Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study

Abstract

Background Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD. Methods Cognitively healthy middle-aged adults (aged 40–59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction. Results In SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (β = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (β = − 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results. Conclusions Established modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major ‘silent’ contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.

The PREVENT dementia programme: baseline demographic, lifestyle, imaging and cognitive data from a midlife cohort study investigating risk factors for dementia

“… 51 WMH volume did not differ by APOEɛ4 status or family history of dementia in unadjusted analysis or adjusted analyses controlling for sex, age, education and site. 18 WMH burden increased with older age in both the unadjusted ( t = 8.15, P < 0.001) and adjusted analysis controlling for sex, education and site ( t = 7.91, P < 0.001). Males (2.99 ml) had greater WMH volumes than females (1.81 ml), even after normalizing for head size [(WMH volume/intracranial volume) ∗ 100%; males = 0.16, females = 0.11]—results were significant in both unadjusted ( ρ = 0.25, P < 0.001) and covariate-adjusted analyses of WMH burden ( t = 5.41, P < 0.001).…”

Age-related hearing loss and dementia risk causality: two-way Mendelian randomization analysis

“…There is no causal genetic relationship between the two, which aligns with the results of the present study. In addition, vascular dementia is the second most common type of dementia after Alzheimer's disease [6,30] . Hearing impairment as a risk factor is associated with vascular dementia, which may be related to in ammatory responses, oxidative stress in cells, or even the pathogenesis of blood circulation disorders.…”

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife

“…Hence, at this early stage whereby all participants in the study are cognitively asymptomatic, we have shown that the dominant risk gene for sporadic AD modulates differentially the association between cerebral perfusion and RDW, mainly in distal vascular territories. Further investigation is thus warranted on how hemodynamic and potentially hemorheological properties could be interacting with APOE4 carriership in impacting cerebrovascular health and physiology, especially in the absence of prominent differences both physiologically and structurally 73 , 74 between APOE4 carriers and non-carriers.…”