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Neurology 2003;61:199-205
© 2003 American Academy of Neurology

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology

M.A. Pappolla, MD PhD, T.K. Bryant-Thomas, BS, D. Herbert, PhD, J. Pacheco, BS, M. Fabra Garcia, BS, M. Manjon, BS, X. Girones, BS, T.L. Henry, BS, E. Matsubara, PhD, D. Zambon, MD, B. Wolozin, MD PhD, M. Sano, PhD, F.F. Cruz-Sanchez, MD, L.J. Thal, MD, S.S. Petanceska, PhD* and L.M. Refolo, PhD*

*Co-last authors.
From the University of South Alabama (Drs. Pappolla and Herbert, and T.K. Bryant-Thomas, J. Pacheco, M. Fabra Garcia, M. Manjon, and T.L. Henry), Mobile; Institute of Neurological and Gerontological Sciences (X. Girones and Drs. Zambon and Cruz-Sanchez), International University of Catalonia, Barcelona, Spain; Okayama University Graduate School of Medicine and Dentistry (Dr. Matsubara), Okayama, Japan; Loyola University (Dr. Wolozin), Maywood, IL; Nathan S. Kline Institute for Psychiatric Research (Dr. Petanceska), Orangeburg, NY; Columbia University College of Physicians and Surgeons (Dr. Sano), New York, NY; University of California at San Diego (Dr. Thal), CA; and Institute for the Study of Aging (Dr. Refolo), New York, NY.

Address correspondence and reprint requests to Dr. Miguel A. Pappolla, USAMC-Department of Pathology, 2451 Fillingim Street, Mobile, AL 36617.

Background: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology.

Objective: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain.

Methods: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects.

Results: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden {rho}2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation.

Conclusions: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.




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