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Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

ABSTRACT: Plasma Abeta42 and Abeta40 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 Abeta42 and Abeta40 increase with age but subsequently decrease when Abeta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Abeta levels in elderly populations, we investigated how plasma Abeta42, Abeta40, and a protofibrillar subspecies of Abeta42 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 Abeta42 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 Abeta42, a decreased Abeta42/Abeta40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Abeta42 levels. Our results suggest individuals with elevated plasma Abeta42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Abeta may reflect compartmentalization of Abeta peptides in the brain.

SUBMITTER: Schupf N

PROVIDER: S-EPMC2544577 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

Schupf Nicole N Tang Ming X MX Fukuyama Hide H Manly Jennifer J Andrews Howard H Mehta Pankaj P Ravetch Jeffery J Mayeux Richard R

Proceedings of the National Academy of Sciences of the United States of America 20080908 37

Plasma Abeta42 and Abeta40 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 Abeta42 and Abeta40 increase with age but subsequently decrease when Abeta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Abeta levels in elderly populations, we investigated how plasma Abeta42, Abeta40, and a prot ...[more]

PMID: 18779561

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Project description:Many factors are involved in Alzheimer's disease (AD) pathology including tau phosphorylation, amyloid β protein (Aβ) accumulation, lipid dysregulation, oxidative stress, and inflammation. The markers of these pathological processes in cerebral spinal fluid are used currently for AD diagnosis. However, peripheral biomarkers are the need of the hour for large population screening for AD. The main objective of the present study is to evaluate the peripheral levels of redox markers, lipid peroxidation (LPO) indicators, and pathological markers in AD patients. Blood was collected from AD patients (n = 45), controls (n = 45), and analyzed for pathological markers of AD including Aβ42 and tau, LPO, and redox indicators. Plasma Aβ42 was significantly (P < 0.001) elevated while total tau was decreased in AD compared to controls. Hydroxynonenal (HNE) and malondialdehyde (MDA) were higher (P < 0.001) in AD patients pointing the enhanced LPO in AD pathology. Receiver operating characteristic curve (ROC) analysis indicated that HNE is a better indicator of LPO compared to MDA. Plasma glutathione (GSH) level was significantly (P < 0.001) low while oxidized glutathione (GSSG) level was higher (P < 0.001) in AD patients with corresponding decrease in GSH/GSSG ratio (P < 0.001). ROC analysis indicated that GSH/GSSG ratio can be used as reliable indicator for redox imbalance in AD with a cutoff value of <8.73 (sensitivity 91.1%, specificity 97.8%). Correlation analysis revealed a positive correlation for both HNE and MDA with Aβ42 and a negative correlation with total tau. Negative correlation was observed between GSH/GSSG ratio and LPO markers. While oxidative stress has been implicated in pathology of various neurodegenerative disorders, the present study pinpoints the direct link between LPO and Aβ production in plasma of AD patients. Normally, at low amyloid concentration in body fluids, this peptide shown to function as a strong metal chelating antioxidant. However, when the Aβ production enhanced as in AD, through gain of functional transformation, Aβ evolves into prooxidant, thereby enhancing oxidative stress and LPO. Altered redox status with enhanced LPO observed in AD blood could contribute to the oxidation and S-glutathionylation proteins, which has to be addressed in future studies.

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Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

Publications

Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

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