Sex differences in brain aging among adults with family history of Alzheimer’s disease and APOE4 genetic risk

Sivaniya Subramaniapillai,Sricharana Rajagopal,Jamie Snytte,A Ross Otto,Gillian Einstein,M Natasha Rajah

doi:10.1016/j.nicl.2021.102620

Sivaniya Subramaniapillai, Sricharana Rajagopal + Show 4 more

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https://doi.org/10.1016/j.nicl.2021.102620

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Abstract

Emerging evidence suggests that Alzheimer’s Disease (AD) risk factors may differentially contribute to disease trajectory in women than men. Determining the effect of AD risk factors on brain aging in women, compared to men, is critical for understanding whether there are sex differences in the pathways towards AD in cognitively intact but at-risk adults. Brain Age Gap (BAG) is a concept used increasingly as a measure of brain health; BAG is defined as the difference between predicted age (based on structural MRI) and chronological age, with negative values reflecting preserved brain health with age. Using BAG, we investigated whether there were sex differences in the brain effects of AD risk factors (i.e., family history of AD, and carrying an apolipoprotein E ε4 allele [+APOE4]) in cognitively intact adults, and if this relationship was moderated by modifiable factors (i.e. body mass index [BMI], blood pressure and physical activity). We undertook a cross-sectional study of structural MRIs from 1067 cognitively normal adults across four neuroimaging datasets. An elastic net regression model found that women with a family history of AD and +APOE4 genotype had more advanced brain aging than their male counterparts. In a sub-cohort of women with those risk factors, higher BMI was associated with less brain aging whereas lower BMI was not. In a sub-cohort of women and men with +APOE4, engaging in physical activity was more beneficial to men’s brain aging than women’s. Our results demonstrate that AD risk factors are associated with greater brain aging in women than men, although there may be more unexplored modifiable factors that influence this relationship. These findings suggest that the complex interplay between unmodifiable and modifiable AD risk factors can potentially protect against brain aging in women and men.

Highlights

Women represent two-thirds of the cases of late-onset Alzheimer’s Disease (AD; Alzheimer’s Association, 2019; Bailly et al, 2019; Mielke et al, 2014; Nebel et al, 2018; Schmidt et al, 2008)
A positive brain age gap (BAG) is linked with dementia, in that some studies show that BAG is a more accurate pre dictor of conversion from Mild Cognitive Impairment (MCI) to AD than other traditional metrics, including cognitive scales and CSF biomarkers (Gaser et al, 2013; Lowe et al, 2016)
T1-weighted (T1w) MRIs were used from four neuroimaging data sets: Dallas Lifespan Brain Study (DLBS), South Asian Lifespan Dataset (SALD), Montreal Memory and Aging Lifespan Study (MMALS), and Presymptomatic Evaluation of Experimental or Novel Treatments for Alz heimer’s Disease (PREVENT-AD)

Summary

Introduction

Women represent two-thirds of the cases of late-onset Alzheimer’s Disease (AD; Alzheimer’s Association, 2019; Bailly et al, 2019; Mielke et al, 2014; Nebel et al, 2018; Schmidt et al, 2008). More sensitive measures for detecting early signs of AD in individuals at risk of the disease are actively investigated One such measure is an individual’s brain age gap (BAG), defined as the difference between predicted brain age and chronological age. A negative BAG reflects preserved brain health in the face of aging and is associated with higher educational attainment (Steffener et al, 2016), and healthy lifestyle factors, such as physical activity (Steffener et al, 2016) and meditation (Luders et al, 2016). A positive BAG reflects decrements in brain health in the face of aging and is associated with poorer physical fitness (Cole et al, 2018), diabetes (Franke et al, 2013), and increased mortality risk (Cole et al, 2018). To our knowledge no study to date has explicitly examined the effect of sex on BAG, and its interaction with AD risk factors (i.e., family history of AD [+FH], and +APOE4 genotype)

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