Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease

Plasma Aβ42 and Aβ40 levels are putative biomarkers for Alzheimer's disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Aβ42 and Aβ40 increase with age but subsequently decrease when Aβ begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Aβ levels in elderly populations, we investigated how plasma Aβ42, Aβ40, and a protofibrillar subspecies of Aβ42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Aβ42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Aβ42, a decreased Aβ42/Aβ40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Aβ42 levels. Our results suggest individuals with elevated plasma Aβ42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Aβ may reflect compartmentalization of Aβ peptides in the brain.