期刊
NEUROLOGY
卷 96, 期 19, 页码 E2414-E2428出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000011883
关键词
-
资金
- National Institute of Neurological Disorders and Stroke (NINDS) [R01NS094610]
- National Institute on Aging (NIA) [P30AG066512-01, R21AG053695, P30 AG062421-01, K08AG064039, P30 AG019610, P30 AG013846, P30 AG062428-01, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P30 AG062422-01]
- NINDS [R01NS094610, R25NS065743]
- Alzheimer's Association [AACF-17-524184]
- NIA/NIH [U01 AG016976]
- NIA [P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P30 AG062429-01, P50 AG023501, P30 AG035982, P30 AG028383]
- [P30 AG053760]
- [P30 AG010124]
- [P50 AG005133]
- [P50 AG005142]
- [P30 AG012300]
- [P30 AG049638]
- [P50 AG005136]
- [P30 AG062715-01]
- [P50 AG005681]
- [P50 AG047270]
The study found that compared to the APOE epsilon 3/epsilon 3 reference genotype, the APOE epsilon 2 and epsilon 4 alleles have opposite effects on the rate of cognitive decline. These effects are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies, indicating that APOE genotype contributes to the heterogeneity in the rate of clinical progression in AD.
Objective To test the hypothesis that the APOE genotype is a significant driver of heterogeneity in Alzheimer disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation. Methods We applied novel reverse-time longitudinal models to analyze the trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores-2 common outcome measures in AD clinical trials-in 1,102 autopsy-proven AD cases (moderate/frequent neuritic plaques and Braak tangle stage III or greater) from the National Alzheimer's Coordinating Center Neuropathology database resembling participants with mild to moderate AD in therapeutic clinical trials. Results APOE epsilon 4 carriers exhibited approximate to 1.5 times faster CDR-SOB increase than APOE epsilon 3/epsilon 3 carriers (2.12 points per year vs 1.44 points per year) and approximate to 1.3 times faster increase than APOE epsilon 2 carriers (1.65 points per year), whereas APOE epsilon 2 vs APOE epsilon 3/epsilon 3 difference was not statistically significant. APOE epsilon 4 carriers had approximate to 1.1 times faster MMSE decline than APOE epsilon 3/epsilon 3 carriers (-3.45 vs -3.03 points per year) and approximate to 1.4 times faster decline than APOE epsilon 2 carriers (-2.43 points per year), whereas APOE epsilon 2 carriers had approximate to 1.2 times slower decline than APOE epsilon 3/epsilon 3 carriers (-2.43 vs -3.03 points per year). These findings remained largely unchanged after controlling for the effect of AD neuropathologic changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies. Conclusion Compared to the APOE epsilon 3/epsilon 3 reference genotype, the APOE epsilon 2 and epsilon 4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD.
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