Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease

Plasma A beta 42 and A beta 40 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 A beta 42 and A beta 40 increase with age but subsequently decrease when A beta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of A beta levels in elderly populations, we investigated how plasma A beta 42, A beta 40, and a protofibrillar subspecies of A beta 42 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 A beta 42 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 A beta 42, a decreased A beta 42/A beta 40 ratio and, with the onset of cognitive impairment, decreased protofibrillar A beta 42 levels. Our results suggest individuals with elevated plasma A beta 42 are at increased risk of AD and that with the onset of disease, the decline in some forms of A beta may reflect compartmentalization of A beta peptides in the brain.