Lifestyle Affects Amyloid Burden and Cognition Differently in Men and Women

Abstract

Objective: Evidence on associations of lifestyle factors with Alzheimer's pathology and cognition are ambiguous, potentially because they rarely addressed inter-relationships of factors and sex effects. While considering these aspects, we examined the relationships of lifestyle factors with brain amyloid burden and cognition.

Methods: We studied 178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective study of volunteers who completed ¹⁸ F-Flutemetamol amyloid positron emission tomography. Using structural equation modeling, we examined associations between latent constructs representing metabolic/vascular risk, physical activity, and cognitive activity with global amyloid burden and cognitive performance. Furthermore, we investigated the influence of sex in this model.

Results: Overall, higher cognitive activity was associated with better cognitive performance and higher physical activity was associated with lower amyloid burden. The latter association was weakened to a nonsignificant level after excluding multivariate outliers. Examination of the moderating effect of sex in the model revealed an inverse association of metabolic/vascular risk with cognition in men, whereas in women metabolic/vascular risk trended toward increased amyloid burden. Furthermore, a significant inverse association between physical activity and amyloid burden was found only in men. Inheritance of an APOE4 allele was associated with higher amyloid burden only in women.

Interpretation: Sex modifies effects of certain lifestyle-related factors on amyloid burden and cognition. Notably, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer's disease through distinct paths in women and men. ANN NEUROL 2022;92:451-463.

FIGURE 1

Path diagram picturing the structural model. Latent constructs of Metabolic/Vascular Risk, Physical Activity, and Cognitive Activity were used to investigate the relationship with Amyloid Burden (log‐transformed) and the Cognition construct with Age and APOE4 as exogenous variables. The ellipse‐shaped variables represent the latent constructs. Black arrows indicate significant paths at *p < 0.05, **p < 0.01, and ***p < 0.001. Grey arrows indicate non‐significant paths. Each single‐headed arrow denotes a unidirectional effect of one variable on another and left–right‐headed arrows indicate correlations between constructs or correlated residuals of indicators. Note that only estimates on paths going to a particular outcome variable are comparable as they are adjusted for each other. R² refers to the amount of variance in Cognition and Amyloid Burden accounted for by the model and involves significant and nonsignificant predictors. Abbreviations: BMI = body mass index; CA = cognitive activity; PA = physical activity; HDL‐C = high‐density lipoprotein cholesterol; TG = triglycerides; HbA1c = hemoglobin A1c; SUVR = standardized uptake value ratio. N = 232.

FIGURE 2

Multigroup comparison. Results of the multigroup analysis model depicted on separate models for (A) men (N = 125) and (B) women (N = 107). Factor loadings are the same for men and women and roughly correspond to the factor loadings in the full model (Fig 1). For a simplified representation, indicators and factor loadings were removed. Values on each path represent standardized estimates, standard error in parentheses, and p value. Abbreviation: SUVR = standardized uptake value ratio.

FIGURE 3

Summarized results of sex comparison. Solid lines indicate significant associations between the manifestation of the corresponding lifestyle‐related factor and amyloid burden (A + B) and cognition (C + D). Dotted lines indicate non‐significant paths. Plots are separately shown for men (A + C) and women (B + D). Abbreviations: CA = cognitive activity; LSF = lifestyle‐related factor; MVR = metabolic/vascular risk; PA = physical activity.