Elsevier

Neurobiology of Aging

Volume 22, Issue 4, July–August 2001, Pages 683-689
Neurobiology of Aging

Memory performance in healthy elderly without Alzheimer’s disease: effects of time and apolipoprotein-E

https://doi.org/10.1016/S0197-4580(01)00223-8Get rights and content

Abstract

Transgenic mice expressing human APOE-ε4 develop an age-dependent decline in memory without pathological features of Alzheimer’s disease (AD). This implicates APOE in the maintenance of memory during normal senescence, but parallel human studies are limited because longitudinal investigations of memory usually do not exclude patients with AD or “questionable” AD (QD). The current study examined the effect of APOE on cognitive function over time in elderly without dementia. We hypothesized that, compared to other APOE alleles memory decline even in healthy elderly would be greater among those with an APOE-ε4.

The results of neuropsychological tests, grouped into domains of memory, language and visuospatial/cognitive function by factor analysis, were examined at three intervals over a seven-year period in 563 healthy elderly without AD or QD using generalized estimating equations. Memory performance declined over time, while scores on the visuospatial/cognitive and language factors did not change. Increased age was associated with lower scores, and higher education with higher scores on all factors at each interval. No APOE allele was associated with performance on a specific cognitive factor at any interval, but the presence of an APOE-ε4 allele was associated with a more rapid decline in the memory factor over the follow-up period. The effect was most pronounced among individuals with less than 10 years of formal education. There was no similar time-dependent relationship between APOE-ε4 and the language or visuospatial/cognitive factors.

Transgenic mice and elderly humans without AD or QD expressing APOE-ε4 show a decline in memory performance over time. These observations provide evidence for an APOE-specific effect on memory during senescence.

Introduction

APOE-ε4 is the major known genetic risk factor for late-onset familial and sporadic AD. Several mechanisms have been proposed to explain how APOE-ε4 increases AD risk. APOE may be an active participant in β-amyloid clearance [25], [30], [40]. APOE deficient mice expressing the APP717 mutation that causes an early-onset, autosomal dominant form of AD deposit a greater number of amyloid plaques [1] and show more pronounced memory impairment than wildtype mice [16]. A direct role for APOE, independent of an interaction with β-amyloid, involving both biochemical and neuronal integrity has been suggested in animal models with impaired memory [16], [20]. Compared with intact mice, APOE deficient mice have decreased synaptic density in cholinergic, noradrenergic and serotinergic projections to relevant brain regions [13] and perform worse in several types of memory tasks [8], [16], [42], [43]. These proposed mechanisms have been supported, in part, by parallel studies in humans. APOE-ε4 is associated with greater β-amyloid plaque density than other APOE alleles among patients with AD [24], [49]. Compared to individuals with other APOE genotypes, individuals with an APOE-ε4 allele develop hippocampal atrophy [31], [33], [35], [44], [50], [65] and are more likely to have cognitive impairment [2], [5], [6], [11], [12], [15], [18], [21], [22], [29], [39], [50], [53], [68]. Whether APOE-ε4 has a direct effect on memory in the absence of disease, or acts only through its association with AD, remains unknown because the majority of studies have been either cross-sectional or have not excluded individuals with QD. The few longitudinal studies have provided divergent results [15], [29], [56]. We designed a series of analyses of data collected in a longitudinal study to determine whether or not APOE influences memory and other cognitive functions in individuals who are free of dementia or cognitive impairment.

Section snippets

Subjects and Setting

Data were included from individuals participating in a prospective study of 2,126 Medicare recipients, 65 years and older, residing in a single community in Northern Manhattan. Each person received the same medical, neurological and neuropsychological evaluations at regular intervals. The cohort was followed over a 7-year period beginning in 1992. Three follow-up examinations took place at 20-month intervals after the baseline interview. Over the study period, the annual mortality rate has been

Results

The demographic characteristics of the 563 healthy elderly are shown in Table 2. There were 390 (69%) women. Twenty-five percent were White, 31% were Black and the remaining were Caribbean Hispanics. The number of women in each ethnic group did not differ significantly. There was a difference in APOE-ε4 allele frequency by ethnic group consistent with published genotype frequencies [36] (African American 18%, Hispanic 12%, White 13%, P = 0.05). Years of education also differed significantly by

Discussion

In this study memory performance declined over time in healthy elderly individuals without AD or QD, but other cognitive skills remained stable. Increased age was associated with lower scores in all cognitive domains while increased education was associated with higher scores. APOE-ε4 was not associated with poor performance in any cognitive domain at any specific time interval. However, there was a statistically significant relationship between APOE-ε4 and change in memory performance over

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    This research was supported by federal grants AG08702, AG07232, and AG01963.

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