Introduction: Cerebral small vessel disease (SVD) is increasingly recognised as a key factor in dementia and cognitive impairment, although its role in the pathogenesis of Alzheimer’s disease (AD) remains poorly understood. Through the investigation of how SVD relates and interacts with (1) molecular AD pathologies and (2) early midlife risk factors of dementia, this body of work aims to advance our understanding of SVD in relation to AD.

Methods: In two separate cohorts, SVD was quantified on 3T MRI through the assessment of white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB), and lacunes. Regional data on SVD location was used to derive composite scores for global SVD burden, and the SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. The first objective was investigated in the Neuroimaging of Inflammation in Memory and Other Disorders (NIMROD) study, which consisted of multimodal PET imaging of older adults with varying degrees of clinical severity. Here, we investigated whether SVD was associated and interacted with the hallmark AD pathologies of amyloid, tau, and neuroinflammation (microglial activation) – these were quantified with PET imaging of [11C]PiB, [18F]AV-1451, and [11C]PK11195, respectively. For insights into the pre-clinical stages of AD pathogenesis, we examined cognitively healthy midlife adults from the PREVENT-Dementia study. We investigated whether well-established risk factors of late-life dementia were related to SVD burden much earlier on, at midlife.

Results: SVD was associated with PET markers of neuroinflammation and tau, and plasma Aβ. Notably, associations with amyloid and tau markers were largely limited to WMH. In healthy middle-aged adults, inherited predisposition to dementia (APOE4, parental family history of dementia) was related to longitudinal SVD progression, but not baseline SVD severity. On the other hand, modifiable risk factors of late-life dementia were associated with midlife SVD burden. The two SVD subtypes were differentially related to AD pathologies and risk factors – neuroinflammation and modifiable risk factors were more closely associated with hypertensive arteriopathy, while amyloid and tau related more closely to cerebral amyloid angiopathy.

Conclusions: Together, our findings implicate SVD in the early pathogenesis of AD and suggest that lifestyle modifications as early as midlife may reduce the vascular-driven component of AD. Findings highlight the need to further inspect the biological underpinnings of WMH and fluid markers of AD pathology.