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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Low, Audrey 
Prats-Sedano, Maria A 
McKiernan, Elizabeth 
Carter, Stephen F 
Stefaniak, James D 

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.

Description

Keywords

APOE4, Alzheimer’s disease, Cerebral small vessel disease, Lifestyle, Modifiable risk factors, Prevention, Adult, Apolipoprotein E4, Cerebral Amyloid Angiopathy, Cerebral Small Vessel Diseases, Dementia, Humans, Hypertension, Magnetic Resonance Imaging, Middle Aged, Risk Factors

Journal Title

Alzheimers Res Ther

Conference Name

Journal ISSN

1758-9193
1758-9193

Volume Title

Publisher

BioMed Central
Sponsorship
National Institute for Health and Care Research (IS-BRC-1215-20014)