Longitudinal change in working memory as a function of APOE genotype in midlife and old age

Abstract

Previous investigations into whether the APOE-ε4 allele exerts cognitive effects at midlife have been inconclusive. We have advanced a “cognitive phenotype” hypothesis arguing that the ε4 allele of the apolipoprotein E gene (APOE) is associated with lower efficiency of neuronal plasticity thereby resulting in poorer cognitive performance independently of the pathology of Alzheimer’s disease (Greenwood et al., 2005). This hypothesis is best tested at midlife, prior to the neuron loss associated with AD diagnosis. This hypothesis predicts that the ε4 allele would alter cognition regardless of age through plasticity mechanisms, but would not induce longitudinal decline in midlife. The alternative “prodrome” hypothesis predicts that the APOE-ε4 allele would be associated with longitudinal cognitive decline as early as midlife due to prodromal effects of AD. We tested these hypotheses with a working memory task in a large cross-sectional sample of cognitively screened APOE-ε4 carriers and non-carriers and also in a small longitudinal sample over 3 years. The sample was divided into middle-aged (mean age 50, range 40-59) and older (mean age 69, range 60-84) individuals. Cross-sectionally, we observed that older, but not middle-aged, APOE-ε4 carriers had lower accuracy than ε4 non-carriers, mainly under the hardest discrimination condition. Longitudinally, we observed increases in accuracy in middle-aged APOE-ε4 carriers, suggesting a cognitive phenotype that includes ability to benefit from experience. We observed a longitudinal decrease in older APOE-ε4 carriers, suggesting an AD prodrome.

Interaction between C-reactive protein and cognitive functions according to APOE gene polymorphism in post-menopausal women

“…A potential factor increasing the risk of the development of cognitive impairment with age is apolipoprotein E (APOE) ε4 carrier status [3, 4]. The human APOE gene is a polymorphic protein, consisting of three alleles (ε2, ε3 and ε4) that code for three protein isoforms, known as APOE2, APOE3, and APOE4.…”

The Elusive Nature of APOE ε4 in Mid-adulthood: Understanding the Cognitive Profile

“…Longitudinal measures (Greenwood et al, 2014) revealed no genotype difference across trials with relatively low WM demand. On trials incorporating a mismatch between encoded and target stimuli, and hence placing greater demand on WM resources, however, performance of ε4+ improved over 3 years, whilst performance of the ε4-group remained stable.…”

“…Several studies suggest that ε4+ show significantly greater memory decline from mid-adulthood (Caselli et al, 2009;Kozauer, Mielke, Chan, Rebok, & Lyketsos, 2008), with this effect isolated to delayed memory in two studies (Greenwood, Sunderland, Putnam, Levy, & Parasuraman, 2005b;Greenwood et al, 2014). Performance change across an average of 3.8 years was investigated for measures of memory (Jochemsen, Muller, van der Graaf, & Geerlings, 2012), with participants stratified by age.…”

Listening Comprehension in Middle-Aged Adults

“…The current report summarizes my results using both cross-sectional and longitudinal approaches, with a particular emphasis on middle-aged adults between the ages of 40 and 60 years. The focus on middle-aged adults will serve to establish whether any observed changes in listening comprehension parallel the well-documented declines in both sensory and cognitive abilities in this age group (Greenwood, Espeseth, Lin, Reinvang, & Parasuraman, 2014;Morrell, Gordon-Salant, Pearson, Brant, & Fozard, 1996).…”

“…On one hand, the expectation might be systematic and progressive declines in listening comprehension across the adult lifespan that parallel age-related declines in auditory thresholds (Morrell et al, 1996) and cognitive abilities (Greenwood et al, 2014). For example, Schneider, Daneman, Murphy, and See (2000) found that when audibility was equated across groups of younger and older adults, they performed similarly on measures of listening comprehension.…”