Apolipoprotein E  4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study

Abstract

Background: Among elderly people without dementia, the apolipoprotein E e4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex. Methods: In a community-dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70-74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT). Results: Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes. Conclusions: Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.

Androgen-Mediated Immune Function Is Altered by the Apolipoprotein E Gene

“…In this case, although a decrease in testosterone level is observed, it does not reach statistically significant values. In addition, males who are homozygous for the APOE4 allele demonstrate a significant downward shift in scores for episodic memory compared with male APOE4 heterozygotes (33). A relationship between learning and memory deficits and APOE genotype has also been observed in mice expressing human APOE3 or human APOE4 under a neuron-directed promoter (neuronal-specific enolase) (34).…”

Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease

“…These results are consistent with a previous study that found a significant association between APOE ε4 and cognitive decline between the ages of 70 to 80 in women only, 24 and with another study that found that episodic memory was more impaired in APOE ε3/ε4 women than in ε3/ε4 men between the ages of 70 to 74. 25 Mechanisms that underlie these sex differences may be linked to physiologic changes associated with menopause and estrogen loss that on average begin at 51 years of age 35 just prior to our risk groups. Studies in animals and humans have reported an interaction between APOE ε4, menopause, and cognitive decline (for a review, see reference 36 ).…”

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

“…This finding has been replicated several times and yet is almost never considered or investigated in clinical AD research where male and female APOE4 carriers are generally viewed as having equal risk(Bretsky et al, 1999; Payami et al, 1996). In the few recent studies that have examined this interaction between APOE4 and gender, female, but not male, APOE4 carriers have shown more pronounced AD-like changes in neuroimaging, neuropathological, and neuropsychological measures when compared to their APOE3 homozygous peers(Corder et al, 2004; Damoiseaux, Seeley, et al, 2012; Fleisher et al, 2005; Lehmann et al, 2006). In mouse models designed for AD research, the same interaction between APOE and gender was identified years ago, so that today many studies only carry out experiments in female mice(Andrews-Zwilling et al, 2010; Raber, Bongers, LeFevour, Buttini, & Mucke, 2002; Raber et al, 1998).…”