IMPORTANCE Late-onset Alzheimer disease (AD) the most common form of dementia places a large burden on families and society. association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria. MAIN OUTCOMES AND MEASURES The primary outcome was the pleiotropic (conjunction) false discovery rate value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer’s Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer’s Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data). RESULTS Eight single-nucleotide polymorphisms (false discovery rate <. 05) were associated with both AD and immune-mediated diseases. Of these rs2516049 (closest gene =. 04 Fraxin for AD and psoriasis 5. 37 × 10? 5 for AD and 6. 03 × 10? 15 for psoriasis) and rs12570088 (closest gene =. 009 for AD and Crohn disease = 5. 73 × 10? 6 for AD and 6. 57 × 10? 5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology SNX25 (=. 01352 and. 03151 respectively); rs2516049 additionally correlated with longitudinal decline on Fraxin Alzheimer’s Disease Assessment Scale cognitive subscale scores (β [SE] 0. 405 [0. 190]; =. 03). Regarding gene expression and transcript expression was significantly altered in AD brains compared with control Fraxin brains (= 1 . 97 × 10? 10; = 7. 57 × 10? 13). CONCLUSIONS AND RELEVANCE Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression. Alzheimer disease (AD) is the most common neurodegenerative disease with an estimated prevalence of 30 million people worldwide a number that is expected to quadruple in the next 40 years. 1 Currently there is no effective treatment that delays onset or slows progression of AD. With the aging of the US population and high costs associated with caring for cognitively impaired elderly individuals identifying strategies that prevent AD is of utmost importance. Inflammation a core feature of many immune-mediated diseases is being increasingly recognized as an important etiologic characteristic of AD. Complement factors and activated microglia are established histopathologic features in brains of patients with AD 2 and observational studies and meta-analyses suggest that elevated C-reactive protein levels are associated with increased risk for developing AD. 3 4 Importantly recent associations between AD and genetic variants encoding Fraxin triggering receptor expressed on myeloid cells 2 (values and odds ratios) for clinically diagnosed AD12 and immune-mediated diseases including CD 13 UC 18 RA 14 T1D 15 CeD 16 and PSOR17 (Table 1). We obtained publicly available AD GWAS summary statistics data from the International Genomics of Alzheimer’s Disease Project (IGAP stages 1 and 2; for additional details see eAppendix 2 in the Supplement and the article by Lambert et al12). In this study we used the IGAP stage 1 cohort which consisted of 17 008 patients with AD (mean [SD] age 74. 7 [7. 7 years; 59. 4% female) and 37 154 controls (mean [SD] age 76. 3 [8. 1] years; 58. 6% female) drawn from 4 different consortia across North America and Europe with genotyped or imputed data at 7 055 881 SNPs (for a Fraxin description of the AD cases and controls within the IGAP stage 1 sub-studies see the article by Lambert et al12). The relevant institutional review boards or ethics committees approved the research protocol of the individual GWASs used in the current analysis and all participants gave written informed consent. The current analysis was finalized on July 21 2015 Table 1 Summary Data From All Genome-wide Association Studies Used in the Current Study For gene expression analyses we used publicly available total RNA expression data from 1647 autopsied brain tissues (from Fraxin dorsolateral prefrontal cortex visual cortex and cerebellum) in a total of 549 brains of 376 patients with AD and 173 nondemented healthy controls from the Gene Expression Omnibus data set {“type”: “entrez-geo”.