Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease

Abstract

Plasma A␤42 and A␤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␤42 and A␤40 increase with age but subsequently decrease when A␤ begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of A␤ levels in elderly populations, we investigated how plasma A␤42, A␤40, and a protofibrillar subspecies of A␤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 followup. Higher plasma A␤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␤42, a decreased A␤42/A␤40 ratio and, with the onset of cognitive impairment, decreased protofibrillar A␤42 levels. Our results suggest individuals with elevated plasma A␤42 are at increased risk of AD and that with the onset of disease, the decline in some forms of A␤ may reflect compartmentalization of A␤ peptides in the brain.plasma amyloid beta40 and beta42 ͉ protofibrillar Abeta A myloid ␤-peptides A␤40 and A␤42 are the two major species generated by sequential proteolytic cleavage by ␤-and ␦-secretases of the amyloid precursor protein (APP) (1). Subsequent deposition of A␤42 has been considered an initial and critical step in the pathogenesis of Alzheimer's disease (AD). Brain levels of A␤42 increase with the development of dementia and are correlated with cognitive decline (2). Mutations in the APP and presenilin (PSEN1 and 2) genes, which result in a dominantly inherited form of early-onset AD, are accompanied by an increase in plasma A␤42 and A␤40 levels in patients before disease onset and are elevated in their unaffected relatives as well (3-5). Furthermore, both A␤42 and A␤40 plasma levels are increased in cognitively normal first-degree relatives of cases with late-onset AD without known mutations (6).The relation between brain and plasma A␤ in health and disease is complex, but studies of AD transgenic mice have provided some insights. Within a few months of birth, APP transgenic mice secreted more A␤42 and A␤40 than their wild-type littermates (7,8), and A␤ secretion is increased throughout the life of APP transgenic mice. Both plasma and cerebrospinal fluid (CSF) levels of A␤42, and to a lesser extent A␤40, increase with age, but both precipitously decrease as A␤42 and A␤40 levels rise in the brain (7). By 1 year, there are frank A␤ plaques, and subsequently there are characteristic agerelated behavioral changes in memory. However, Lesne and colleagues (9) reported that the behavioral effects are not the result of the A␤ accumulation in brain, but the increase in the protofibrillar subspecies of A␤.These observations in mice represent a model for changes in plasma A␤ as a biomarker associated with AD in humans.Among nondemented...

Immune profiling of Alzheimer patients

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