Plasma Amyloid-β Levels, Cerebral Small Vessel Disease, and Cognition: The Rotterdam Study

Background: Plasma amyloid-β (Aβ) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Aβ isoforms, i.e., Aβ1-40 and Aβ 1-42 have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma Aβ levels including novel Aβ 1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementia Objective: To examine the association of plasma Aβ levels (i.e., Aβ1-38, Aβ 1-40, and Aβ 1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. Methods: We analyzed plasma A-1 levels in 1201 subjects from two independent cohorts of the Rotterdam Study. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Aβ levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-Analysis with fixed effects. Results: Higher levels of plasma Aβ 1-38, Aβ 1-40, Aβ 1-42, and Aβ 1-40/ Aβ 1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels ofAβ1-40 andAβ 1-40/ Aβ1-42 were significantly associated with largerWMH volumes. With regard to cognition, a higher level of Aβ 1-38 Aβ 1-40 and Aβ 1-40/ Aβ 1-42 was related to worse performance on cognitive test specifically in memory domain. Conclusion: Higher plasma levels of Aβ levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Aβ levels thus mark the presence of vascular brain pathology.

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