Neuropathology-Independent Association Between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum

Abstract

Background and objectives: We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies.

Methods: We analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling.

Results: Carrying the APOEε4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOEε3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOEε4 carriers declined faster than APOEε3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOEε4 vs APOEε3/ε3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOEε4 vs APOEε3/ε3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOEε4 vs APOEε3/ε3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOEε4 vs APOEε3/ε3). Compared with slow decliners, fast decliners were more likely to carry the APOEε4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy.

Discussion: In a large national sample selected to represent the normal aging-early AD continuum, the APOEε4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.

Figure 1. Flowchart of Study Participants

CDR-SOB = Clinical Dementia Rating scale Sum Of Boxes; CERAD = Consortium to Establish a Registry for Alzheimer Disease; MMSE = Mini-Mental State Examination; NFT = neurofibrillary tangle; NP = neuritic plaque.

Figure 2. Effects of APOE Genotype on CDR-SOB and MMSE Trajectories

Model 3–based trajectories for CDR-SOB (A) and MMSE (B) scores with the intercept at the time of death calculated for an 86-year-old woman with 15 years of education and autopsy findings of CERAD NP score moderate and Braak NFT stage III/IV. Graphs depict the 3 APOE groups in latent class 1 (slow decliners) and latent class 2 (fast decliners) as well as the differences APOEε4 vs APOEε3 and APOEε2 vs APOEε3. Shaded areas correspond to the 95% CIs. CDR-SOB = Clinical Dementia Rating scale Sum Of Boxes; CERAD = Consortium to Establish a Registry for Alzheimer Disease; MMSE = Mini-Mental State Examination; NFT = neurofibrillary tangle; NP = neuritic plaque.

Figure 3. Effects of APOE Genotype on Cognitive Domain–Specific Trajectories

Model 3–based trajectories for memory- (A), attention- (B), executive- (C), and language-specific (D) composite z scores with the intercept at the time of death calculated for an 86-year-old woman with 15 years of education and autopsy findings of CERAD NP score moderate and Braak NFT stage III/IV. Graphs depict the 3 APOE groups in latent class 1 (slow decliners) and latent class 2 (fast decliners) as well as the differences APOEε4 vs APOEε3 and APOEε2 vs APOEε3. Shaded areas correspond to the 95% CIs. CERAD = Consortium to Establish a Registry for Alzheimer Disease; NFT = neurofibrillary tangle; NP = neuritic plaque.