Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study

Audrey Low,Li Su,James D Stefaniak,Elijah Mak,Maria-Eleni Dounavi,Graciela Muniz-Terrera,Karen Ritchie,Craig W Ritchie,Hugh S Markus,John T O'Brien

doi:10.1016/j.neurobiolaging.2020.10.029

Audrey Low, Li Su + Show 8 more

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https://doi.org/10.1016/j.neurobiolaging.2020.10.029

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Abstract

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.

Highlights

Alzheimer's disease (AD) is a neurodegenerative disorder traditionally characterized by aberrant protein accumulation in the brain
We investigate longitudinal changes in small vessel disease (SVD) and inflammation in relation with established heritable risk factors, apolipoprotein ε4 (APOE4) (Strittmatter and Roses, 1996), and parental family history (FH) of dementia (Scarabino et al, 2016)
We examined the effect of inherited predisposition to dementia on SVD and systemic inflammation in healthy midlife adults at baseline and longitudinally

Summary

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder traditionally characterized by aberrant protein accumulation in the brain. Our understanding of AD etiology has expanded, implicating cerebral small vessel disease (SVD) and inflammation as key players in its pathogenesis (Bos et al, 2018; Heneka et al, 2015; Kinney et al, 2018; Wardlaw et al, 2013). The timing and contribution of these alterations early in the disease process remain unclear. This is an important gap to fill, as developing our understanding of vascular and inflammatory changes in the preclinical phase sheds light on the early trajectory and mechanistic pathways leading up to dementia, and facilitates early detection and disease management. In AD, subclinical biological changes are detectable many years before observable symptom onset (Ritchie et al, 2016).

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