Decreased clearance of CNS beta-amyloid in Alzheimer's disease

Abstract

Alzheimer's disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer's disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer's disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer's disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer's disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer's disease is characterized by an overall impairment in Aβ clearance.

Figure 1

Aβ kinetics in the CNS of twelve AD participants (red triangles) and twelve controls (blue circles). The amount of labeled Aβ42 and Aβ40 was measured and compared between groups to measure production and clearance rates of both Aβ species. (A) The average normalized labeled Aβ42 time course. (B) Aβ42 clearance rate during the clearance phase (hours 24–36). (C) Normalized labeled Aβ40 time course. (D) Aβ40 clearance in AD compared to controls. (E) The average fractional synthesis rates of Aβ42 and Aβ40 in AD participants and cognitively normal controls. (F) The average fractional clearance rates of Aβ42 and Aβ40.