Longitudinal Modeling of Age-Related Memory Decline and theAPOEε4 Effect

Abstract

Objective Age-related cognitive decline trajectories were compared in apolipoprotein E (APOE) e4 homozygotes (HMZ), heterozygotes (HTZ), and noncarriers (NC) in the absence of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). Background At how young an age memory decline diverges from that of noncarriers in healthy people with elevated genetic risk for late-onset AD due to APOE e4 is unknown. Methods Cognitively normal participants age 21-97 years were recruited with local ads, grouped using an APOE e4 enrichment paradigm, and had longitudinal neuropsychological testing. Anyone who developed MCI or dementia during followup was excluded. Acceleration of the rates of decline for predetermined cognitive measures were compared between APOE e4/4 HMZ, e3/4 HTZ, and e4 NC using a mixed model for longitudinal change with age. Results 79 e4 HMZ, 238 HTZ and 498 NC were included. APOE e4 carriers were younger (mean 58.0 vs 61.4 years, p<0.001) and had more years of followup (5.3 v 4.7 years, p=0.01), with equivalent education (15.4 years) and gender (69% women). With accelerating declines beginning prior to age 60 in e4 carriers, longitudinal decline in memory in e4 carriers accelerated more than in NC (p=0.0253) with a possible e4 gene-dose effect (p=0.0231) in which longitudinal decline in e4 HMZ accelerated more than in NC (p=0.0087). Weaker similar effects were also found on a visuospatial and general mental status measure. Conclusions Age-related memory decline in APOE e4 carriers diverges from NC prior to age 60 and appears most severe in HMZ despite ongoing normal clinical status.

Episodic memory and executive functions in cognitively healthy individuals display distinct neuroanatomical correlates which are differentially modulated by aging

“…Further longitudinal studies are required to disentangle the precise modulatory role of aging in reverting these relationships in resilient versus vulnerable cognitive aging. Likewise, future studies shall take into account the modulatory role of the APOE‐ε4 allelic load, which has been previously associated to deficient hippocampal pruning (Chung et al, 2016) and significant cognitive decline assessed longitudinally (Caselli et al, 2009). …”

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…With a stronger contrast between patients and controls, the discriminating power of regional EC differences may be useful for diagnostic purposes. Although APOE status is a risk factor for AD (Caselli et al., 2009; Ossenkoppele et al., 2013; Strittmatter, Saunders, et al., 1993), many other processes are involved in causing dementia, so the difference between APOE‐ε4 carriers and noncarriers may be a relatively small AD‐related effect on the brain network.…”

Depression and Risk of Dementia: Exploring the Interface

“…8 Consequently, a similar accelerated increase in depressive symptoms would be anticipated if depression is intrinsic to the Alzheimer's disease syndrome.…”

“…Previously, in the same cohort, the APOE ε4 carriers were shown to have accelerated age-related memory decline despite not crossing the boundary to abnormal cognitive function. 8 If depression is intrinsic to Alzheimer's disease, we would expect a gradual increase in depressive symptoms and incident depression even at this preclinical stage and that this change would happen in tandem with the cognitive changes.…”