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SEX DIFFERENCES IN MODIFIABLE AND NON-MODIFIABLE RISK FACTORS ON MIDLIFE CEREBRAL SMALL VESSEL DISEASE: THE PREVENT-DEMENTIA STUDY
SEX DIFFERENCES IN MODIFIABLE AND NON-MODIFIABLE RISK FACTORS ON MIDLIFE CEREBRAL SMALL VESSEL DISEASE: THE PREVENT-DEMENTIA STUDY
Abstract
Background and Aims
Cerebral small vessel disease (SVD) is a key factor in dementia, often manifesting prior to symptom onset. However, sex differences on modifiable and non-modifiable risk factors on cerebrovascular health in healthy midlife adults are not well-documented.
Methods
Cognitively-healthy middle-aged adults (40-59y) underwent 3T MRI (n=630). To assess SVD, we quantified white matter hyperintensity volume (WMHv), enlarged perivascular spaces (EPVS), microbleeds, lacunes, and derived composite scores of global SVD burden, hypertensive arteriopathy and cerebral amyloid angiopathy (CAA-SVD). Modifiable midlife risk factors were based on the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Sex*risk interactions were analysed using general linear models (predicting individual SVD markers) and structural equation modelling (SEM; analysing latent variables of risk and of SVD).
Results
Sex interacted with APOE4 in relation to WMHv (t=-2.39, p=0.017) and centrum semiovale EPVS (t=-2.19, p=0.029), such that APOE4 related to greater SVD in females but not males (Figure 1). Conversely, sex*age interactions demonstrated that the effect of age on SVD were more pronounced in males than in females (global SVD: t=2.03, p=0.042; WMHv : t=1.97, p=0.049; basal ganglia EPVS: t=2.16, p=0.031, microbleeds: t=3.09, p=0.002) (Figure 2). In SEM, the effect of modifiable risk on CAA-SVD (but not global SVD or hypertensive arteriopathy) was amplified in males (Figure 3) (b=0.21, p=0.002).
Conclusions
As early as midlife, SVD related to differential risk factors in males (age, modifiable risk factors) and females (APOE4), and differed by SVD subtype. Such sex differences could shed light on biological underpinnings and targeted interventions.