Association of APOE Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease

Abstract

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 ε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOE ε3/ε3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than APOE ε2 carriers (1.65 points per year), whereas APOE ε2 vs APOE ε3/ε3 difference was not statistically significant. APOE ε4 carriers had ≈1.1 times faster MMSE decline than APOE ε3/ε3 carriers (-3.45 vs -3.03 points per year) and ≈1.4 times faster decline than APOE ε2 carriers (-2.43 points per year), whereas APOE ε2 carriers had ≈1.2 times slower decline than APOE 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 APOE ε3/ε3 reference genotype, the APOE 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 APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD.

Figure 1. Flowchart of Study Participants

ADNC = Alzheimer disease neuropathological changes; CERAD = Consortium to Establish a Registry of Alzheimer’s Disease; NACC = National Alzheimer’s Coordinating Center; NP = neuritic plaque; UDS = Uniform Data Set.

Figure 2. Effect of APOE Alleles on Global Functional and Cognitive Outcome Measures (CDR-SOB and MMSE) Scores

(A and E) Model-based cognitive trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) (A) and Mini-Mental State Examination MMSE (E) scores by APOE allele groups (APOE ε3/ε3, APOE ε2, and APOE ε4 carriers) with the intercept at the time of death calculated for an 82-year-old woman with 15 years of education and autopsy findings of frequent Consortium to Establish a Registry of Alzheimer’s Disease (CERAD) neuritic plaque (NP) score and Braak neurofibrillary tangle (NFT) stage V/VI, but without adjustments for the effect of these neuropathologic variables on the rate of cognitive decline or for comorbid pathologies (model 1). (C and G) Model-based cognitive trajectories of CDR-SOB (C) and MMSE (G) scores by APOE group with the intercept at the time of death calculated for an 82-year-old woman with 15 years of education and autopsy findings of frequent CERAD NP score and Braak NFT stage V/VI and no comorbid pathologies and with adjustments for the effect of AD neuropathologic variables (CERAD and Braak) on the rate of cognitive decline and for comorbid pathologies (model 2). Note the nearly identical trajectories with and without controlling for neuropathology. (B, D, F, and H) Difference of model-based cognitive trajectories of CDR-SOB (B and D) and MMSE (F and H) scores between APOE allele groups (APOE ε2 and APOE ε4 vs APOE ε3/ε3 carriers) under models 1 (B and F) and 2 (D and H). Shaded areas represent the corresponding 95% confidence intervals.

Figure 3. Effect of APOE Alleles on Cognitive Domain–Specific Composite Measures

(A, C, E, and G) Model-based cognitive trajectories of (A) memory, (C) executive, (E) attention, and (G) language composite-measures z scores by APOE allele with the intercept at the time of death calculated for an 82-year-old woman with 15 years of education and autopsy findings of frequent Consortium to Establish a Registry of Alzheimer’s Disease (CERAD) neuritic plaque score and Braak neurofibrillary tangle stage V/VI and no comorbid pathologies and with adjustments for the effect of Alzheimer disease neuropathologic variables (CERAD and Braak) on the rate of cognitive decline and for comorbid pathologies (model 2). (B, D, F, and H) Difference of model-based cognitive trajectories of (B) memory, (D) executive, (F) attention, and (H) language composite-measures z scores between APOE allele groups (APOE ε2 and APOE ε4 vs APOE ε3/ε3 carriers) under model 2. Shaded areas represent the corresponding 95% confidence intervals.