Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging

Abstract

Objective: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men.

Methods: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, ¹⁸F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology).

Results: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aβ deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001).

Conclusions: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.

Figure 1. 18F-fluoro-2-deoxyglucose (FDG)–PET brain glucose metabolism as a function of chronologic vs endocrine aging

Statistical parametric maps (SPMs) display FDG uptake reductions in (A) asymptomatic perimenopausal women, (B) perimenopausal women, and (C) menopausal women vs men. SPMs are represented on a color-coded scale (1 < z < 3, where z > 2 corresponds to p < 0.001) and displayed on a standardized MRI.

Figure 2. Pittsburgh compound B (PiB)–PET β-amyloid deposition as a function of chronologic vs endocrine aging

Statistical parametric maps (SPMs) display increased ¹¹C-PiB uptake in (A) asymptomatic perimenopausal women, (B) perimenopausal women, and (C) menopausal women vs men. SPMs are represented on a color-coded scale (1 < z < 3, where z > 2 corresponds to p < 0.001) and displayed on a standardized MRI.

Figure 3. MRI brain volumes as a function of chronologic vs endocrine aging

Statistical parametric maps (SPMs) display (left) gray matter and (right) white matter volume reductions in (A) asymptomatic perimenopausal women, (B) perimenopausal women, and (C) menopausal women vs men. SPMs are represented on different color-coded scales (1 < z < 3, where z > 2 corresponds to p < 0.001) and displayed on a standardized MRI.

Figure 4. Comparing Alzheimer disease (AD) biomarker abnormalities across groups

(A) ¹⁸F-fluoro-2-deoxyglucose (FDG) uptake. (B) Pittsburgh compound B (PiB) uptake. (C) Gray matter volumes. (D) White matter volumes. Biomarkers are extracted from frontal cortex clusters showing maximal statistical differences across groups and displayed on the same scale. Values are grand-mean scaled, reference-adjusted mean values, SEM. *p < 0.05, **p < 0.01. CNT = asymptomatic perimenopausal women by age; PERI = symptomatic perimenopausal women; MENO = postmenopausal women.