Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

Abstract

Background: We evaluated the amounts of amyloid beta (Abeta)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Abeta plasma levels and Alzheimer's disease (AD) pathology.

Methods: Amyloid beta levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects.

Results: Plasma Abeta levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Abeta40 than disease-free vessels. Inactivated platelets contained more Abeta peptides than activated ones. Substantially more Abeta was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Abeta.

Conclusions: Efforts to use plasma levels of Abeta peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Abeta values is also due in part to the ability of Abeta to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Abeta plasma levels. Furthermore, the long-range impact of Abeta immunotherapy on peripheral Abeta sources should also be considered.

Figure 1

Longitudinal comparison of AD (black) and ND control (white) plasma Aβ levels as measured by ELISA. Measurements were taken at baseline (T=0) and at 3, 6 and 12 months. The horizontal bars represent the mean values. A) Aβ40 pg/ml B) Aβ42 pg/ml.

Figure 2

Plasma Aβ levels measured by ELISA in the therapeutic study with donepezil. Measurements were taken at baseline and 12 weeks later (follow-up). A) Aβ40 pg/ml in donepezil-initiation group B) Aβ42 pg/ml in donepezil-initiation group C) Aβ40 pg/ml in stable-donepezil group D) Aβ42 pg/ml in stable-donepezil group.