Background: APOEɛ4 and sex have been linked to increased risk for conversion to Alzheimer's disease (AD). However, the relationship between APOEɛ4 gene dose, sex, and AD biomarkers remains understudied.
Objective: To investigate the effect of APOEɛ4 dose on AD biomarkers in a sample of older adults with mild cognitive impairment (MCI), and to examine whether APOEɛ4 dose modifies AD risk differently in MCI women and men.
Methods: We examined cross-sectional AD biomarkers for participants with MCI (n = 930, 55-96 years old) from three large aging cohorts. Region of interest MRI volumes, global cognition, and episodic memory were analyzed by number of APOEɛ4 alleles and stratified by sex.
Results: Across all participants, number of APOEɛ4 alleles was associated with smaller hippocampal and amygdala volumes and poorer cognition. When stratified by sex, women showed an APOEɛ4 dose effect for bilateral hippocampal and left amygdala volumes and cognition. In contrast, men showed an APOEɛ4 dose effect for hippocampal volumes with a trend in amygdala, but cognition did not differ between men with 1 and 2 APOEɛ4 alleles. Women with 2 APOEɛ4 alleles had poorer memory between 65-69 and poorer global cognition between 70-74 compared to men with 2 APOEɛ4 alleles.
Conclusion: APOEɛ4 confers a dose effect on AD biomarkers in patients with MCI, and the number of APOEɛ4 alleles has a greater detrimental impact in women than men, which may be specific to a critical time window.
Keywords: APOE; Alzheimer’s disease; MRI; genetics; hippocampus; memory; mild cognitive impairment; sex effects.