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Plasma amyloid β protein is elevated in late-onset Alzheimer disease families

From the Departments of Neuroscience (N.E.-T., L.H.Y., D.M.Y., M.C.B., M.L.H., S.G.Y.) and Neurology (F.P., N.R.G.-R.), Mayo Clinic Jacksonville, FL; Department of Neurology (N.E.-T.), Mayo Clinic Rochester, MN; and Wisconsin Alzheimer’s Institute and Geriatrics and Gerontology (S.A.), Madison.

Address correspondence and reprint requests to Dr Younkin, Department of Neuroscience, 4500 San Pablo Road South, Jacksonville, FL 32224 younkin.steve{at}mayo.edu

Objective: Plasma Aβ levels are elevated in early-onset Alzheimer disease (AD) caused by autosomal dominant mutations. Our objective was to determine whether similar genetic elevations exist in late-onset AD (LOAD).

Methods: We measured plasma Aβ in first-degree relatives of patients with LOAD in a cross-sectional series and in extended LOAD families. We screened these subjects for pathogenic mutations in early-onset AD genes and determined their ApoE genotypes.

Results: Plasma Aβ is significantly elevated in the LOAD first-degree relatives in comparison to unrelated controls and married-in spouses. These elevations are not due to ApoE 4 or pathogenic coding mutations in the known early-onset AD genes.

Conclusions: The findings provide strong evidence for the existence of novel, as yet unknown genetic factors that affect late-onset Alzheimer disease by increasing Aβ.

Abbreviations: AD = Alzheimer disease; COV = coefficient of variation; ELISA = enzyme-linked immunosorbent assay; EOFAD = early-onset familial AD; IDE = insulin-degrading enzyme; LOAD = late-onset AD; MMSE = Mini-Mental State Examination; NGR = neurology examination; RFLP = restriction fragment length polymorphism.

Editorial, page 586

e-Pub ahead of print on October 3, 2008, at www.neurology.org.

Supported in part by NIH grants AG18023 (S.G.Y.), AG06656 (S.G.Y.), AG16574 (Mayo Clinic AD Research Center grant), and a Robert H. and Clarice Smith Fellowship (N.E.T.) and as part of the Robert H. and Clarice Smith and Abigail Van Buren AD Research Program.

Disclosure: Drs. Graff-Radford, L.H. Younkin, and S.G. Younkin have been included as inventors in a patent application filed by the Mayo Clinic on the Aβ42/Aβ40 ratio as a predictive test for MCI and AD.

Received December 4, 2006. Accepted in final form June 1, 2007.

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