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Published online before print May 28, 2008, doi:10.1212/01.wnl.0000303973.71803.81)
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 Volume 71, Number 2, July 8, 2008
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NEUROLOGY 2008;71:85-92
© 2008 American Academy of Neurology

Biochemical markers in persons with preclinical familial Alzheimer disease

J. M. Ringman, MD, S. G. Younkin, MD, PhD, D. Pratico, MD, W. Seltzer, PhD, G. M. Cole, PhD, D. H. Geschwind, MD, PhD, Y. Rodriguez-Agudelo, PhD, B. Schaffer, MA, J. Fein, MA, S. Sokolow, PhD, E. R. Rosario, PhD, K. H. Gylys, PhD, A. Varpetian, MD, L. D. Medina, BA and J. L. Cummings, MD

From Alzheimer Disease Research Center, UCLA Department of Neurology (J.M.R., G.M.C., D.H.G., B.S., L.D.M., J.L.C.), School of Nursing (J.F., S.S., K.H.G.), and Department of Medicine (E.R.R.), University of California, Los Angeles; Department of Pharmacology (S.G.Y.), Mayo Clinic, Jacksonville, FL; Department of Pharmacology (D.P.), Temple University, Philadelphia, PA; Athena Diagnostics, Inc. (W.S.), Worcester, MA; Greater Los Angeles Veterans Affairs Geriatric Research (G.M.C.), Education, and Clinical Center; National Institute of Neurology and Neurosurgery (Y.R.-A.), Mexico City, Mexico; and Department of Neurology (A.V.), Keck School of Medicine, USC, Rancho Los Amigos National Rehabilitation Center, Downey, CA.

Address correspondence and reprint requests to Dr. John M. Ringman, UCLA Department of Neurology, Alzheimer Disease Research Center, 10911 Weyburn Ave, Suite 200, Los Angeles, CA 90095-7226 jringman{at}mednet.ucla.edu

Background: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease.

Methods: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Aβ40, Aβ42, F2-isoprostanes) and CSF (F2-isoprostanes, t-tau, p-tau181, Aβ40, Aβ42, and Aβ42/Aβ40 ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs).

Results: Plasma Aβ42 levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Aβ42/Aβ40 (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Aβ42 levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Aβ42 to Aβ40 was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau181 levels were elevated in presymptomatic FAD MCs. CSF levels of F2-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031).

Conclusions: Our data indicate that Aβ42 is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Aβ42 to Aβ40 was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau181 are sensitive indicators of presymptomatic disease. Our finding of elevated F2-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.

Abbreviations: AD = Alzheimer disease; APP = amyloid precursor protein; CDR = Clinical Dementia Rating; FAD = familial Alzheimer disease; MC = mutation carrier; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; NC = noncarrier; PSEN1 = presenilin-1.

Editorial, page 78

e-Pub ahead of print on May 28, 2008, at www.neurology.org.

Supported by PHS K08 AG-22228, CA DHS #04-35522, the Shirley and Jack Goldberg Trust, and the Brotman Foundation of California. Further support for this study came from Alzheimer’s Disease Research Center Grants P50 AG-16570, PHS R01 AG-21055 from the National Institute on Aging, General Clinical Research Centers Program M01-RR00865, an Alzheimer’s Disease Research Center of California grant, and the Sidell Kagan Foundation.

Disclosure: William Seltzer is a consultant for Athena Diagnostics. Otherwise, the authors have nothing relevant to this study to disclose.

Received July 20, 2007. Accepted in final form November 8, 2007.


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