D2 dopamine receptor A1 allele in Alzheimer disease and aging
G. W. Small, E. P. Noble, S. S. Matsuyama, L. F. Jarvik, S. Komo, A. Kaplan, T. Ritchie, M. L. Pritchard, A. M. Saunders, P. M. Conneally, A. D. Roses, J. L. Haines and M. A. Pericak-Vance
Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine; VA Medical Center, West Los Angeles, Calif, USA.
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 A1 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 A1 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 A1 allele frequency with
age. CONCLUSIONS: The A1 allele does not contribute to AD risk, alone or in
combination with the APOE*4 allele. The DRD2 A1 allele frequencies decrease
with age in both patients and controls. Thus, studies of DRD2 disease
association need to control for age.
