Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, while the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with a low Alzheimer’s dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of the disease.

This table provides a summary of all cases with the clinical diagnosis of Alzheimer's dementia and all cognitively unimpaired controls with APOE genotypes in the ADGC database. Participants in the combined group consisted of neuropathologically confirmed autopsy and neuropathologically unconfirmed clinical subjects, excluding neuropathologically misclassified subjects. Since the ADGC used both clinical and neuropathological criteria to prioritize autopsy participants in the ADGC database, the table does not include a substantial number of clinically characterized but neuropathologically mischaracterized cases and controls. The neuropathologically confirmed group contained participants available with clinical diagnosis, the APOE genotype, and an age variable (age at dementia onset, age at death, or age at last clinical evaluation). Affection status of cases and controls in the autopsied sample was defined by clinical diagnosis.

Supplementary
The neuropathologically unconfirmed group includes clinically diagnosed but neuropathologically uncharacterized cases and controls.
AAO: Estimated age at dementia onset (when available) in the Alzheimer's dementia cases in years.
AAD: Age at death in the neuropathologically confirmed cases and controls in years.
AAE: Age at last clinical evaluation (when available) in the combined cases and controls in years.
Mean (Mean) and standard deviation (SD) for AAO, AAD, and AAE ranged from Mean-SD and Mean+SD, Mean±SD. For genotypic association tests, odds ratio (OR), 95% confidence interval (CI), and P value (P) for each APOE genotype compared to the APOE3/3 genotype were calculated under a logistic regression model.

Supplementary
For allelic association tests, OR, CI, and P associated with APOE2 allelic dose in APOE4 non-carriers (APOE2/2<2/3<3/3) and APOE4 allelic dose in APOE2 non-carriers (APOE4/4>3/4>3/3) in an additive genetic model were generated under a logistic regression model. The combined group included the 28,864 cases and controls from the neuropathologically confirmed and unconfirmed groups.

Supplementary
Association tests in a logistic regression model were conducted using clinical diagnosis as an outcome without adjustment (Model 1), with age and sex as covariates (Model 2), and with age, sex, and autopsy status as covariates (Model 3).
For genotypic association tests, odds ratio (OR), 95% confidence interval (CI), and P value (P) for each APOE genotype compared to the APOE3/3 genotype were calculated under a logistic regression model.

Supplementary
Ref: reference genotype to test association of each APOE genotype in a linear regression model Mean (Mean) and standard deviation (SD) for AAO, AAD, and AAE ranged from Mean-SD and Mean+SD, Mean±SD.
Beta estimate (BETA), standard error (SE), and P value (P) for each APOE genotype compared to the APOE3/3 genotype as a reference (ref) were calculated under a linear regression model.
Unadjusted: results from a linear regression for CERAD scores or Braak stages without adjusting for any covariates.
Adjusted for AAD and Sex: results from a linear regression for CERAD scores or Braak stages after adjusting for age at death (AAD) and sex as covariates.