The Relation between Apolipoprotein A-I and Dementia
The Honolulu-Asia Aging Study
Jane S. Saczynski1, Lon White2,3, Rita L. Peila1, Beatriz L. Rodriguez2,3, and Lenore J. Launer1
1Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging,
2Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI.
3Pacific Health Research Institute, Honolulu, HI.
Received for publication July 28, 2006; accepted for publication October 19, 2006.
The association between apolipoproteins and neurodegeneration is unclear. The authors examined the asso-
ciation of dementia with serum levels of apolipoprotein A-I (ApoA-I) alone and in combination with the apolipopro-
tein E genotype (ApoE). Subjects were Japanese-American men in Hawaii followed since 1965 in the Honolulu
Heart Program cohort and the Honolulu-Asia Aging Study. Lipid levels were assessed in 1980–1982. Dementia
was diagnosed in 1991–1993, 1994–1996, and 1997–1999 by using a multistep procedure and international
guidelines. The sample consisted of 929 men (107 dementia cases). The relation between ApoA-I and dementia
was examined by using Cox proportional hazards models adjusted for age, education, and cardiovascular risk
factors. Compared with men in the lowest quartile, men in the highest quartile of ApoA-I concentration had
a significantly lower risk of dementia (hazard ratio ¼ 0.25, 95% confidence interval: 0.08, 0.78). Compared with
men with both risk factors, those with a high ApoA-I concentration and no ApoE e4 had a significantly lower risk of
dementia (hazard ratio ¼ 0.21, 95% confidence interval: 0.08, 0.52). Previous work has demonstrated an inverse
relation between ApoA-I and cardiovascular disease, and the authors extended these findings to the risk of
dementia. These results raise the possibility that different lipoprotein components of cholesterol may be differen-
tially associated with dementia.
apolipoproteins; apolipoproteins E; dementia; lipids
Abbreviations: ApoA-I, apolipoprotein A-I; ApoE, apolipoprotein E; CI, confidence interval; HDL, high density lipoprotein;
HR, hazard ratio.
Editor’s note: An invited commentary on this article is
published on page 993.
Evidence is increasing for an association between Alz-
heimer’s disease and lipids (1, 2). Lipids may influence
neurodegeneration through direct effects on the neurons or
vessels (3), through atherosclerosis (4), or by chronic in-
flammation of the brain (5–7). High density lipoprotein
(HDL)–like particles traffic cholesterol in the brain and
are related to cholesterol metabolism, which may play an
important role in amyloid b metabolism and deposition in
the brain (8).
HDL particles are heterogeneous in size and apolipopro-
tein composition. It has been suggested that variability in
these aspects of the HDL molecule may affect the anti-
atherogenic properties of the lipoprotein. Apolipoprotein
Correspondence to Dr. Jane S. Saczynski, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Gateway
Building, Room 3C-309, 7201 Wisconsin Avenue, Bethesda, MD 20892 (e-mail: firstname.lastname@example.org).
985 Am J Epidemiol 2007;165:985–992
American Journal of Epidemiology
Copyright ª 2007 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved; printed in U.S.A.
Vol. 165, No. 9
Advance Access publication February 13, 2007
by guest on December 28, 2015
40. Barzilai N, Atzmon G, Schechter C, et al. Unique lipoprotein
phenotype and genotype associated with exceptional longev-
ity. JAMA 2003;290:2030–40.
41. Eckert G, Kirsch C, Leutz, et al. Cholesterol modulates amy-
loid beta-peptide’s membrane interactions. Pharmacopsy-
42. Fagan AM, Younkin LH, Morris JC, et al. Differences in the
Abeta40/Abeta42 ratio associated with cerebrospinal fluid
lipoproteins as a function of apolipoprotein E genotype. Ann
43. Navab M, Anantharamaiah GM, Fogelman AM. The role of
high-density lipoprotein in inflammation. Trends Cardiovasc
44. Navab M, Hama SY, Cooke CJ, et al. Normal high density
lipoprotein inhibits three steps in the formation of mildly
oxidized low density lipoprotein. J Lipid Res 2000;41:
45. Garner B, Waldeck AR, Witting PK, et al. Oxidation of high
density lipoproteins. Evidence for direct reduction of lipid
hydroperoxides by methionine residues of apolipoprotein A-I
and A-II. J Biol Chem 1998;273:6088–95.
46. Kontush A, Chapman MJ. Antiatherogenic small, dense
HDL—guardian angel of the arterial wall? Nat Clin Pract
Cardiovasc Med 2006;3:144–53.
47. Ma J, Brewer B, Potter H. Alzheimer Ab neurotoxicity: pro-
motion by antichymotrypsin, ApoE4; inhibition by Ab-related
peptides. Neurobiol Aging 1996;17:773–80.
48. Herz J, Beffert U. Apolipoprotein E receptors: linking brain
development and Alzheimer’s disease. Nat Rev Neurosci
49. Gong JS, Kobayashi M, Hayashi H, et al. Apolipoprotein E
(ApoE)-isoform-dependent lipid release from astrocytes pre-
pared from human ApoE3- and ApoE4-knock-in mice. J Biol
50. Michikawa M, Fan QW, Isobe I, et al. Apolipoprotein E
exhibits isoform-specific promotion of lipid efflux from
astrocytes and neurons in culture. J Neurochem 2000;74:
51. Michikawa M, Yanagisawa K. Apolipoprotein E4 isoform-
specific actions on neuronal cells in culture. Mech Ageing Dev
52. Zhong S, Sharp DS, Grove JS, et al. Increased coronary heart
disease in Japanese-American men with mutation on the
cholesteryl ester transfer protein gene despite increased HDL
levels. J Clin Invest 1996;97:2917–23.
53. Nagano M, Yamashita S, Hirano K, et al. Molecular mech-
anisms of cholesteryl ester transfer protein deficiency in
Japanese. J Atheroscler Thromb 2004;11:110–21.
992 Saczynski et al.
Am J Epidemiol 2007;165:985–992
by guest on December 28, 2015