Does the Female Advantage in Verbal Memory Contribute to Underestimating Alzheimer's Disease Pathology in Women versus Men?

Abstract

There is a growing recognition of sex differences in Alzheimer's disease (AD). Females show an advantage over males on tests of verbal memory, which are used to diagnose AD and its precursor, amnestic mild cognitive impairment (aMCI). Women retain this advantage in aMCI despite reduced hippocampal volume and temporal lobe glucose metabolism. Here we examined whether this female advantage endures despite evidence of AD-specific pathology, cortical amyloid-β (Aβ) deposition measured with [18F]AV45 (florbetapir) positron emission tomography. Participants with normal cognition (N = 304), aMCI (N = 515), and AD dementia (N = 175) were drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Across and within diagnostic groups, we conducted linear regressions to examine the interaction of sex with cortical Aβ burden on immediate and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) adjusting for age, education, and APOE4. In the overall group, sex by cortical Aβ interaction was significant for delayed recall only. Overall, delayed recall performance was significantly better in women versus men among those with low to moderate Aβ burden, but women and men performed similarly among those with high Aβ burden. In diagnosis-stratified analyses, a significant sex by cortical Aβ interaction was observed for delayed recall in the aMCI group, but not in the normal or AD dementia groups. Thus, women maintain a verbal memory advantage over men in aMCI despite similar levels of AD pathology. Although this advantage may benefit women by delaying verbal memory impairment until more advanced pathology, it may also delay diagnosis of aMCI and treatment intervention.

Keywords: Amyloid; cognitive reserve; memory; positron-emission tomography; sex.

Figure 1.. RAVLT immediate recall scores as a function of cortical [¹⁸F]AV45 SUVR and sex in the (A) overall group, (B) Normals, (C) aMCI and (D) AD dementia.

Note. Sex × cortical [¹⁸F]AV45 SUVR interaction just missed significance in the overall sample (A, p=0.06), and was not significant in diagnosis-specific groups of Normals (B), aMCI (C) and AD (D) (p’s>0.05). SUVR = standardized uptake value ratio, RAVLT = Rey Auditory Verbal Learning Test. β = sex-specific standardized regression coefficient of the relationship between RAVLT scores and cortical [¹⁸F]AV45 SUVR controlling for age, education and ApoE4 and diagnosis (overall sample only). aMCI = amnestic mild cognitive impairment. AD = Alzheimer’s disease.

Figure 2.. RAVLT delayed recall scores as a function of cortical [¹⁸F]AV45 SUVR and sex in the (A) overall group, (B) Normals, (C) aMCI and (D) AD dementia.

Note. Sex × cortical [¹⁸F]AV45 SUVR interaction was significant in the overall sample (A, p=0.0007) and in aMCI (C, p=0.009), but not in Normals (B) or AD (D) (p’s>0.05). SUVR= standardized uptake value ratio. RAVLT = Rey Auditory Verbal Learning Test. β = sex-specific standardized regression coefficient of the relationship between RAVLT scores and cortical [¹⁸F]AV45 controlling for age, education, ApoE4 and diagnosis (overall sample only). aMCI = amnestic mild cognitive impairment. AD = Alzheimer’s disease.