Accelerated decline in apolipoprotein E-ε4 homozygotes with Alzheimer's disease

Background: The apolipoprotein E-epsilon 4 (APOE-epsilon 4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon 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: epsilon 2/3 (n = 14), epsilon 3/3 (n = 75), epsilon 3/4 (n = 82), and epsilon 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 epsilon 4/4 group had an increased rate of decline (11.9 points per year) relative to the epsilon 2/3 (5.8 points per year; p < 0.003), epsilon 3/3 (9.3 points per year; p < 0.076), and epsilon 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; the epsilon 4/4 group had a increased rate of decline (22.2 points per year) relative to the epsilon 2/3 (9.7 points per year; p < 0.0006), epsilon 3/4 (15.8 points per year; p < 0.020), and epsilon 3/3 (18.2 points per year; p < 0.173) groups. The epsilon 2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105. Conclusions: APOE-epsilon 4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon 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.