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Original Investigation
June 2016

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

Author Affiliations
  • 1Department of Neurology, University of California, San Francisco
  • 2Department of Psychiatry, Washington University, St Louis, Missouri
  • 3Department of Neurosciences, University of California, San Diego, La Jolla
  • 4Department of Cognitive Sciences, University of California, San Diego, La Jolla
  • 5Department of Psychiatry, University of California, San Diego, La Jolla
  • 6Department of Radiology, University of California, San Diego, La Jolla
  • 7Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 8Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
  • 9Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  • 10Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco
  • 11Department of Neurology, Massachusetts General Hospital, Boston
  • 12Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 13Norwegian PSC Research Center and KG Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
  • 14Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway
JAMA Neurol. 2016;73(6):691-697. doi:10.1001/jamaneurol.2016.0150

Importance  Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies.

Objective  To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD.

Design, Setting, and Participants  In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer’s Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide 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 P 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 P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10−5 for AD, and 6.03 × 10−15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 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 (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer’s Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10−10; IPMK: β [SE], −0.096 [0.013]; P = 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.