A common single nucleotide polymorphism in DIO2, Thr92AlaD2, has been associated with a transcriptome typically found in neurodegenerative diseases in postmortem human brain tissue. To determine whether Thr92AlaD2 is associated with incident Alzheimer disease (AD). Population-based study; human brain tissue microarray. Community-based cohorts from Chicago and northeastern Illinois and religious clergymen from across the United States constituted the primary population. A representative sample of the U.S. population was used for secondary analyses. 3054 African Americans (AAs) and 9304 European Americans (EAs). Incident AD. In the primary population, AAs with Thr92AlaD2 had 1.3 times [95% confidence interval (CI), 1.02 to 1.68; P = 0.048] greater odds of developing AD. AAs from a second population with Thr92AlaD2 showed a trend toward increased odds of dementia (odds ratio, 1.33; 95% CI, 0.99 to 1.78; P = 0.06) and 1.35 times greater odds of developing cognitive impairment not demented (CIND; 95% CI, 1.09 to 1.67; P = 0.006). Meta-analysis showed that AAs with Thr92AlaD2 had 1.3 times increased odds of developing AD/dementia (95% CI, 1.07 to 1.58; P = 0.008). In EAs, no association was found between Thr92AlaD2 and AD, dementia, or CIND. Microarray of AA brain tissue identified transcriptional patterns linked to AD pathogenesis. Thr92AlaD2 was associated with molecular markers known to underlie AD pathogenesis in AAs, translating to an observed phenotype of increased odds of developing AD/dementia in AAs in these populations. Thr92AlaD2 might represent one factor contributing to racial discrepancies in incident AD.