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Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease.
Neurology 1998; 51(1):149-53Neur

Abstract

BACKGROUND

The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon4 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: epsilon2/3 (n = 14), epsilon3/3 (n = 75), epsilon3/4 (n = 82), and epsilon4/4 (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 epsilon4/4 group had an increased rate of decline (11.9 points per year) relative to the epsilon2/3 (5.8 points per year; p < 0.003), epsilon3/3 (9.3 points per year; p < 0.076), and epsilon3/4 (9.6 points per year; p < 0.055) groups. At a lower DRS score (DRS = 80), even larger differences were observed among genotypes; the epsilon4/4 group had a increased rate of decline (22.2 points per year) relative to the epsilon2/3 (9.7 points per year; p < 0.0006), epsilon3/4 (15.8 points per year; p < 0.020), and epsilon3/3 (18.2 points per year; p < 0.173) groups. The epsilon2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105.

CONCLUSIONS

APOE-epsilon4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon2 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.

Authors+Show Affiliations

Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle 98018, USA. scraft@u.washington.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9674794

Citation

Craft, S, et al. "Accelerated Decline in Apolipoprotein E-epsilon4 Homozygotes With Alzheimer's Disease." Neurology, vol. 51, no. 1, 1998, pp. 149-53.
Craft S, Teri L, Edland SD, et al. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology. 1998;51(1):149-53.
Craft, S., Teri, L., Edland, S. D., Kukull, W. A., Schellenberg, G., McCormick, W. C., ... Larson, E. B. (1998). Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology, 51(1), pp. 149-53.
Craft S, et al. Accelerated Decline in Apolipoprotein E-epsilon4 Homozygotes With Alzheimer's Disease. Neurology. 1998;51(1):149-53. PubMed PMID: 9674794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. AU - Craft,S, AU - Teri,L, AU - Edland,S D, AU - Kukull,W A, AU - Schellenberg,G, AU - McCormick,W C, AU - Bowen,J D, AU - Larson,E B, PY - 1998/7/23/pubmed PY - 1998/7/23/medline PY - 1998/7/23/entrez SP - 149 EP - 53 JF - Neurology JO - Neurology VL - 51 IS - 1 N2 - BACKGROUND: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon4 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: epsilon2/3 (n = 14), epsilon3/3 (n = 75), epsilon3/4 (n = 82), and epsilon4/4 (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 epsilon4/4 group had an increased rate of decline (11.9 points per year) relative to the epsilon2/3 (5.8 points per year; p < 0.003), epsilon3/3 (9.3 points per year; p < 0.076), and epsilon3/4 (9.6 points per year; p < 0.055) groups. At a lower DRS score (DRS = 80), even larger differences were observed among genotypes; the epsilon4/4 group had a increased rate of decline (22.2 points per year) relative to the epsilon2/3 (9.7 points per year; p < 0.0006), epsilon3/4 (15.8 points per year; p < 0.020), and epsilon3/3 (18.2 points per year; p < 0.173) groups. The epsilon2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105. CONCLUSIONS: APOE-epsilon4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon2 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. SN - 0028-3878 UR - https://www.unboundmedicine.com/medline/citation/9674794/Accelerated_decline_in_apolipoprotein_E_epsilon4_homozygotes_with_Alzheimer's_disease_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&amp;PAGE=linkout&amp;SEARCH=9674794.ui DB - PRIME DP - Unbound Medicine ER -