OBJECTIVE

To test the hypothesis that the 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

ε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than ε3/ε3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than ε2 carriers (1.65 points per year), whereas ε2 vs ε3/ε3 difference was not statistically significant. ε4 carriers had ≈1.1 times faster MMSE decline than ε3/ε3 carriers (-3.45 vs -3.03 points per year) and ≈1.4 times faster decline than ε2 carriers (-2.43 points per year), whereas ε2 carriers had ≈1.2 times slower decline than ε3/ε3 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 ε3ε3 reference genotype, the ε2 and ε4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential allele effects on AD and comorbid pathologies. Thus, genotype contributes to the heterogeneity in rate of clinical progression in AD.