For nearly 20 years, the prevalent view has been that women who carry copies of the ε4 allele of the apolipoprotein E (APOE) gene have a greater risk of developing Alzheimer disease (AD) than men with the same number of copies.¹ The ε4 allele is the main genetic risk factor for late-onset Alzheimer disease (AD),² and sex-based differences in AD risk have important implications for treatment trials, diagnostics, and therapeutics.³ Additionally, the sex-dependent relationship between APOE and mild cognitive impairment (MCI), which is often a transitional phase from cognitively normal (NL) aging to dementia,⁴ is unclear. Studies are in general agreement that the APOE ε4 allele is a risk factor for developing MCI,^5-11 but there is controversy as to whether it increases^10,12-14 or does not increase^9,11,15,16 the risks of transitioning from MCI to AD or dementia. The 3 most common alleles of the APOE gene are ε2, ε3, and ε4; whereas carrying the ε4 allele increases one’s risk of developing AD, the ε2 allele conversely has a putative protective effect that is associated with longevity and a lower AD risk.¹⁷

Manual segmentation from magnetic resonance imaging (MR) is the gold standard for evaluating hippocampal atrophy in Alzheimer's disease (AD). Nonetheless, different segmentation protocols provide up to 2.5-fold volume differences. Here we surveyed th

Objectives: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non–Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). Methods: We measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [¹⁸F]-fluorodeoxyglucose–PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A− and N+/N− based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A−N+ cases. Results: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A−N−, A+N−, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N− and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A−N−, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N− patients did not (hazard ratio = 1.13, p = 0.771). In A+N− and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073). Conclusions: Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.