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

Background: Plasma amyloid-beta (A beta) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma A beta isoforms, i.e., A beta(1-40) and A beta(1-42) have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma A beta levels including novel A beta(1-38) relate to vascular brain disease and cognition in a preclinical-phase of dementia Objective: To examine the association of plasma A beta levels (i.e., A beta(1-38), A beta(1-40), and A beta(1-42)) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. Methods: We analyzed plasma A beta 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 A beta 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 A beta(1-38), A beta (1-40), A beta(1-42), and A beta(1-40)/A beta(1-42) ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels ofA beta(1-40) andA beta(1-40)/A beta(1-42) were significantly associated with larger WMH volumes. With regard to cognition, a higher level of A beta(1-38) A beta(1-40) and A beta(1-40)/A beta(1-42) was related to worse performance on cognitive test specifically in memory domain. Conclusion: Higher plasma levels of A beta levels are associated with subclinical markers of vascular disease and poorer memory. Plasma A beta levels thus mark the presence of vascular brain pathology.