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Gary W. Small, MD; Ernest P. Noble, PhD, MD; Steven S. Matsuyama, PhD; Lissy F. Jarvik, MD, PhD; Scott Komo, MS; Andrea Kaplan; Terry Ritchie, PhD; Meredyth L. Pritchard, MS; Ann M. Saunders, PhD; P. Michael Conneally, PhD; Allen D. Roses, MD; Jonathan L. Haines, PhD; Margaret A. Pericak-Vance, PhD

Arch Neurol. 1997;54(3):281-285.

Abstract
Background
The apolipoprotein E4 (APOE*4) allele is a major risk factor for the common forms of late-onset Alzheimer disease (AD), but does not account for all the genetic variation in late-onset AD; hence, other genetic markers must be examined. The D₂ dopamine receptor (DRD2) A1 allele is associated with abnormal brain function and decreased DRD2s. These receptors are decreased in hippocampus and amygdala in AD, and allele frequencies may vary with age.

Objective
To study APOE and DRD2 genotypes in patients with AD and cognitively intact controls of varying ages.

Design
The DRD2 and APOE genotypes were examined in 832 unrelated white subjects, including 554 patients with AD (486 sporadic; 68 familial) and 278 controls. Logistic regressions tested Al allele effects on disease status and age, and DRD2 linkage with AD was investigated in 60 families with late-onset AD.

Setting
University medical centers.

Subjects
Patients (mean±SD age, 74.6±8.1 years; range, 52-98 years) had probable AD, according to standard consensus diagnostic criteria; controls (mean±SD age, 69.2±8.6 years; range, 50-93 years) were cognitively intact.

Main Outcome Measures
Disease status, age, and DRD2 linkage with AD.

Results
No association between the DRD2 and APOE alleles was found, and the presence of the Al allele did not increase the risk for AD. There was also no evidence of linkage between DRD2 and AD. Age analyses, including both patients and controls, indicated a decrease in Al allele frequency with age.

Conclusions
The Al allele does not contribute to AD risk, alone or in combination with the APOE*4 allele. The DRD2 Al allele frequencies decrease with age in both patients and controls. Thus, studies of DRD2 disease association need to control for age.

Author Affiliations
From the Department of Psychiatry and Biobehavioral Sciences (Drs Small, Noble, Matsuyama, Jarvik, and Ritchie, Mr Komo, and Ms Kaplan), Neuropsychiatric Institute (Drs Small, Noble, Matsuyama, and Jarvik, Mr Komo, and Ms Kaplan), Alzheimer's Disease Center (Drs Small, Matsuyama, and Jarvik), and the Alcohol Research Center and Brain Research Institute (Drs Noble and Ritchie), UCLA School of Medicine; VA Medical Center, West Los Angeles, Calif (Drs Small, Matsuyama, and Jarvik); Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC (Ms Pritchard and Drs Saunders, Roses, and Pericak-Vance); Indiana University, Indianapolis (Dr Conneally); and the Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown (Dr Haines).

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