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INTRODUCTION: 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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms. METHODS: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole‐genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP). RESULTS: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole‐genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD. DISCUSSION: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations. Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site. [ABSTRACT FROM AUTHOR]

Objectives Cognitive training (CT) has been investigated as a means of delaying age-related cognitive decline in older adults. However, its impact on biomarkers of age-related structural brain atrophy has rarely been investigated, leading to a gap in our understanding of the linkage between improvements in cognition and brain plasticity. This study aimed to explore the impact of CT on cognitive performance and brain structure in older adults. Methods One hundred twenty-four cognitively normal older adults recruited from 2 study sites were randomly assigned to either an adaptive CT (n  = 60) or a casual game training (active control, AC, n  = 64). Results After 10 weeks of training, CT participants showed greater improvements in the overall cognitive composite score (Cohen's d  = 0.66, p  < .01) with nonsignificant benefits after 6 months from the completion of training (Cohen's d  = 0.36, p  = .094). The CT group showed significant maintenance of the caudate volume as well as significant maintained fractional anisotropy in the left internal capsule and in left superior longitudinal fasciculus compared to the AC group. The AC group displayed an age-related decrease in these metrics of brain structure. Discussion Results from this multisite clinical trial demonstrate that the CT intervention improves cognitive performance and helps maintain caudate volume and integrity of white matter regions that are associated with cognitive control, adding to our understanding of the changes in brain structure contributing to changes in cognitive performance from adaptive CT. Clinical Trial Registration NCT03197454 [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late‐onset AD although early‐onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology. METHODS: Whole‐genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries. RESULTS: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local‐ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. DISCUSSION: This novel resource complements over 50,000 control and late‐onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range. Highlights: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late‐onset AD although early‐onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease.The Early‐Onset Alzheimer's Disease Whole‐genome Sequencing Project is a collaborative initiative to generate a large‐scale genomics resource for early‐onset Alzheimer's disease with extensive harmonized phenotype data.Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local‐ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits.The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS. [ABSTRACT FROM AUTHOR]

Background: Although African Americans are twice as likely to develop Alzheimer's Disease (AD), individuals with African ancestry are under‐represented in genetic research of the disease. In the largest AD genome‐wide association studies to date for African‐Americans (Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified several novel susceptibility loci in addition to APOE, including ABCA7, API5, RBFOX1, and IGF1R. Method: We performed a genome‐wide association meta‐analysis of 2,844 AD cases and 6,251 cognitively healthy controls of African ancestry (AA) assembled across 17 different cohorts. Single‐variant association analysis was conducted adjusting for age, sex, principal components, and subsequently APOE, applying logistic regression for case‐control and general estimating equations for family‐based datasets. Within‐study results were meta‐analyzed using METAL, and followed by gene‐based, pathway, scRNA‐seq, and colocalization analyses. Result: Single variant meta‐analysis identified a novel genome‐wide significant AD risk locus in the MPDZ gene on chromosome 9p23 (rs141610415, MAF =.002, P = 3.68×10−9). MPDZ (MUPP1) is a vital component of the NMDAR signaling complex in excitatory synapses of hippocampal neurons critical for learning and memory. Two additional novel common loci and 9 novel rare loci approached genome‐wide significance at P<9×10−7. Genes at these loci are acting in biologically plausible pathways: signal transduction (PLEKHG1), synaptic transmission (CNTNAP4), synaptic connectivity (SDK1), neural development/function (SRGAP3, KIDINS220, UNC5C, TSSC1, TANC2), and neuronal differentiation (ASCL1). Single‐cell RNA‐sequence analysis shows that all genes are expressed in the brain, and that expression of the orthologs of SRGAP3, TANC2, and MMP16 is upregulated with amyloid toxicity in zebrafish. Pathway analyses support the notion that immune response, transcription/DNA repair, lipid processing, and intracellular trafficking are major AD‐associated pathways in African Americans. Except for SIPA1L2 and ACER3, all previously reported loci, including ABCA7, API5, RBFOX1 and IGF1R, remain genome‐wide or close to genome‐wide significant. Conclusion: We identified several novel loci for AD in individuals with African ancestry with the strongest association observed for MPDZ involved in hippocampal synaptic signaling. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be critical to identify additional disease‐associated loci in individuals of African ancestry. [ABSTRACT FROM AUTHOR]

Introduction: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms., Methods: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP)., Results: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD., Discussion: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations., Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site., Competing Interests: There are no competing interests to report. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: 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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology., Methods: Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries., Results: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits., Discussion: This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range., Highlights: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS., (© 2023 the Alzheimer's Association.)