Progression of cerebral small vessel disease in healthy middle‐aged adults associated with inherited risk of Alzheimer’s disease: The PREVENT‐Dementia study

Abstract

AbstractBackgroundSubclinical brain changes in Alzheimer’s disease (AD) are detectable many years before symptom onset. While cerebral small vessel disease (SVD) has been well‐established as a key pathology in AD, whether genetic predisposition to AD influences markers of SVD in midlife remains unclear. In this study, we compare the longitudinal change in SVD burden between cognitively healthy middle‐aged adults with and without genetic predisposition to AD, and their effect on cognitive decline.Method151 cognitively‐normal participants (age 52.0 ± 5.5; PREVENT‐Dementia study) underwent 3T MRI and cognitive assessment at baseline and two‐year follow‐up. Genetic predisposition to AD was assessed by family history of parental dementia (FH) and APOE4 carriership. White matter hyperintensity (WMH) volumes were segmented and manually corrected on FLAIR MRI and cerebral microbleeds (CMB) on susceptibility‐weighted imaging (Figure 1). WMH volume was adjusted for total intracranial volume and inverse‐normal transformed. SVD progression was compared between groups using ANCOVA and linear mixed modelling in R controlling for sex, age, and education.ResultCross‐sectionally, WMH and CMB did not differ by FH or APOE4 status. However, longitudinal data showed greater WMH progression in FH+ subjects (t=3.94, p<.001) and APOE4+ (t=2.09, p=.038) (Figure 2). The effect of FH on WMH progression was stronger for periventricular WMH (t=3.65, p<.001; deep WMH: t=2.13, p=.035), while APOE4+ subjects displayed greater progression of deep (t=3.30, p=.001), but not periventricular WMH (t=1.17, p=.243). CMB progression did not differ by FH or APOE4 status. Significant three‐way interaction indicated that longitudinal decline in processing speed was associated with global and deep WMH progression in FH+ but not FH‐ subjects (global: t=2.05, p=.042; deep: t=2.90, p=.004; periventricular: t=0.87, p=.384) (Figure 3), while no effect was observed regarding APOE4 carriership.ConclusionCognitively‐healthy individuals with a genetic predisposition to AD displayed greater WMH progression in midlife. WMH progression was associated with longitudinal decline in processing speed in those with FH of parental dementia, but not in those without FH. Taken together, findings suggest that WMH progression is evident decades before dementia might occur, and may be of clinical relevance in predicting cognitive decline particularly in individuals at increased inherited risk of AD.