Sex modifies the APOE‐related risk of developing Alzheimer disease

Abstract

Objective The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Methods Cox proportional hazards analysis was used to compute hazards ratios (HR) for an APOE-by-sex interaction on conversion in controls (N=5,496) and MCI patients (N=2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the AD Neuroimaging Initiative. Results Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR=1.81 women; HR=1.27 men; interaction P=0.0106). The interaction remained significant in a pre-defined sub-analysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, male and female carriers were more likely to convert to AD (HR=2.16 women; HR=1.64 men). The effect was nominally stronger in women, but the interaction was not significant (P=0.136). In the sub-analysis restricted to APOE3/3 and APOE 3/4 genotypes, the interaction was significant (P= 0.022; HR=2.17 women; HR=1.51 men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients in total-tau and the tau-to-Abeta-ratio (P=0.0088 and P=0.020, respectively; more AD-like in women). Interpretation APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

“…This analysis was performed twice, for the APOE ε4− group and the APOE ε4+ group. We expected that sex differences may modify the effects of genetic risk on EF performance and decline [73]. Therefore, sex was included as a covariate in both group analyses.…”

Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice

“…In AD mice, a difference in cognitive function by sex is observed both at baseline and in response to treatment targeting ApoE receptor signaling (Hinrich et al, 2016). Moreover, women are disproportionately more likely than men to develop the disease, primarily due to longer lifespan (Bachman et al, 1992), and ApoE4 has a stronger effect on AD risk in women compared with men (Altmann et al, 2014), but only because of the greater life expectancy that females enjoy. Since plasma and brain ApoE levels are slightly reduced in ApoE4 individuals (Slooter et al, 1998;Beffert et al, 1999), the mechanism by which ApoE4 causes enhanced risk in women may include a greater susceptibility of women to reduced ApoE.…”

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

“…An additional interaction that modifies AD risk is sex and APOE genotype. Clinical data indicate that the APOE4-induced risk for AD is significantly greater, perhaps exclusive to, females compared with males (77)(78)(79). Mechanistically, APOE4 may increase AD risk in women via multiple pathways involving the cardiovascular system (80), cellular aging (81), and importantly, A␤ accumulation.…”