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4 homozygotes with Alzheimer's diseaseFrom the Geriatric Research, Education, and Clinical Center (Drs. Craft and Schellenberg), VA Puget Sound Health Care System, and the Departments of Psychiatry and Behavioral Sciences (Drs. Craft and Teri), Epidemiology (S.D. Edland and Dr. Kukull), Medicine (Drs. Schellenberg, McCormick, Bowen, and Larson), and Neurology (Dr. Bowen), University of Washington School of Medicine, Seattle.
Address correspondence and reprint requests to Dr. Suzanne Craft, Geriatric Research, Education, and Clinical Center (182B), VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98018<scraft@u.washington.edu>.
Background: The apolipoprotein E-
4 (APOE-4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-4 homozygotes have an earlier age at onset, increased amyloid burden, and decreased acetylcholine levels-findings that suggest differences in disease severity or rate of progression. Studies of genotype differences in rate of decline, however, have produced negative results that may be due to methodologic biases. The current study examined rate of decline in the largest sample of APOE-genotyped AD patients for whom longitudinal cognitive data have been reported.
Methods: Newly diagnosed patients with probable AD (n = 201) comprised four genotype groups: 2/3 (n = 14), 3/3 (n = 75), 3/4 (n = 82), and 4/4 (n = 30). The Dementia Rating Scale (DRS) was administered at baseline and then annually for 1 to 6 years (mean, 2.5 years). For each subject, a DRS slope was calculated reflecting annual rate of decline. Rate of decline as measured by DRS slope differed according to genotype, with the effect modified by DRS score (p < 0.014). At the mean DRS score observed in our sample (DRS = 105), the 4/4 group had an increased rate of decline (11.9 points per year) relative to the2/3 (5.8 points per year; p < 0.003), 3/3(9.3 points per year; p < 0.076), and 3/4 (9.6 points per year; p < 0.055) groups. At a lower DRS score(DRS = 80), even larger differences were observed among genotypes; the4/4 group had a increased rate of decline (22.2 points per year) relative to the 2/3 (9.7 points per year; p < 0.0006), 3/4 (15.8 points per year; p < 0.020), and3/3 (18.2 points per year; p < 0.173) groups. The2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105.
Conclusions: APOE-4 homozygosity is associated with a faster rate of cognitive decline, whereas the 2 allele slows disease progression. These findings suggest that APOE plays a mechanistic role in the progression of AD, and is not simply related to disease onset.
Supported by NIA U01 AG-06781 (Alzheimer's Disease Patient Registry, E.B.L., P.I.), R01 AG-10880 (S.C.), R01 AG-05136 (S.D.E.), Alzheimer's Association IIRG 95-1151 (S.C.), and the Department of Veterans Affairs.
Received October 27, 1997. Accepted in final form March 19, 1998.
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