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INTRODUCTION Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer's disease (AD) risk by independent lines of evidence. We explored this association by comparing the frequencies of viral species identified in a large sample of AD cases and controls. METHODS DNA sequence reads that did not align to the human genome in sequences were mapped to viral reference sequences, quantified, and then were tested for association with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets. RESULTS Several viruses were significant predictors of AD according to the machine learning classifiers. Subsequent regression analyses showed that herpes simplex type 1 (HSV‐1) (odds ratio [OR] = 3.71, p = 8.03 × 10−4) and human papillomavirus 71 (HPV‐71; OR = 3.56, p = 0.02), were significantly associated with AD after Bonferroni correction. The phylogenetic‐related cluster of Herpesviridae was significantly associated with AD in several strata of the data (p < 0.01). DISCUSSION Our results support the hypothesis that viral infection, especially HSV‐1, is associated with AD risk.

INTRODUCTION We recently described that the African‐specific A allele of rs10423769, which lies in an area of segmental duplications, reduces Alzheimer's disease (AD) risk by ∼ 75% in apolipoprotein E (APOE) ε4 homozygotes. METHODS Short and long‐read sequencing were used to identify the haplotype harboring rs10423769_A and examine DNA methylation and structural variation (SV). RESULTS A unique 21 kb haplotype is shared amongst all rs10423769_A carriers (r2 > 0.95) and is present in all African ancestry tested. We identified methylation differences between the non‐protective and rs10423769_A haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2‐family transcription factor binding motifs in LD with the protective haplotype. Further, rs10423769 is an eQTL for ZNF222. DISCUSSION The protective haplotype is unique, with haplotype changes in DNA methylation and SV that could contribute to the protective mechanism of rs10423769_A. The study generates hypothesis for future studies on this important protective mechanism for APOEε4 carriers. Highlights We investigated an African‐specific haplotype harboring a protective locus for APOEε4 carriers that significantly reduces the risk for Alzheimer Disease. The protective locus lies in an area of segmental duplications 2MB from APOE. We found that the protective haplotype is unique within the segmental duplications. The haplotype is found in all African ancestry tested but not in other ancestries. Long read whole genome sequencing identified an expanded VNTR associated with the protective haplotype containing multiple MEF2 transcription factor binding motifs. Differences in DNA methylation were found between the protective and the reference haplotype.

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.

INTRODUCTION Plasma phosphorylated threonine 181 of tau (pTau181) and amyloid beta (Aβ) are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, the generalizability of existing biomarker data is not assured. METHODS In 2086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvian), we measured plasma pTau181 and Aβ42/Aβ40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed. RESULTS pTau181 and Aβ42/Aβ40 were consistent across cohorts. Higher levels of pTau181 were associated with AD, while Aβ42/Aβ40 had minimal differences. Correspondingly, pTau181 had a greater predictive value than Aβ42/Aβ40; however, the area under the curve differed between cohorts. DISCUSSION pTau181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but its predictive value may vary. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses. Highlights This is a diverse ancestry study of plasma biomarkers for AD. Plasma biomarkers were assessed in African Americans, Caribbean Hispanics, and Peruvians. Biomarker levels were consistent across the diverse cohorts. Plasma phosphorylated tau was higher in AD in all cohorts. Plasma biomarker findings in diverse cohorts largely generalize with existing European studies.

INTRODUCTION This study investigates ancestry‐specific changes in induced pluripotent stem cell (iPSC)‐derived oligodendroglia genomic regulation in Alzheimer's disease (AD), addressing diversity gaps by including African, Amerindian, and European ancestries in the analysis. METHODS We generated 12 iPSC lines from AD patients and controls with different apolipoprotein E (APOE) genotypes, APOE ε3/ ε3 and APOE ε4/ ε4, across three ancestries. Lines were differentiated into neural spheroids containing oligodendrocyte lineage cells and analyzed by single‐nucleus RNA sequencing, Assay for Transposase‐Accessible Chromatin with sequencing (ATACseq)APO, and High‐throughput Chromosome Conformation Capture (Hi‐C). RESULTS We identified ancestry‐specific differences in gene expression and chromatin accessibility of AD genome‐wide association study candidate genes. APOE ε4/ ε4 carriers across all ancestries showed upregulated cholesterol biosynthesis genes with decreased myelination markers. iPSC‐derived oligodendrocytes demonstrated high correlation (R2 > 0.85) with human brain transcriptomes. DISCUSSION Our findings highlight the importance of studying diverse ancestries in AD research and suggest early APOE ε4 effects on cholesterol metabolism. The validated iPSC model provides a valuable tool for investigating ancestry‐specific disease mechanisms. Highlights First study comparing iPSC‐derived oligodendroglia across three ancestries. APOE ε4 carriers show upregulated cholesterol synthesis in oligodendroglia. Reduced myelin gene expression observed in APOE ε4/ε4 oligodendroglia. Ancestry‐specific differences found in AD GWAS genes and chromatin states. Novel insights into oligodendrocyte biology relevant to Alzheimer’s disease.

INTRODUCTION Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD). METHODS We performed a pleiotropy genome‐wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic‐based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms. RESULTS Genome‐wide significant pleiotropy for BP and cognitive performance with JPH2, GATA3, PAX2, LOC105371656, and SUFU in the total sample; RTN4, ULK2, SORBS2, and LOC100128993 in prospective cohorts; and ADAMTS3 and LINC02946 in clinic‐based cohorts. Six pleiotropic loci influence cognition directly, and six genes were differentially expressed between pathologically confirmed AD cases with and without antemortem cognitive impairment. DISCUSSION Our results provide insight into mechanisms underlying hypertension and AD. Highlights Genome‐wide significant pleiotropy in blood pressure (BP) and cognitive performance measures were identified with 11 novel loci: JPH2, GATA3, PAX2, LOC105371656, SUFU in the total sample; RTN4, ULK2, SORBS2, LOC100128993 in prospective cohorts; and ADAMTS3, LINC02946 in clinic‐based cohorts. SUFU, RTN4, SORBS2, ADAMTS3, and GATA3 affected cognition directly rather than through BP. ACTR1A, HIF1AN, ADAMTS3, RTN4, SORBS2, and SUFU at pleiotropic loci were differentially expressed among controls and pathologically confirmed AD cases with and without clinical symptoms.

INTRODUCTION ABCA7 (ATP binding cassette subfamily A member 7) encodes a lipid transporter associated with increasing risk for Alzheimer's disease (AD). A 44‐base pair deletion in ABCA7 (rs142076058; p.Arg578Alafs) is a strong risk factor in individuals of African ancestry (AA). However, the biological consequences of this deletion are poorly understood. METHODS We expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess cellular localization and impact on lipid metabolism, respectively. Additionally, induced pluripotent stem cell (iPSC)‐derived neurons carrying the deletion were functionally assessed compared to isogenic controls. RESULTS Truncated ABCA7 localized to endoplasmic reticulum and plasma membranes similarly to the wild type in HEK cells but induced significant lipid droplet accumulation in HepG2 cells and iPSC‐derived neurons while reducing mitochondrial membrane potential in iPSC‐derived neurons. DISCUSSION These findings show that the AA‐specific ABCA7 deletion disrupts lipid and mitochondrial homeostasis, supporting a mechanistic link between the ABCA7 deletion and increased AD risk. Highlights Truncated ATP binding cassette subfamily A member 7 (ABCA7) remains stable and localizes to endoplasmic reticulum and plasma membranes in HEK cells. Truncated ABCA7 disrupts lipid droplet regulation in HepG2 cells and neurons. ABCA7 shows the highest expression in neurons among brain cell types. ABCA7 truncation impairs lipid metabolism and mitochondrial health in neurons.

INTRODUCTION Transactive response DNA binding protein 43 kDa (TDP‐43) proteinopathy has been linked to cognitive decline and often co‐occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP‐43 proteinopathy and HS, we performed genome‐wide association studies (GWASs) of HS and TDP‐43 inclusions. METHODS Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP‐43: N = 4669). Statistical analyses included association analysis with HS and TDP‐43 inclusions and meta‐analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region. RESULTS Two regions achieved genome‐wide significance with TDP‐43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome‐wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP‐43 proteinopathy. DISCUSSION We identified associations with TDP‐43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic‐predominant age‐related TDP‐43 encephalopathy. Highlights HS and TDP‐43 contribute to dementia and often co‐occur. The etiology and relationship of HS and TDP‐43 remains unclear. HS and TDP‐43 share genetic risk factors in the genes APOE and TMEM106B. Genes have direct effects on HS, with additional effects mediated through TDP‐43.

BACKGROUND Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS We conducted the largest sex‐aware genetic study on late‐life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex‐stratified and sex‐interaction genome‐wide association studies in 24,216 non‐Hispanic White and 3367 non‐Hispanic Black participants. RESULTS We identified three sex‐specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ‐SCHIP), including an X‐chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex‐specific pathway and found sex‐specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex‐specific genes, pathways, and genetic correlations that related to late‐life memory. Highlights Demonstrated the heritable component of late‐life memory is similar across sexes. Identified two genetic loci with a sex‐interaction with baseline memory. Identified an X‐chromosome locus associated with memory decline in females. Highlighted sex‐specific candidate genes and pathways associated with memory. Revealed sex‐specific shared genetic architecture between memory and complex traits.

INTRODUCTION Cognitive SuperAgers (SAs) are individuals aged 80+ with exceptional episodic memory performance for their age, exceeding middle‐aged adult norms. This study integrates family‐ and association‐based methods to identify genetic variants associated with SAs in the Midwestern Amish population. METHODS Eighty‐three Amish SAs were grouped into 16 pedigrees for parametric and non‐parametric linkage analysis. Variants in linked regions (heterogeneity logarithm of the odds [HLOD] or Kong and Cox logarithm of the odds [LOD*] ≥ 3) were tested for association with SAs using two contrasts: SA versus Alzheimer's disease (AD; n = 40) and SA versus cognitively unimpaired (CU), age‐matched non‐SA individuals (CU80+; n = 157). RESULTS Evidence of linkage for SAs was observed on chromosomes 1, 2, 7, 16, and 20, with the strongest signal around the AD‐associated locus WDR12 on chromosome 2. Association analysis for SA versus AD identified eight variants in HIVEP3 (chromosome 1) that were nominally significant when comparing SA versus CU80+. DISCUSSION WDR12 and HIVEP3 are potential candidate genes contributing to SAs in the Amish population. Highlights Genetic linkage analysis in Amish SA pedigrees identified regions on chromosomes 1, 2, 7, 16, and 20. The strongest linkage was observed in the AD‐associated WDR12 gene on chromosome 2. Regional mapping within linked regions identified associated variants within HIVEP3 on chromosome 1. Variants in HIVEP3 have been linked to AD and AD‐related characteristics.