Of 624 people who met these criteria, 611 (97.9%) completed
at least 2 evaluations (mean, 5.5 evaluations; 97.3% of possible evaluations
in survivors). Analyses are based on this group.
CLINICAL EVALUATION
At baseline, each person had a uniform evaluation, which was repeated
annually, with examiners blinded to previously collected information as previously
described.21-24
It included a medical history, neurologic examination, cognitive function
testing, and review of brain scan when available. On the basis of this evaluation,
a board-certified neurologist classified people with respect to AD and other
common neurologic disorders. The diagnosis of dementia and AD was based on
the criteria of the joint working group of the National Institute of Neurological
and Communicative Disorders and Stroke and the Alzheimer's Disease and Related
Disorders Association (NINCDS/ADRDA).25 Dementia
required a history of cognitive decline and impairment in at least 2 cognitive
domains, one of which had to be memory for the dementia to meet AD criteria.
Those who met these criteria and had another condition judged to contribute
to cognitive impairment, termed "possible AD" in the NINCDS/ADRDA system,
were also included. A total of 53 persons met dementia criteria at baseline
and they were excluded from the analyses.
COGNITIVE FUNCTION ASSESSMENT
A set of 21 tests was administered as part of each evaluation. One test,
the Mini-Mental State Examination,26 was used
only for descriptive purposes, and another test, Complex Ideational Material,27 was not used in analyses because of a very skewed
distribution. The remaining 19 tests were grouped into 5 domains of cognitive
function, based in part on a previous factor analysis.24
(1) Episodic memory: Word List Memory, Recall, and Recognition from the Consortium
to Establish a Registry for Alzheimer Disease neuropsychological battery,28 immediate and delayed recall of the East Boston Story,29 and Story A from Logical Memory.30
(2) Semantic memory: 20-item version of Boston Naming Test,31
Verbal Fluency,28 15-item version of Extended
Range Vocabulary,32 20-item version of National
Adult Reading Test,33 and subsequent modifications.34-35 (3) Working memory: Digit Span Forward
and Digit Span Backward,30 Digit Ordering,36 and Alpha Span.37
(4) Perceptual speed: Symbol Digit Modalities Test–Oral Version38 and Number Comparison.32
(5) Visuospatial ability: 15-item version of Judgment of Line Orientation39 and a 17-item version of Standard Progressive Matrices.40
A composite measure of each cognitive domain was formed, as previously
described,24 by converting raw scores on the
tests grouped in that domain to z scores, using the baseline mean and SD,
and computing the average. To assess the differential association of 4
with episodic memory compared with other cognitive domains, we computed the
mean score in domains other than episodic memory to yield a nonmemory composite.
Composite measures to contrast with each of the other 4 cognitive domain measures
were constructed in the same way, by averaging scores from the other domain
measures.
APOE GENOTYPING
Blood was collected at each participating Religious Orders Study site
with acid citrate dextrose anticoagulant and stored at room temperature; it
underwent lymphocyte separation within 24 hours of collection. DNA was extracted
from approximately 2 to 3 million cells using a Puregene DNA isolation kit
(Gentra, Minneapolis, Minn), with APOE genotypes determined according to the
method described by Hixson and Vernier.41 Genotyping
was done by an investigator blinded to all clinical data.
DATA ANALYSIS
For all analyses, participants were divided into those with 1 or more 4
alleles (ie, 2/4, 3/4, and 4/4) and those without an 4
allele (ie, 2/2, 2/3, and 3/3).
We used a Cox proportional hazards model to assess how the presence
of 4 affected the risk of developing AD during the 6 years of observation,
adjusting for the potentially confounding effects of age, sex, and education.42
Random effects models were used to characterize individual paths of
change in each cognitive measure and to examine how the 4 allele was
associated with initial level of function and annual rate of change.24, 43-44 In this growth curve
approach, each individual's path is assumed to follow the mean path of the
group except for random effects that cause the initial level of function (ie,
intercept) to be higher or lower and the rate of change (ie, slope) to be
faster or slower. These random effects were assumed to follow a bivariate
normal distribution. They were used to estimate individual growth curves,
which were plotted. Model assumptions about linearity, normality, and independence
and homoscedasticity of errors were assessed graphically and analytically,
and found to be adequately met.
To assess the association of the 4 allele with change in each
cognitive domain, we constructed separate random effects models for each of
the 5 cognitive domain measures. Each model included terms for time (in years
since baseline), the presence of 4, and their interaction. The term
for time indicates the average annual rate of cognitive change in those without 4.
The term for 4 indicates the average effect of 4 on cognitive
score at baseline. The interaction term indicates the average effect of 4
on rate of cognitive change per year. Each model was also adjusted for the
effects of age, sex, and education.
To test the hypothesis that the 4 allele is selectively associated
with loss of episodic memory, we conducted a series of analyses contrasting
the episodic memory measure with a composite measure of the other cognitive
domains. First, we constructed separate random effects models for the episodic
memory measure and the nonmemory composite, each with a term for time, and
estimated individual intercepts (ie, baseline level of function) and slopes
(ie, annual rate of change) on each measure. Second, we constructed a model
that used both sets of intercepts as outcomes. The model terms included an
indicator of which outcome was being analyzed (coded 0 for the episodic memory
intercept and 1 for the nonmemory composite intercept), 4, and their
interaction. Terms were also included to control for the effects of age, sex,
and education. The interaction of the indicator with 4 denotes whether 4
was more strongly associated with baseline impairment in episodic memory than
with baseline impairment in the nonmemory composite measure. Third, we constructed
a similar model that used both sets of slopes as outcomes. In this model,
the interaction of the indicator with 4 denotes whether 4 was
more strongly associated with decline in episodic memory than with decline
in the nonmemory composite.
To determine if cognitive systems other than episodic memory were selectively
affected by 4, we repeated the 3 analytic steps outlined for each of
the remaining cognitive domain measures. In each case, the domain measure
was contrasted with a composite measure of the other 4 domains.
RESULTS
ASSOCIATION OF APOE 4 WITH INCIDENT AD
The distribution of APOE genotypes in study participants was as follows: 2/2
= 1; 2/3 = 72; 2/4 = 13; 3/3 = 377; 3/4 = 139; and 4/4
= 9. This distribution is comparable with those reported in several population-based
studies.45-48
Subgroups of those with or without at least 1 4 allele were similar
in demographics and baseline Mini-Mental State Examination scores (Table 1).
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Table 1. Descriptive Information About Participants in the APOE Subgroups*
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During the 6 years of observation, 102 persons developed AD (92 with
probable and 10 with possible AD). Their APOE genotypes were as follows: 2/3
= 8; 2/4 = 7; 3/3 = 58; 3/4 = 26; and 4/4 = 3. Four
persons developed dementia due to other causes (eg, stroke, Parkinson disease).
A proportional hazards model was used to assess whether the expected association
of 4 with risk of developing AD was present in this cohort, excluding
these 4 persons with other causes of dementia and adjusting for age, sex,
and education. Compared with those without 4, the relative risk of developing
AD in those with 4 was 1.92 (95% confidence interval [CI], 1.27-2.91).
Comparable results were obtained when those with possible AD were excluded.
ASSOCIATION OF APOE 4 WITH DECLINE IN DIFFERENT COGNITIVE DOMAINS
Table 2 presents the baseline
mean and SD of each of the cognitive domain measures. We constructed separate
random effects models to see how the presence of APOE 4 was related
to baseline level of function and annual rate of change in each domain after
adjustment for demographic variables (Table
3).
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Table 2. Mean and SD of Each Cognitive Domain Measure at Baseline*
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Table 3. Summary of Random Effects Models Examining the Relation of
APOE 4 to Baseline Level of Function and Annual Rate of Change in Different
Domains of Cognitive Function*
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In those without an 4 allele, the episodic memory score declined
an average of 0.021 standard units per year (95% CI, -0.026 to –0.016),
as shown by the term for time. Those with 4 had lower initial memory
scores than those without 4, by an average of 0.140 units (P<.01). In addition, those with 4 declined more rapidly, by
an average of 0.067 units (P<.001), which represents
more than a 3-fold increase compared with those without 4.
Those without an 4 allele also declined in each of the other cognitive
domains, with the average annual rates of decline ranging from 0.021 units
(visuospatial ability) to 0.068 units (perceptual speed). Those with 4
had lower visuospatial ability at baseline than those without 4, by
an average of 0.130 units (P<.05), but 4
was not significantly related to baseline levels of semantic memory, working
memory, or perceptual speed. Annual rate of decline was more rapid in all
domains for those with 4 compared with those without it, with increases
of approximately 50% in working memory and perceptual speed and of approximately
150% in semantic memory and visuospatial ability.
COMPARISON OF APOE 4 EFFECTS ON DIFFERENT COGNITIVE SYSTEMS
Figure 1 shows the average
paths of change in episodic memory (A) and a composite measure of the other
4 cognitive domains (B) during the 6 years of observation in the APOE subgroups.
The deleterious effect of 4 on episodic memory seems to be stronger
and to emerge earlier than its effect on the nonmemory composite.
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Figure 1. Average paths of change in episodic
memory (A) and a composite measure of other cognitive domains (B) in typical
participants with or without at least 1 apolipoprotein E 4 allele.
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To test the hypothesis that APOE 4 selectively affected episodic
memory at baseline, we constructed a model that used baseline scores on both
episodic memory and the nonmemory composite as outcomes. The model terms included
an indicator of which outcome was being analyzed (ie, episodic memory or nonmemory
composite), 4, and their interaction. The estimate of this interaction
term is presented in the first row of Table
4. It indicates that at baseline, the 4 association with episodic
memory impairment was marginally stronger than its association with impairment
in the nonmemory composite (P = .06).
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Table 4. Differential Effect of APOE 4 in Each Cognitive Domain
Compared With a Composite of the Other Cognitive Domains
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To test the hypothesis that 4 selectively affected decline in
episodic memory, we repeated the previous analysis, except that annual rates
of change in episodic memory and in the nonmemory composite were used as outcomes
instead of the baseline scores on those measures. The interaction of 4
with the indicator term, presented in the second row of Table 4, was significant, denoting that 4 had a stronger association
with decline in episodic memory than with decline in the nonmemory composite.
To ascertain whether cognitive domains other than episodic memory were
differentially affected by 4, we repeated the same analytic steps for
each of the other cognitive domains. Table
4 presents the key interaction term from each of the analyses comparing 4
effects on a cognitive domain measure with its effects on a composite of the
other 4 domains, and Figure 2 shows
the average decline in each domain compared with the decline in the composite
of the other 4 domains in the APOE subgroups. In semantic memory, 4
had a weaker association with baseline level of the domain measure compared
with the composite measure but 4 was not differentially associated with
annual change. Baseline function in the other 3 domains was not differentially
associated with 4 but rate of change was. In each case, 4 had
a weaker association with change in the domain measure than it did with change
in the composite measure.
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Figure 2. Average paths of change in cognitive
domains (A) and composite measures (B) in typical participants with or without
at least 1 apolipoprotein E 4 allele. The composite measure paired with
each cognitive domain is the average of the other 4 cognitive domains.
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COMMENT
Because the APOE 4 allele is associated with increased risk of
AD, it must, at some level, also be related to decline in multiple cognitive
systems. However, the extent to which 4 has a relatively selective effect
on episodic memory has been difficult to establish in previous research. In
this 6-year longitudinal study of older persons, we found that possession
of 1 or more 4 alleles was associated with rate of decline in all forms
of cognitive function. However, the effect of 4 on change in episodic
memory was much more pronounced. Further, at baseline, 4 had a marginally
stronger association with impairment in episodic memory compared with other
cognitive functions, suggesting that 4 effects on episodic memory precede
those on other cognitive systems. Overall, these results support the hypothesis
that 4 has a relatively selective effect on episodic memory.
The biological mechanisms through which the 4 allele affects cognitive
function and the development of AD are not well understood. Some studies have
reported an association between 4 and level of AD pathology, particularly  -amyloid
accumulation.49 By contrast, APOE is also involved
in neuronal repair and survival50-51
and in atherosclerosis,52-53 suggesting
that 4 may be related to disease through other mechanisms. Further, 4
has been related to dementia in other diseases that are not typically associated
with selective impairment of episodic memory. Although clinicopathological
studies will be needed to more definitively address this issue, our results
are consistent with the idea that 4 influences risk of AD primarily
by affecting the usual biological process that leads to AD rather than by
some other mechanism.
Previous longitudinal studies have found that 4 is associated
with decline on tests of episodic memory,4, 15, 17-19
perceptual speed,12, 14, 20
and global cognition.11-12,16, 18, 20
Our results build on these findings by showing that 4 is associated
with decline in all cognitive systems but that its effect on episodic memory
is relatively stronger than its effects on other forms of thinking.
Confidence in these findings is strengthened by several factors. First,
there was an average of more than 5 evenly spaced observations per person,
making it possible to reliably characterize change in individuals. Second,
follow-up participation in survivors exceeded 95%, making it unlikely that
attrition could substantially bias estimates of change. Third, composites
of 2 or more individual cognitive function tests were used as outcomes, reducing
the opportunity for floor and ceiling effects and other sources of measurement
error to affect estimates of change. Fourth, the hypothesis that 4 has
a stronger association with episodic memory than with other cognitive functions
was supported by both cross-sectional and longitudinal data.
Several limitations should be noted. First, findings in this selected
group may not generalize to other groups. Participants were predominantly
white, and there is evidence that APOE effects differ in other ethnic/racial
groups.54 On average, participants also differ
from older people in the US population in education and lifestyle. It is possible
that within-group similarities in lifestyle may have helped to highlight the
behavioral effects of genetic differences by reducing the confounding effects
of other environmental variables associated with cognitive decline and AD.
Second, we cannot rule out the possibility that psychometric differences between
the outcome measures may have contributed to their differential association
with APOE 4.
AUTHOR INFORMATION
Accepted for publication January 7, 2002.
Author contributions: Study concept and design (Drs Wilson, Evans, and Bennett); acquisition of data (Drs Wilson, Schneider, Aggarwal, Cochran, Berry-Kravis, Fox,
Evans, Bennett, and Ms Bach); analysis and interpretation of data (Drs Wilson, Barnes, Beckett, and Bennett); drafting of
the manuscript (Drs Wilson, Aggarwal, Bennett, and Ms Bach); critical revision of the manuscript for important intellectual content (Drs Wilson, Schneider, Barnes, Beckett, Cochran, Berry-Kravis,
Fox, Evans, and Bennett); statistical expertise (Drs Beckett and Bennett); obtained funding (Drs
Schneider, Evans, and Bennett); administrative, technical, and material
support (Drs Wilson, Barnes, Cochran, Berry-Kravis, Fox,
Evans, Bennett, and Ms Bach); study supervision (Drs Aggarwal and Bennett and Ms Bach).
This research was supported by grants R01 AG15819, K08 AG00849, and
P30 AG10161 from the National Institute on Aging, Bethesda, Md.
We are indebted to the altruism and support of the hundreds of nuns,
priests, and brothers from the following groups participating in the Religious
Orders Study: Archdiocesan priests of Chicago, Ill, Dubuque, Iowa, and Milwaukee,
Wis; Benedictine Monks, Lisle, Ill, and Collegeville, Minn; Benedictine Sisters
of Erie, Erie, Pa; Benedictine Sisters of the Sacred Heart, Lisle, Ill; Capuchins,
Appleton, Wis; Christian Brothers, Chicago, Ill, and Memphis, Tenn; Diocesan
priests of Gary, Ind; Dominicans, River Forest, Ill; Felician Sisters, Chicago,
Ill; Franciscan Handmaids of Mary, New York, NY; Franciscans, Chicago, Ill;
Holy Spirit Missionary Sisters, Techny, Ill; Maryknolls, Los Altos, Calif,
and Maryknoll, NY; Norbertines, DePere, Wis; Oblate Sisters of Providence,
Baltimore, Md; Passionists, Chicago, Ill; Presentation Sisters, BVM, Dubuque,
Iowa; Servites, Chicago, Ill; Sinsinawa Dominican Sisters, Chicago, Ill, and
Sinsinawa, Wis; Sisters of Charity, BVM, Chicago, Ill, and Dubuque, Iowa;
Sisters of the Holy Family, New Orleans, La; Sisters of the Holy Family of
Nazareth, DesPlaines, Ill; Sisters of Mercy of the Americas, Chicago, Ill,
Aurora, Ill, and Erie, Pa; Sisters of St Benedict, St Cloud and St Joseph,
Minn; Sisters of St Casimir, Chicago, Ill; Sisters of St Francis of Mary Immaculate,
Joliet, Ill; Sisters of St Joseph of LaGrange, LaGrange Park, Ill; Society
of Divine Word, Techny, Ill; Trappists, Gethsemani, Ky, and Peosta, Iowa;
Wheaton Franciscan Sisters, Wheaton, Ill.
We also thank Todd Beck, MS, for statistical programming, and Carolyn
DeVivo and Eithne Barton for preparing the manuscript.
Corresponding author and reprints: Robert S. Wilson, PhD, Rush Alzheimer's
Disease Center, 1645 W Jackson Blvd, Suite 675, Chicago, IL 60612 (e-mail: rwilson{at}rush.edu).
From the Rush Alzheimer's Disease Center and Rush Institute for Healthy
Aging (Drs Wilson, Schneider, Barnes, Beckett, Aggarwal, Cochran, Fox, Evans,
and Bennett, and Ms Bach) and Departments of Neurological Sciences (Drs Wilson,
Schneider, Barnes, Aggarwal, Cochran, Berry-Kravis, Fox, Evans, and Bennett),
Psychology (Drs Wilson and Barnes), Internal Medicine (Drs Beckett and Evans),
Pathology (Dr Cochran), and Pediatrics and Biochemistry (Dr Berry-Kravis),
Rush-Presbyterian St Luke's Medical Center, Chicago, Ill.
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