AbstractBackgroundType 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are common diseases in aging populations. Multiple large epidemiological studies suggest that T2DM is strongly associated with cognitive impairment and dementia. Prior studies suggest T2DM may be an important modifier of the relationship between AD and APOE, which is the strongest known genetic risk factor of AD.MethodWe obtained study data from the National Alzheimer’s Coordinating Center (NACC) and included 30,483 participants aged ≥60 years at baseline. T2DM status was determined based on any self‐reported diabetes diagnosis or anti‐diabetes treatment during annual assessments. To facilitate analysis, we created two binary variables to classify participants with regard to T2DM (presence or absence) and APOEε4 (carrier or non‐carrier) status. Cognitive domain scores for memory, attention, language and executive function were standardized using z‐scored neuropsychological tests administered at annual visits. Multivariable linear mixed‐effects models with a cross‐product interaction term between T2DM and APOEε4 status, including main effects, assessed whether the association of APOEε4 with domain‐specific cognitive change was modified by T2DM status. In the subset of participants who underwent autopsy (n = 5,663), we examined whether T2DM modified the association between APOEε4 and neuropathological features using multivariable logistic regression.ResultA significant interaction exists between T2DM and APOE genotype. APOEε4 carriers with T2DM had more rapid declines in attention, language, memory, and executive cognitive scores over time. APOEε4 non‐carriers with T2DM had lesser impairment compared to APOE ε4 carriers without T2DM. Among the autopsied participants, non‐APOE ε4 carriers with T2DM had larger odds of infarcts/lacunes and atherosclerosis. Compared to non‐APOE ε4 carriers without T2DM, APOE ε4 carriers with or without T2DM showed higher odds of AD neuropathological changes (ADNC), but lower odds of ADNC among non‐APOE ε4 carriers with T2DM.ConclusionT2DM modifies the association between APOE ε4 and cognitive decline and AD neuropathological features. T2DM in non‐APOE ε4 carriers increased the risk of infarcts/lacunes but not ADNC.