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African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10 -6 ) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10 -2 ) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10 -2 ) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10 -2 ). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Background Sex differences in progression and pathology of Alzheimer's disease (AD) suggest sex‐specific factors influencing its development. While studies have established APOE‐genotype as contributing to AD risk differently in men and women, few have searched for additional genetic sex differences in AD. To identify sex‐specific AD genetic associations, we conducted genome‐wide sex‐aware meta‐analyses in the Alzheimer's Disease Genetics Consortium (ADGC) and Alzheimer's Disease Sequencing Project (ADSP) datasets. Method Sex‐interaction and sex‐stratified analyses were performed in multi‐ancestry genome‐wide imputed AD datasets from the ADGC (N = 25,284 cases, 60% female and 33,455 controls, 63% female; ancestry/ethnicity distribution: 63.7% European, 15.6% African, 15.2% Hispanic/Latino, 5.5% Asian). STAAR aggregation‐based rare‐variant testing was also conducted in coding and non‐coding genomic regions on an ancestrally diverse sample of 8,697 AD cases and 14,758 controls with whole‐genome sequencing from the ADSP. Result Cross‐ancestry sex‐stratified analyses identified several loci with evidence of interaction (p <0.05) and suggestive significance in one sex (p <5x10‐6) and not the other (p >0.05). These include male specific variants in STXBP6, MAP4K5 and the known AD locus PICALM. Genetic loci associated in females and not males include NPAS3, ZNF438 and a genome‐wide result in NECTIN2 near the APOE locus. Top ancestry‐specific results include associations at COL4A2 in Asian‐ancestry males and C16orf96 in African‐ancestry females. Cross‐ancestry rare‐variant aggregation‐based testing revealed four novel genome‐wide significant associations in females including with missense variants in SH3BP1. Five population specific associations were also discovered including with missense variants in SERTAD4 in a genetically‐defined Hispanic/Amerindian/African ancestral population cluster and promoter variants of PSMA5 in a European population cluster. Seven male‐specific effects were also discovered including genome‐wide significant cross‐ancestry associations with an enhancer region of MORC1 and a promoter of ITPKA. Conclusion We identified sex‐specific AD associations at loci with AD‐relevant genes including STXBP6 (involved in AD relevant processes such as endolysosomal transport and synaptic transmission), NPAS3 (neurogenesis), COL4A2 (cerebral vasculature), ITPKA (learning/memory processes), PAQR3 (cholesterol homeostatis and neuronal function), and MORC1 (recently associated in a UK Biobank exome‐wide sequencing study of dementia (Zhang et al. Alz & Dementia 2024). Understanding the nature of these associations could help explain sex differences in risk and progression for AD.

Background The Alzheimer's Disease Sequencing Project (ADSP) aims to uncover genomic variants that increase risk for or protect against Alzheimer's disease (AD) across various ancestral populations. The most recent ADSP whole genome sequencing (WGS) data release (R4) includes data from 36,000+ individuals across 37 study cohorts. Method Extensive quality control was conducted at the genotype, variant, and sample levels. Analyses focused on AD and related dementias (ADRDs) with cases and controls restricted to age ≥55 years. Two main genetic association approaches were applied: 1) Population‐specific analysis‐ Genetic similarity clusters for defining populations were identified using a Gaussian mixture model. Analyses included generalized linear mixed model single‐variant tests for common variants with SAIGE; meta‐analysis of common variants across populations using METASOFT; and set‐based rare variant analyses for coding and noncoding regions with STAAR, followed by meta‐analysis using MetaSTAAR. 2) Pooled population analysis‐ Gene‐based association tests including common and rare variants were conducted using GENESIS/R, accounting for sex, technical covariates, population structure, and empirical relationships. Rare variant analyses aggregated predicted loss‐of‐function and deleterious missense variants, with Bonferroni correction. Result For the population‐specific analysis, we defined nine clusters of individuals (8,697 ADRD cases and 14,758 controls) based on genetic similarity using high‐quality variants. The meta‐analysis of common variants identified two known ADRD‐associated loci (APOE and CR1) and four novel genomic loci (LMO1, FHIT, RPS3AP52, and AC013762.1) that reached genome‐wide significance (p <5×10‐8). For the pooled analysis, common variant associations confirmed the signals in APOE and CR1. Additionally, rare variant gene‐based analysis identified KIRREL1 (p = 1.01×10‐6) and TNFRSF10B (p = 2.25×10‐6) as significantly associated in population‐specific meta‐analysis and TNS1 as suggestively associated with ADRD (p = 3.05×10‐6) in pooled analysis. Conclusion Analyses of ADSP WGS data identified a novel genome‐wide significant association at LMO1 (11p15), a gene involved in transcriptional regulation with potential relevance to neuronal health, and a suggestive association at TNS1 (2q35), previously linked to cognitive decline in non‐demented older adults. Further studies in diverse populations from the ADSP are expected to uncover additional common and rare variant associations, offering new insights into ADRD pathogenesis.

Sex differences in progression and pathology of Alzheimer's disease (AD) suggest sex-specific factors influencing its development. While studies have established APOE-genotype as contributing to AD risk differently in men and women, few have searched for additional genetic sex differences in AD. To identify sex-specific AD genetic associations, we conducted genome-wide sex-aware meta-analyses in the Alzheimer's Disease Genetics Consortium (ADGC) and Alzheimer's Disease Sequencing Project (ADSP) datasets. Sex-interaction and sex-stratified analyses were performed in multi-ancestry genome-wide imputed AD datasets from the ADGC (N = 25,284 cases, 60% female and 33,455 controls, 63% female; ancestry/ethnicity distribution: 63.7% European, 15.6% African, 15.2% Hispanic/Latino, 5.5% Asian). STAAR aggregation-based rare-variant testing was also conducted in coding and non-coding genomic regions on an ancestrally diverse sample of 8,697 AD cases and 14,758 controls with whole-genome sequencing from the ADSP. Cross-ancestry sex-stratified analyses identified several loci with evidence of interaction (p <0.05) and suggestive significance in one sex (p <5x10-6) and not the other (p >0.05). These include male specific variants in STXBP6, MAP4K5 and the known AD locus PICALM. Genetic loci associated in females and not males include NPAS3, ZNF438 and a genome-wide result in NECTIN2 near the APOE locus. Top ancestry-specific results include associations at COL4A2 in Asian-ancestry males and C16orf96 in African-ancestry females. Cross-ancestry rare-variant aggregation-based testing revealed four novel genome-wide significant associations in females including with missense variants in SH3BP1. Five population specific associations were also discovered including with missense variants in SERTAD4 in a genetically-defined Hispanic/Amerindian/African ancestral population cluster and promoter variants of PSMA5 in a European population cluster. Seven male-specific effects were also discovered including genome-wide significant cross-ancestry associations with an enhancer region of MORC1 and a promoter of ITPKA. We identified sex-specific AD associations at loci with AD-relevant genes including STXBP6 (involved in AD relevant processes such as endolysosomal transport and synaptic transmission), NPAS3 (neurogenesis), COL4A2 (cerebral vasculature), ITPKA (learning/memory processes), PAQR3 (cholesterol homeostatis and neuronal function), and MORC1 (recently associated in a UK Biobank exome-wide sequencing study of dementia (Zhang et al. Alz & Dementia 2024). Understanding the nature of these associations could help explain sex differences in risk and progression for AD.

The Alzheimer's Disease Sequencing Project (ADSP) aims to uncover genomic variants that increase risk for or protect against Alzheimer's disease (AD) across various ancestral populations. The most recent ADSP whole genome sequencing (WGS) data release (R4) includes data from 36,000+ individuals across 37 study cohorts. Extensive quality control was conducted at the genotype, variant, and sample levels. Analyses focused on AD and related dementias (ADRDs) with cases and controls restricted to age ≥55 years. Two main genetic association approaches were applied: 1) Population-specific analysis- Genetic similarity clusters for defining populations were identified using a Gaussian mixture model. Analyses included generalized linear mixed model single-variant tests for common variants with SAIGE; meta-analysis of common variants across populations using METASOFT; and set-based rare variant analyses for coding and noncoding regions with STAAR, followed by meta-analysis using MetaSTAAR. 2) Pooled population analysis- Gene-based association tests including common and rare variants were conducted using GENESIS/R, accounting for sex, technical covariates, population structure, and empirical relationships. Rare variant analyses aggregated predicted loss-of-function and deleterious missense variants, with Bonferroni correction. For the population-specific analysis, we defined nine clusters of individuals (8,697 ADRD cases and 14,758 controls) based on genetic similarity using high-quality variants. The meta-analysis of common variants identified two known ADRD-associated loci (APOE and CR1) and four novel genomic loci (LMO1, FHIT, RPS3AP52, and AC013762.1) that reached genome-wide significance (p <5×10 ). For the pooled analysis, common variant associations confirmed the signals in APOE and CR1. Additionally, rare variant gene-based analysis identified KIRREL1 (p = 1.01×10 ) and TNFRSF10B (p = 2.25×10 ) as significantly associated in population-specific meta-analysis and TNS1 as suggestively associated with ADRD (p = 3.05×10 ) in pooled analysis. Analyses of ADSP WGS data identified a novel genome-wide significant association at LMO1 (11p15), a gene involved in transcriptional regulation with potential relevance to neuronal health, and a suggestive association at TNS1 (2q35), previously linked to cognitive decline in non-demented older adults. Further studies in diverse populations from the ADSP are expected to uncover additional common and rare variant associations, offering new insights into ADRD pathogenesis.

Background In 2024, the Lancet Commission on Dementia published another iteration of risk factors and observed that almost half of the burden of dementia is potentially preventable by tackling 14 modifiable risk factors. We performed a preliminary analysis of the risk factors in the African datasets of the ongoing Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD‐ADSP) study. Method The READD‐ADSP is an ongoing case‐control study recruiting and evaluating 13,000 participants consisting of 5,000 Africans, 4,000 Black Americans, and 4,000 Hispanic/Latino individuals to elucidate the complete genetic background of AD for the development of global treatments and preventions. The African Dementia Consortium (AfDC) is coordinating ongoing recruitment in ten sub‐Saharan African countries. Protocols were developed to ensure standardized data collection, phenotype harmonization, and culturally informed diagnostic algorithms. We present results of preliminary analysis exploring 12 of the Lancet Commission's 14 modifiable risk factors (excluding LDL‐c and air pollution). A multivariable logistic regression analysis was used to assess the effect sizes of the dementia risk factors in the study population. Result Data consisted of 1469 participants (626 cases and 843 controls; mean age 75.3 =/‐9.5 yrs; 41.5% male). Mean age of the cases was 77.0±9.5years while that of controls was 74.1±9.2years (p <0.001). Older age, female sex, hypertension, hearing loss, depression, physical inactivity, low level of education, and social isolation were significantly more prevalent among cases compared to controls. However, self‐reported Visual loss was more prevalent in the control population. Factors independently associated with dementia in this analysis include age (AOR 1.03: 1.02‐1.04), hypertension (AOR=1.35; 1.06‐1.72) alcohol use (AOR=0.34, 0.13‐0.87), depression (AOR=2.60; 2.09‐3.23) and self‐reported visual impairment (AOR=0.62; 0.48‐0.80). Age, sex, hypertension, and alcohol exhibit region‐specific differences in magnitude and direction between East and West Africa, while depression and self‐reported visual impairment show consistent effects. However, potential confounding remains a concern due to cross‐regional variations in some factors. Conclusion Our findings highlight the unique contributions of multi‐modal risk factors to dementia burden among Africans. As additional data are collected, further analyses will examine the interactive effects of region, ethnicity and other factors.

African descent populations have a lower Alzheimer disease risk from ApoE [epsilon]4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE [epsilon]4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE [epsilon]4 allele and the SNP rs10423769_(A) allele, ([beta] = -0.54,SE = 0.12,p-value = 7.50x10.sup.-6) in the discovery data set, and replicated this finding in Ibadan ([beta] = -1.32,SE = 0.52,p-value = 1.15x10.sup.-2) and Puerto Rican ([beta] = -1.27,SE = 0.64,p-value = 4.91x10.sup.-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the \"protective\" direction but failing to pass a 0.05 significance threshold ([beta] = -1.51,SE = 0.84,p-value = 7.26x10.sup.-2). The presence of the rs10423769_(A) allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE [epsilon]4/[epsilon]4 carriers lacking the A allele to 2.1 for ApoE [epsilon]4/[epsilon]4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943.

In 2024, the Lancet Commission on Dementia published another iteration of risk factors and observed that almost half of the burden of dementia is potentially preventable by tackling 14 modifiable risk factors. We performed a preliminary analysis of the risk factors in the African datasets of the ongoing Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP) study. The READD-ADSP is an ongoing case-control study recruiting and evaluating 13,000 participants consisting of 5,000 Africans, 4,000 Black Americans, and 4,000 Hispanic/Latino individuals to elucidate the complete genetic background of AD for the development of global treatments and preventions. The African Dementia Consortium (AfDC) is coordinating ongoing recruitment in ten sub-Saharan African countries. Protocols were developed to ensure standardized data collection, phenotype harmonization, and culturally informed diagnostic algorithms. We present results of preliminary analysis exploring 12 of the Lancet Commission's 14 modifiable risk factors (excluding LDL-c and air pollution). A multivariable logistic regression analysis was used to assess the effect sizes of the dementia risk factors in the study population. Data consisted of 1469 participants (626 cases and 843 controls; mean age 75.3 =/-9.5 yrs; 41.5% male). Mean age of the cases was 77.0±9.5years while that of controls was 74.1±9.2years (p <0.001). Older age, female sex, hypertension, hearing loss, depression, physical inactivity, low level of education, and social isolation were significantly more prevalent among cases compared to controls. However, self-reported Visual loss was more prevalent in the control population. Factors independently associated with dementia in this analysis include age (AOR 1.03: 1.02-1.04), hypertension (AOR=1.35; 1.06-1.72) alcohol use (AOR=0.34, 0.13-0.87), depression (AOR=2.60; 2.09-3.23) and self-reported visual impairment (AOR=0.62; 0.48-0.80). Age, sex, hypertension, and alcohol exhibit region-specific differences in magnitude and direction between East and West Africa, while depression and self-reported visual impairment show consistent effects. However, potential confounding remains a concern due to cross-regional variations in some factors. Our findings highlight the unique contributions of multi-modal risk factors to dementia burden among Africans. As additional data are collected, further analyses will examine the interactive effects of region, ethnicity and other factors.