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Item A global view of the genetic basis of Alzheimer disease(Springer Nature, 2023) Reitz, Christiane; Pericak-Vance, Margaret A.; Foroud, Tatiana; Mayeux, Richard; Medical and Molecular Genetics, School of MedicineThe risk of Alzheimer disease (AD) increases with age, family history and informative genetic variants. Sadly, there is still no cure or means of prevention. As in other complex diseases, uncovering genetic causes of AD could identify underlying pathological mechanisms and lead to potential treatments. Rare, autosomal dominant forms of AD occur in middle age as a result of highly penetrant genetic mutations, but the most common form of AD occurs later in life. Large-scale, genome-wide analyses indicate that 70 or more genes or loci contribute to AD. One of the major factors limiting progress is that most genetic data have been obtained from non-Hispanic white individuals in Europe and North America, preventing the development of personalized approaches to AD in individuals of other ethnicities. Fortunately, emerging genetic data from other regions - including Africa, Asia, India and South America - are now providing information on the disease from a broader range of ethnicities. Here, we summarize the current knowledge on AD genetics in populations across the world. We predominantly focus on replicated genetic discoveries but also include studies in ethnic groups where replication might not be feasible. We attempt to identify gaps that need to be addressed to achieve a complete picture of the genetic and molecular factors that drive AD in individuals across the globe.Item APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample(MDPI, 2019-08-16) Choi, Kyu Yeong; Lee, Jang Jae; Gunasekaran, Tamil Iniyan; Kang, Sarang; Lee, Wooje; Jeong, Jangho; Lim, Ho Jae; Zhang, Xiaoling; Zhu, Congcong; Won, So-Yoon; Choi, Yu Yong; Seo, Eun Hyun; Lee, Seok Cheol; Gim, Jungsoo; Chung, Ji Yeon; Chong, Ari; Byun, Min Soo; Seo, Sujin; Ko, Pan-Woo; Han, Ji-Won; McLean, Catriona; Farrell, John; Lunetta, Kathryn L.; Miyashita, Akinori; Hara, Norikazu; Won, Sungho; Choi, Seong-Min; Ha, Jung-Min; Jeong, Jee Hyang; Kuwano, Ryozo; Song, Min Kyung; An, Seong Soo A.; Lee, Young Min; Park, Kyung Won; Lee, Ho-Won; Choi, Seong Hye; Rhee, Sangmyung; Song, Woo Keun; Lee, Jung Sup; Mayeux, Richard; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Choo, IL Han; Nho, Kwangsik; Kim, Ki-Woong; Lee, Dong Young; Kim, SangYun; Kim, Byeong C.; Kim, Hoowon; Jun, Gyungah R.; Schellenberg, Gerard D.; Ikeuchi, Takeshi; Farrer, Lindsay A.; Lee, Kun Ho; Radiology and Imaging Sciences, School of MedicineVariants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10-94; GT: OR = 15.87, p = 2.62 × 10-9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10-108; GT: OR = 12.63, p = 3.44 × 10-64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.Item Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians(Wiley, 2024) Ho, Pei-Chuan; Yu, Wai Haung; Tee, Boon Lead; Lee, Wan-Ping; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Choi, Yun-Beom; Yang, Hyun-Sik; Vardarajan, Badri N.; Tzuang, Marian; Lieu, Kevin; Lu, Anna; Faber, Kelley M.; Potter, Zoë D.; Revta, Carolyn; Kirsch, Maureen; McCallum, Jake; Mei, Diana; Booth, Briana; Cantwell, Laura B.; Chen, Fangcong; Chou, Sephera; Clark, Dewi; Deng, Michelle; Hong, Ting Hei; Hwang, Ling-Jen; Jiang, Lilly; Joo, Yoonmee; Kang, Younhee; Kim, Ellen S.; Kim, Hoowon; Kim, Kyungmin; Kuzma, Amanda B.; Lam, Eleanor; Lanata, Serggio C.; Lee, Kunho; Li, Donghe; Li, Mingyao; Li, Xiang; Liu, Chia-Lun; Liu, Collin; Liu, Linghsi; Lupo, Jody-Lynn; Nguyen, Khai; Pfleuger, Shannon E.; Qian, James; Qian, Winnie; Ramirez, Veronica; Russ, Kristen A.; Seo, Eun Hyun; Song, Yeunjoo E.; Tartaglia, Maria Carmela; Tian, Lu; Torres, Mina; Vo, Namkhue; Wong, Ellen C.; Xie, Yuan; Yau, Eugene B.; Yi, Isabelle; Yu, Victoria; Zeng, Xiaoyi; St. George-Hyslop, Peter; Au, Rhoda; Schellenberg, Gerard D.; Dage, Jeffrey L.; Varma, Rohit; Hsiung, Ging-Yuek R.; Rosen, Howard; Henderson, Victor W.; Foroud, Tatiana; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Feldman, Howard H.; Mayeux, Richard; Chui, Helena; Jun, Gyungah R.; Ta Park, Van M.; Chow, Tiffany W.; Wang, Li-San; Medical and Molecular Genetics, School of MedicineIntroduction: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. Methods: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. Results: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. Discussion: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. Highlights: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.Item Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals(American Medical Association, 2015-11) Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina; Department of Psychiatry, IU School of MedicineIMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.Item Convergent genetic and expression data implicate immunity in Alzheimer's disease(Elsevier, 2015-06) Jones, Lesley; Lambert, Jean-Charles; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Vedernikov, Alexey; Escott-Price, Valentina; Stone, Timothy; Richards, Alexander; Bellenguez, Céline; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Gerrish, Amy; Jun, Gyungah; DeStefano, Anita L.; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Jones, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letteneur, Luc; Kornhuber, Johanes; Tárraga, Lluís; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Emilsson, Valur; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Kehoe, Pat; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleὀ, Alberti; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick; Hardy, John; Naranjo, Maria Candida Deniz; Razquin, Cristina; Bosco, Paola; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Moebus, Susanne; Mecocci, Patrizia; del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R.; Mayhaus, Manuel; Jessen, Frank; Dichgans, Martin; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alavarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee FAG; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John SK; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Pastor, Pau; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Farrer, Lindsay A.; van Duijn, Cornelia M.; Van Broekhoven, Christine; Ramirez, Alfredo; Schellenberg, Gerard D.; Seshadri, Sudha; Amouyel, Philippe; Williams, Julie; Holmans, Peter A.; Department of Medical & Molecular Genetics, IU School of MedicineBackground Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.Item Correlation of plasma and neuroimaging biomarkers in Alzheimer’s disease(Wiley, 2022) Brickman, Adam M.; Manly, Jennifer J.; Honig, Lawrence S.; Sanchez, Danurys; Reyes-Dumeyer, Dolly; Lantigua, Rafael A.; Vonsattel, Jean Paul; Teich, Andrew F.; Kang, Min Suk; Dage, Jeffrey L.; Mayeux, Richard; Neurology, School of MedicineBlood-based phosphorylated tau (Ptau) 181 and 217 biomarkers are sensitive and specific for Alzheimer's disease. In this racial/ethnically diverse cohort study, participants were classified as biomarker positive (Ptau+) or negative (Ptau-) based on Ptau 181 and 217 concentrations and as cognitively impaired (Sym) or unimpaired (Asym). The four groups, Ptau-/Asym, Ptau+/Asym, Ptau-/Sym, and Ptau+/Sym, differed by age, APOE-4 allele frequency, total tau, neurofilament light chain, and cortical thickness measured by MRI. Our results add to increasing evidence that plasma Ptau 181 and 217 concentrations are valid Alzheimer's disease biomarkers in diverse populations.Item Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity(American Medical Association, 2023-04-03) Honig, Lawrence S.; Kang, Min Suk; Lee, Annie J.; Reyes-Dumeyer, Dolly; Piriz, Angel; Soriano, Belisa; Franco, Yahaira; Dominguez Coronado, Zoraida; Recio, Patricia; Rivera Mejía, Diones; Medrano, Martin; Lantigua, Rafael A.; Teich, Andrew F.; Dage, Jeffrey L.; Mayeux, Richard; Neurology, School of MedicineImportance: Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. Objective: To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. Design, setting, and participants: In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main outcomes and measures: Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures: Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. Results: This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. Conclusions and relevance: In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.Item Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry(Wiley, 2024) Ray, Nicholas R.; Kunkle, Brian W.; Hamilton-Nelson, Kara; Kurup, Jiji T.; Rajabli, Farid; Qiao, Min; Vardarajan, Badri N.; Cosacak, Mehmet I.; Kizil, Caghan; Jean-Francois, Melissa; Cuccaro, Michael; Reyes-Dumeyer, Dolly; Cantwell, Laura; Kuzma, Amanda; Vance, Jeffery M.; Gao, Sujuan; Hendrie, Hugh C.; Baiyewu, Olusegun; Ogunniyi, Adesola; Akinyemi, Rufus O.; Alzheimer’s Disease Genetics Consortium; Lee, Wan-Ping; Martin, Eden R.; Wang, Li-San; Beecham, Gary W.; Bush, William S.; Xu, Wanying; Jin, Fulai; Wang, Liyong; Farrer, Lindsay A.; Haines, Jonathan L.; Byrd, Goldie S.; Schellenberg, Gerard D.; Mayeux, Richard; Pericak-Vance, Margaret A.; Reitz, Christiane; Biostatistics and Health Data Science, School of MedicineIntroduction: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. Methods: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. Results: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, p = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. Discussion: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. Highlights: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at p < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.Item Genetic associations with psychosis and affective disturbance in Alzheimer's disease(Wiley, 2024-05-23) Antonsdottir, Inga Margret; Creese, Byron; Klei, Lambertus; DeMichele-Sweet, Mary Ann A.; Weamer, Elise A.; Garcia-Gonzalez, Pablo; Marquie, Marta; Boada, Mercè; Alarcón-Martín, Emilio; Valero, Sergi; NIA-LOAD Family Based Study Consortium; Alzheimer's Disease Genetics Consortium (ADGC); AddNeuroMed Consortium; Liu, Yushi; Hooli, Basavaraj; Aarsland, Dag; Selbaek, Geir; Bergh, Sverre; Rongve, Arvid; Saltvedt, Ingvild; Skjellegrind, Håvard K.; Engdahl, Bo; Andreassen, Ole A.; Borroni, Barbara; Mecocci, Patrizia; Wedatilake, Yehani; Mayeux, Richard; Foroud, Tatiana; Ruiz, Agustín; Lopez, Oscar L.; Kamboh, M. Ilyas; Ballard, Clive; Devlin, Bernie; Lyketsos, Constantine; Sweet, Robert A.; Medical and Molecular Genetics, School of MedicineIntroduction: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. Methods: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). Results: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. Discussion: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated. Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms. Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not. Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.Item Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing(Springer Nature, 2019-03) Kunkle, Brian W.; Grenier-Boley, Benjamin; Sims, Rebecca; Bis, Joshua C.; Damotte, Vincent; Naj, Adam C.; Boland, Anne; Vronskaya, Maria; van der Lee, Sven J.; Amlie-Wolf, Alexandre; Bellenguez, Céline; Frizatti, Aura; Chouraki, Vincent; Martin, Eden R.; Sleegers, Kristel; Badarinarayan, Nandini; Jakobsdottir, Johanna; Hamilton-Nelson, Kara L.; Moreno-Grau, Sonia; Olaso, Robert; Raybould, Rachel; Chen, Yuning; Kuzma, Amanda B.; Hiltunen, Mikko; Morgan, Taniesha; Ahmad, Shahzad; Vardarajan, Badri N.; Epelbaum, Jacques; Hoffmann, Per; Boada, Merce; Beecham, Gary W.; Garnier, Jean-Guillaume; Harold, Denise; Fitzpatrick, Annette L.; Valladares, Otto; Moutet, Marie-Laure; Gerrish, Amy; Smith, Albert V.; Qu, Liming; Bacq, Delphine; Denning, Nicola; Jian, Xueqiu; Zhao, Yi; Del Zompo, Maria; Fox, Nick C.; Choi, Seung-Hoan; Mateo, Ignacio; Hughes, Joseph T.; Adams, Hieab H.; Malamon, John; Sanchez-Garcia, Florentino; Patel, Yogen; Brody, Jennifer A.; Dombroski, Beth A.; Deniz Naranjo, Maria Candida; Daniilidou, Makrina; Eiriksdottir, Gudny; Mukherjee, Shubhabrata; Wallon, David; Uphill, James; Aspelund, Thor; Cantwell, Laura B.; Garzia, Fabienne; Galimberti, Daniela; Hofer, Edith; Butkiewicz, Mariusz; Fin, Bertrand; Scarpini, Elio; Sarnowski, Chloe; Bush, Will S.; Meslage, Stéphane; Kornhuber, Johannes; White, Charles C.; Song, Yuenjoo; Barber, Robert C.; Engelborghs, Sebastiaan; Sordon, Sabrina; Voijnovic, Dina; Adams, Perrie M.; Vandenberghe, Rik; Mayhaus, Manuel; Cupples, L. Adrienne; Albert, Marilyn S.; De Deyn, Peter P.; Gu, Wei; Himali, Jayanadra J.; Beekly, Duane; Squassina, Alessio; Hartmann, Annette M.; Orellana, Adelina; Blacker, Deborah; Rodriguez-Rodriguez, Eloy; Lovestone, Simon; Garcia, Melissa E.; Doody, Rachelle S.; Munoz-Fernadez, Carmen; Sussams, Rebecca; Lin, Honghuang; Fairchild, Thomas J.; Benit, Yolanda A.; Holmes, Clive; Karamujić-Čomić, Hata; Frosch, Matthew P.; Thonberg, Hakan; Maier, Wolfgang; Roshchupkin, Gennady; Ghetti, Bernardino; Giedraitis, Vilmantas; Kawalia, Amit; Li, Shuo; Huebinger, Ryan M.; Kilander, Lena; Moebus, Susanne; Hernández, Isabel; Kamboh, M. Ilyas; Brundin, RoseMarie; Turton, James; Yang, Qiong; Katz, Mindy J.; Concari, Letizia; Lord, Jenny; Beiser, Alexa S.; Keene, C. 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Andre; Royall, Donald R.; Dufouil, Carole; Maletta, Raffaele Giovanni; de Rojas, Itziar; Sano, Mary; Brice, Alexis; Cecchetti, Roberta; St. George-Hyslop, Peter; Ritchie, Karen; Tsolaki, Magda; Tsuang, Debby W.; Dubois, Bruno; Craig, David; Wu, Chuang-Kuo; Soininen, Hilkka; Avramidou, Despoina; Albin, Roger L.; Fratiglioni, Laura; Germanou, Antonia; Apostolova, Liana G.; Keller, Lina; Koutroumani, Maria; Arnold, Steven E.; Panza, Francesco; Gkatzima, Olymbia; Asthana, Sanjay; Hannequin, Didier; Whitehead, Patrice; Atwood, Craig S.; Caffarra, Paolo; Hampel, Harald; Quintela, Inés; Carracedo, Ángel; Lannfelt, Lars; Rubinsztein, David C.; Barnes, Lisa L.; Pasquier, Florence; Frölich, Lutz; Barral, Sandra; McGuinness, Bernadette; Beach, Thomas G .; Johnston, Janet A.; Becker, James T.; Passmore, Peter; Bigio, Eileen H.; Schott, Jonathan M.; Bird, Thomas D.; Warren, Jason D.; Boeve, Bradley F.; Lupton, Michelle K.; Bowen, James D.; Proitsi, Petra; Boxer, Adam; Powell, John F.; Burke, James R.; Kauwe, John S.K.; Burns, Jeffrey M.; Mancuso, Michelangelo; Buxbaum, Joseph D.; Bonuccelli, Ubaldo; Cairns, Nigel J.; McQuillin, Andrew; Cao, Chuanhai; Livingston, Gill; Carlson, Chris S.; Bass, Nicholas J.; Carlsson, Cynthia M.; Hardy, John; Carney, Regina M.; Bras, Jose; Carrasquillo, Minerva M.; Guerreiro, Rita; Allen, Mariet; Chui, Helena C.; Fisher, Elizabeth; Masullo, Carlo; Crocco, Elizabeth A.; DeCarli, Charles; Bisceglio, Gina; Dick, Malcolm; Ma, Li; Duara, Ranjan; Graff-Radford, Neill R.; Evans, Denis A.; Hodges, Angela; Faber, Kelley M.; Scherer, Martin; Fallon, Kenneth B.; Riemenschneider, Matthias; Fardo, David W.; Heun, Reinhard; Farlow, Martin R.; Kölsch, Heike; Ferris, Steven; Leber, Markus; Foroud, Tatiana M.; Heuser, Isabella; Galasko, Douglas R.; Giegling, Ina; Gearing, Marla; Hüll, Michael; Geschwind, Daniel H.; Gilbert, John R.; Morris, John; Green, Robert C.; Mayo, Kevin; Growdon, John H.; Feulner, Thomas; Hamilton, Ronald L.; Harrell, Lindy E.; Drichel, Dmitriy; Honig, Lawrence S.; Cushion, Thomas D.; Huentelman, Matthew J.; Hollingworth, Paul; Hulette, Christine M.; Hyman, Bradley T.; Marshall, Rachel; Jarvik, Gail P.; Meggy, Alun; Abner, Erin; Menzies, Georgina E.; Jin, Lee-Way; Leonenko, Ganna; Real, Luis M.; Jun, Gyungah R.; Baldwin, Clinton T.; Grozeva, Detelina; Karydas, Anna; Russo, Giancarlo; Kaye, Jeffrey A.; Kim, Ronald; Jessen, Frank; Kowall, Neil W.; Vellas, Bruno; Kramer, Joel H.; Vardy, Emma; LaFerla, Frank M.; Jöckel, Karl-Heinz; Lah, James J.; Dichgans, Martin; Leverenz, James B.; Mann, David; Levey, Allan I.; Pickering-Brown, Stuart; Lieberman, Andrew P.; Klopp, Norman; Lunetta, Kathryn L.; Wichmann, H-Erich; Lyketsos, Constantine G.; Morgan, Kevin; Marson, Daniel C.; Brown, Kristelle; Martiniuk, Frank; Medway, Christopher; Mash, Deborah C.; Nöthen, Markus M.; Masliah, Eliezer; Hooper, Nigel M.; McCormick, Wayne C.; Daniele, Antonio; McCurry, Susan M.; Bayer, Anthony; McDavid, Andrew N.; Gallacher, John; McKee, Ann C.; van den Bussche, Hendrik; Mesulam, Marsel; Brayne, Carol; Miller, Bruce L.; Riedel-Heller, Steffi; Miller, Carol A.; Miller, Joshua W.; Al-Chalabi, Ammar; Morris, John C.; Shaw, Christopher E.; Myers, Amanda J.; Wiltfang, Jens; O'Bryant, Sid; Olichney, John M.; Alvarez, Victoria; Parisi, Joseph E.; Singleton, Andrew B.; Paulson, Henry L.; Collinge, John; Perry, William R.; Mead, Simon; Peskind, Elaine; Cribbs, David H.; Rossor, Martin; Pierce, Aimee; Ryan, Natalie S.; Poon, Wayne W.; Nacmias, Benedetta; Potter, Huntington; Sorbi, Sandro; Quinn, Joseph F.; Sacchinelli, Eleonora; Raj, Ashok; Spalletta, Gianfranco; Raskind, Murray; Caltagirone, Carlo; Bossù, Paola; Orfei, Maria Donata; Reisberg, Barry; Clarke, Robert; Reitz, Christiane; Smith, A. David; Ringman, John M.; Warden, Donald; Roberson, Erik D.; Wilcock, Gordon; Rogaeva, Ekaterina; Bruni, Amalia Cecilia; Rosen, Howard J.; Gallo, Maura; Rosenberg, R.N.; Ben-Shlomo, Yoav; Sager, Mark A.; Mecocci, Patrizia; Saykin, Andrew J.; Pastor, Pau; Cuccaro, Michael L.; Vance, Jeffery M.; Schneider, Julie A.; Schneider, Lori S.; Slifer, Susan; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Swerdlow, Russell H.; Tang, Mitchell; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vinters, Harry V.; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Wilhelmsen, Kirk C.; Williamson, Jennifer; Wingo, Thomas S.; Woltjer, Randall L.; Wright, Clinton B.; Yu, Chang-En; Yu, Lei; Saba, Yasaman; Pilotto, Alberto; Bullido, Maria J.; Peters, Oliver; Crane, Paul K.; Bennett, David; Bosco, Paola; Coto, Eliecer; Boccardi, Virginia; De Jager, Phil L.; Lleo, Alberto; Warner, Nick; Lopez, Oscar L.; Ingelsson, Martin; Deloukas, Panagiotis; Cruchaga, Carlos; Graff, Caroline; Gwilliam, Rhian; Fornage, Myriam; Goate, Alison M.; Sanchez-Juan, Pascual; Kehoe, Patrick G.; Amin, Najaf; Ertekin-Taner, Nilifur; Berr, Claudine; Debette, Stéphanie; Love, Seth; Launer, Lenore J.; Younkin, Steven G.; Dartigues, Jean-Francois; Corcoran, Chris; Ikram, M. Arfan; Dickson, Dennis W.; Nicolas, Gael; Campion, Dominique; Tschanz, JoAnn; Schmidt, Helena; Hakonarson, Hakon; Clarimon, Jordi; Munger, Ron; Schmidt, Reinhold; Farrer, Lindsay A.; Van Broeckhoven, Christine; O'Donovan, Michael C.; DeStefano, Anita L.; Jones, Lesley; Haines, Jonathan L.; Deleuze, Jean-Francois; Owen, Michael J.; Gudnason, Vilmundur; Mayeux, Richard; Escott-Price, Valentina; Psaty, Bruce M.; Ramirez, Alfredo; Wang, Li-San; Ruiz, Agustin; van Duijn, Cornelia M.; Holmans, Peter A.; Seshadri, Sudha; Williams, Julie; Amouyel, Phillippe; Schellenberg, Gerard D.; Lambert, Jean-Charles; Pericak-Vance, Margaret A.; Pathology and Laboratory Medicine, School of MedicineRisk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.