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

BACKGROUND: Plasma amyloid-beta (Abeta) levels are increasingly studied as a potential, accessible marker of cognitive impairment and dementia. The most common plasma Abeta isoforms, i.e., Abeta1-40 and Abeta1-42 have been linked with risk of Alzheimer's disease. However, it remains under-explored whether plasma Abeta levels including novel Abeta1-38 relate to vascular brain disease and cognition in a preclinical-phase of dementiaObjective:To examine the association of plasma Abeta levels (i.e., Abeta1-38, Abeta1-40, and Abeta1-42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. METHODS: We analyzed plasma Abeta1 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 Abeta 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 Abeta1-38, Abeta1-40, Abeta1-42, and Abeta1-40/ Abeta1-42 ratio were associated with increasing lacunar and microbleeds counts. Moreover, higher levels of Abeta1-40 and Abeta1-40/ Abeta1-42 were significantly associated with larger WMH volumes. With regard to cognition, a higher level of Abeta1-38 Abeta1-40 and Abeta1-40/ Abeta1-42 was related to worse performance on cognitive test specifically in memory domain. CONCLUSION: Higher plasma levels of Abeta levels are associated with subclinical markers of vascular disease and poorer memory. Plasma Abeta levels thus mark the presence of vascular brain pathology