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OBJECTIVES: To reexamine a health-protective role of the common apolipoprotein E ( APOE) polymorphism focusing on connections between the APOEℇ2—containing genotypes and impairments in instrumental activities of daily living (IADLs) in older (≥65) men and women and to examine how diagnosed coronary heart disease (CHD), Alzheimer's disease, colorectal cancer, macular degeneration, and atherosclerosis may mediate these connections. DESIGN: Retrospective cross-sectional study. SETTING: The unique disability-focused data from a genetic subsample of the 1999 National Long Term Care Survey linked with Medicare service use files. PARTICIPANTS: One thousand seven hundred thirty-three genotyped individuals interviewed regarding IADL disabilities. MEASUREMENTS: Indicators of IADL impairments, five geriatric disorders, and ℇ2-containing genotypes. RESULTS: The ℇ2/3 genotype is a major contributor to adverse associations between the ℇ2 allele and IADL disability in men (odds ratio (OR)=3.09, 95% confidence interval (CI)=1.53–6.26), although it provides significant protective effects for CHD (OR=0.55, 95% CI=0.33–0.92), whereas CHD is adversely associated with IADL disability (OR=2.18, 95% CI=1.28–3.72). Adjustment for five diseases does not significantly alter the adverse association between ℇ2-containing genotypes and disability. Protective effects of the ℇ2/3 genotype for CHD (OR=0.52, 95% CI=0.27–0.99) and deleterious effects for IADLs (OR=3.50, 95% CI=1.71–7.14) for men hold in multivariate models with both these factors included. No significant associations between the ℇ2-containing genotypes and IADL are found in women. CONCLUSION: The ℇ2 allele can play a dual role in men, protecting them against some health disorders, while promoting others. Strong adverse relationships with disability suggest that ℇ2-containing genotypes can be unfavorable factors for the health and well-being of aging men. [ABSTRACT FROM AUTHOR]