Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia, cognitive impairment, and decline

Abstract

We examined longitudinal associations between ApoE4 + status and several cognitive outcomes and tested effect modification by sex. Data on 644 Non-Hispanic White adults, from the Baltimore Longitudinal Study of Aging (BLSA) were used. Dementia onset, cognitive impairment and decline were assessed longitudinally. After 27.5 years median follow-up, 113 participants developed dementia. ApoE4 + predicted dementia significantly (HR=2.89; 95% CI: 1.93-4.33), with non-significant sex differences. Taking all time points for predicting cognition, women had significantly stronger positive associations than men between ApoE4 + status and impairment or decline on the California Verbal Learning Test (CVLT-delayed recall and List A total recall) and on Verbal Fluency Test-Categories. This ApoE4×sex interaction remained significant with bonferroni correction only for CVLT-delayed recall. Taking time points prior to dementia for cognitive predictions, the positive association between impairment in CVLT-delayed recall and ApoE4 + status remained stronger among women, though only before bonferroni correction. While ApoE4+ status appears to be a sex neutral risk factor for dementia, its association with verbal memory and learning decline and impairment was stronger among women.

Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning

“…Possessing the APOE4 allele is a well-established risk factor for susceptibility to nonfamilial Alzheimer's disease (26), and a lower age of onset and higher risk of Alzheimer's disease (72,311,421). There is a greater risk for Alzheimer's disease in women with APOE4 compared to men (60). HT interacts with genetic background, as women specifically without an APOE4 allele have improved mood and cognition with estradiol-based HT (617).…”

Obesity and sex interact in the regulation of Alzheimer's disease

“…Additionally, female apoE4 carriers exhibit a significantly greater risk than male apoE4 carriers of converting to MCI, and from MCI to dementia (Altmann et al, 2014). ApoE4 is also more strongly linked to cognitive dysfunction (Beydoun et al, 2012) and brain atrophy (Holland et al, 2013; Liu et al, 2010) in women. Healthy older female, but not male, apoE4 carriers have decreased default mode network activity that is correlated with cerebrospinal fluid levels of tau protein (Damoiseaux et al, 2012).…”

Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction

“…Beydoun et al found a main effect of APOE on conversion from healthy aging to AD (Beydoun et al, 2012). Though the effect was numerically greater in women than men, the formal interaction was not significant.…”