Most biomedical data currently available for any disease is derived from studies in non-Hispanic white (NHW) populations. Specifically, clinical information, genetics as well as biomarkers for frontotemporal dementia (FTD) have been studied predominantly in those NHW populations. For example, a role for depression and cardiovascular symptoms in increased risk for cognitive impairment has been reported; but little information is available on their risk effect in (diverse) FTD. Our current cohort consists of 135 FTD patients (71% Hispanic, 21% NHW, 6.5% Black/African American), with continuing enrollment from University of Miami (FL), Caribbean Center for the Study of Memory and Cognition (PR) and Instituto Nacional de Ciencias Neurologicas (Peru). All patients were evaluated using NACC Uniform DataSet or equivalent in their preferred language; ∼53% of the cohort also completed the FTD module forms. We compared clinical presentation (age-at-onset, ratio behavioral to language variant) in NHW versus Hispanic patients. Additionally, we studied association of Clinical Dementia Rating (CDR) scores with cardiovascular symptoms and depression (Geriatric Depression Score or Cornell Score for Depression). We did not identify a significant difference in age-at-onset, global CDR or ratios of behavioral FTD (bvFTD) versus primary progressive aphasia (PPA) as first symptoms between the NHW and Hispanic patients. We observed association of depression with global CDR≥2, across all patients (p = 0.003) and in Hispanic or Black/African American patients specifically (both p∼0.04). This difference was not driven by bvFTD or PPA subtypes specifically. No significant association was observed for global CDR with diabetes, hypertension or hyperlipidemia in all, Hispanic or NHW patients. Biomedical research of FTD in underrepresented population groups is necessary as data from research in NHW is not always generalizable across race/ethnicity. Our data suggests that the reported association of depression with higher CDR scores is valid in diverse FTD patient groups; whereas we see less evidence for cardiovascular symptoms being associated with risk for FTD. We are working to expand our efforts characterizing the full clinical and biological presentation of FTD in non-NHW population groups. The biomedical characterization of FTD across race/ethnicity will help the understanding of disease mechanisms in all patients, ultimately preventing further health disparities.

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:Genome-wide association studies (GWAS) studies in Alzheimer's disease (AD) demonstrate ancestry-specific loci. Previous studies in the regulatory architecture have only been conducted in Europeans (EUs), thus studies in additional ancestries are needed. Given the prevalence of AD genes expressed in microglia, we initiated our studies in induced pluripotent stem cell (iPSC) -derived microglia. METHODS:We created iPSC-derived microglia from 13 individuals of either high Amerindian (AI), African (AF), or EU global ancestry, including both AD and controls. RNA-seq, ATAC-seq, and pathway analyses were compared between ancestries in both AD and non-AD genes. RESULTS:Twelve AD genes were differentially expressed genes (DEGs) and/or accessible between ancestries, including ABI3, CTSB, and MS4A6A. A total of 5% of all genes had differential ancestral expression, but differences in accessibility were less than 1%. The DEGs were enriched in known AD pathways. DISCUSSION:This resource will be valuable in evaluating AD in admixed populations and other neurological disorders and understanding the AD risk differences between populations. HIGHLIGHTS:First comparison of the genomics of AI, AF, and EU microglia. Report differences in expression and accessibility of AD genes between ancestries. Ancestral expression differences are greater than differences in accessibility. Good transcriptome correlation was seen between brain and iPSC-derived microglia. Differentially expressed AD genes were in known AD pathways.

Genome-wide association studies (GWAS) in Alzheimer’s disease (AD) are consistently discovering genetic variants linked to the risk of developing this neurodegenerative condition. However, the effect size of the shared associated loci varies across populations as well as each population can have unique associations. This phenomenon could be explained by ancestry-dependent changes in the genomic regulatory architecture (GRA) influencing the expression of these genes, similar to the effect of different local ancestry on the risk of AD in APOE4 carriers. Thus, understanding of GRA in the context of AD is imperative but currently most GRA data available is predominantly European, limiting our ability to comprehensively interpret the variability associated with AD risk genes across populations. For this study we focused on oligodendroglia, a cell lineage that has been historically overlooked but that is emerging as key players in AD due to their involvement in various pathological processes, including neuroinflammation, oxidative stress, and synaptic dysfunction. Here, we report ancestry-dependent differences in the GRA of iPSC derived oligodendroglia with African, Amerindian, or European global ancestry. We obtained PBMCs from individuals with Alzheimer’s disease (AD) or without cognitive impairment, each with over 85% global ancestry of a specific ancestral background. These cells were then transformed into induced pluripotent stem cells (iPSC) and subsequently differentiated into oligodendroglia-containing 3D neural cultures. On the 76th day of differentiation, we harvested and lysed the cells to isolate nuclei for Multiomic profiling including Single Cell ATAC and Single Cell RNA-seq, we analyzed the chromatin accessibility and transcriptomes to identify ancestry-dependent changes genome-wide and in AD GWAS hits. We found several AD GWAS hits differentially expressed between ancestries in OPCs and in the more mature oligodendrocyte population (including APP and CLU ) and some differentially accessible peaks associated to some of these genes (predominantly PRDM7 ). Nevertheless, OPCs showed more ancestry-specific regulation than the more mature oligodendrocytes. Our findings offer ancestry-specific understanding of oligodendroglia chromatin changes and gene regulation in the context of AD. These results present a comprehensive perspective on the genetic regulatory architecture of oligodendroglia and constitute a resource for gene identification studies in the African American and Hispanic populations.

In the US, African Americans (admixed with African and European) followed by Hispanics (admixed with Amerindian, African, and European) are the most affected groups compared to non-Hispanic Whites (NHW). While genetic diversity and admixture play crucial roles in disease risk, the ancestry-specific mechanisms remain poorly understood with most AD-related studies focusing on NHW. Despite the recent field efforts to include genetically admixed populations, there continues to be a lack of functional studies in AD across the different cell types in these populations. Given the importance of Microglia in AD, we here characterize the genetic regulatory architecture (GRA) on iPSC-derived Microglia (MGL) in African and Amerindian genomes. iPSC lines derived from controls and AD patients with >90% genomic content from different ancestries (Amerindian, African, and European) were differentiated into MGL. We performed bulk RNA-seq and ATAC-seq, followed by differential expression and accessibility analyses to study the GRA of these admixed populations and its contributions to AD. We identified 1,103 differentially expressed genes (DEGs) and 267 differentially accessible genes (DAGs) across ancestries. We observed the most differences on both chromatin accessibility and gene expression levels between AI and AF. On the chromatin level and in the context of AD, we observed 2 DAGs ( PRDM7 and SCIMP ) between AI and AF, and 1 DAG between AI and EU ( PRDM7 ). In addition, we identified 10 AD-risk modifying genes that are differentially expressed between AI and AF ancestries ( ABI3, CTSB, JAZF1, MS4A6A, PILRA, PLEKHA1, RASGEF1C, SORL1, TREM2 , and TREML2 ) and 3 DEGs between AI and EU ( JAZF1, MS4A6A , and SORL1 ). We identified several DEGs to be involved in lipid metabolism, cholesterol biosynthesis and metabolism, lysosomal activity, and immune response - all highly relevant processes in AD pathology. We provide new insights into ancestry-specific genetic risk factors in AD pathophysiology. Here, we report novel transcriptomic and chromatin accessibility data in microglia of AI and AF ancestries that potentially contribute to a differential genetic risk in AD in the different ancestries. Interestingly, those ancestries with greatest migratory differences revealed the largest DEG.

Background: This study aims to elucidate ancestry-specific changes to the genomic regulatory architecture in induced pluripotent stem cell (iPSC)-derived oligodendroglia, focusing on their implications for Alzheimer's disease (AD). This work addresses the lack of diversity in previous iPSC studies by including ancestries that contribute to African American (European/African) and Hispanic/Latino populations (Amerindian/African/European). Methods: We generated 12 iPSC lines—four African, four Amerindian, and four European— from both AD patients and non-cognitively impaired individuals, with varying APOE genotypes (APOE3/3 and APOE4/4). These lines were differentiated into neural spheroids containing oligodendrocyte lineage cells. Single-nuclei RNA sequencing and ATAC sequencing were employed to analyze transcriptional and chromatin accessibility profiles, respectively. Differential gene expression, chromatin accessibility, and Hi-C analyses were conducted, followed by pathway analysis to interpret the results. Results: We identified ancestry-specific differences in gene expression and chromatin accessibility. Notably, numerous AD GWAS-associated genes were differentially expressed across ancestries. The largest number of differentially expressed genes (DEGs) were found in European vs. Amerindian and African vs. Amerindian iPSC-derived oligodendrocyte progenitor cells (OPCs). Pathway analysis of APOE4/4 carriers vs APOE3/3 carriers exhibited upregulation of a large number of disease and metabolic pathways in APOE4/4 individuals of all ancestries. Of particular interest was that APOE4/4 carriers had significantly upregulated cholesterol biosynthesis genes relative to APOE3/3 individuals across all ancestries, strongest in iOPCs. Comparison of iOPC and iOL transcriptome data with corresponding human frontal cortex data demonstrated a high correlation (R2 > 0.85). Conclusions: This research emphasizes the importance of including diverse ancestries in AD research to uncover critical gene expression differences between populations and ancestries that may influence disease susceptibility and therapeutic interventions. The upregulation of cholesterol biosynthesis genes in APOE4/4 carriers of all three ancestries supports the concept that APOE4 may produce disease effects early in life, which could have therapeutic implications as we move forward towards specific therapy for APOE4 carriers. These findings and the high correlation between brain and iPSC-derived OPC and OL transcriptomes support the relevance of this approach as a model for disease study.

IntroductionHispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. Puerto Ricans (PR), a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We aimed to conduct a genome-wide association study (GWAS) and comprehensive analyses to identify novel AD susceptibility loci and characterize known AD genetic risk loci in the PR population.Materials and methodsOur study included Whole Genome Sequencing (WGS) and phenotype data from 648 PR individuals (345 AD, 303 cognitively unimpaired). We used a generalized linear-mixed model adjusting for sex, age, population substructure, and genetic relationship matrix. To infer local ancestry, we merged the dataset with the HGDP/1000G reference panel. Subsequently, we conducted univariate admixture mapping (AM) analysis.ResultsWe identified suggestive signals within the SLC38A1 and SCN8A genes on chromosome 12q13. This region overlaps with an area of linkage of AD in previous studies (12q13) in independent data sets further supporting. Univariate African AM analysis identified one suggestive ancestral block (p = 7.2×10−6) located in the same region. The ancestry-aware approach showed that this region has both European and African ancestral backgrounds and both contributing to the risk in this region. We also replicated 11 different known AD loci -including APOE- identified in mostly European studies, which is likely due to the high European background of the PR population.ConclusionPR GWAS and AM analysis identified a suggestive AD risk locus on chromosome 12, which includes the SLC38A1 and SCN8A genes. Our findings demonstrate the importance of designing GWAS and ancestry-aware approaches and including underrepresented populations in genetic studies of AD.

Alzheimer's disease (AD) risk differs between population groups, with African Americans and Hispanics being the most affected groups compared to non-Hispanic Whites. Genetic factors contribute significant risk to AD, but the genetic regulatory architectures (GRA) have primarily been studied in Europeans. Many AD genes are expressed in microglia; thus, we explored the impact of genetic ancestry (Amerindian (AI), African (AF), and European (EU)) on the GRA in iPSC-derived microglia from 13 individuals (~4 each with high global ancestry, AD and controls) through ATAC-seq and RNA-seq analyses. We identified several differentially accessible and expressed genes (2 and 10 AD-related, respectively) between ancestry groups. We also found a high correlation between the transcriptomes of iPSC-derived and brain microglia, supporting their use in human studies. This study provides valuable insights into genetically diverse microglia beyond the analysis of AD. ### Competing Interest Statement The authors have declared no competing interest.

The variant G206A in Presenilin-1 ( PSEN1 ) gene has been identified almost exclusively in Alzheimer Disease (AD) Puerto Rican families. This variant represents a founder effect on the African background. The G206A variant associates with extreme variability in age of onset (AOO), ranging from 30 to 90 years. In contrast, other variants at the same amino acid of PSEN1 (G206N, G206S) have a tighter range of AOO (30-35 years). We aim to identify the molecular mechanisms involved in the AOO variability between G206A carriers through functional analysis of induced pluripotent stem cells (iPSCs). Genotyping data were phased using SHAPEIT to identify local ancestry and RFMix to estimate genetic ancestry. p-Tau181 levels were tested from plasma using Simoa (Quanterix HD-X). iPSCs of G206A carriers with different AOO were reprogrammed using non-integrating Sendai virus. These clonal lines were assessed for pluripotency and chromosomal stability Isogenic construction of G206A iPSC lines is currently in progress. We screened for G206A carriers using whole genome from 896 individuals (182 families) and identified 43 carriers (39 AD and 4 cognitively unimpaired <65 years) from 8 families and 3 isolated cases. 55% of AD G206A carriers had AOO <65. A single African haplotype was identified in all G206Acarriers. We observed higher pTau181 levels in AD G206A carriers with early age of onset, compared to those with late onset. Association analysis did not identify APOE4 or SYNJ1 polymorphisms as contributing to the differences in AOO within G206A carriers. To perform functional studies, we selected three with early (<65) and three with late (>65) AOO AD peripheral blood mononuclear cells (PBMCs)that were reprogrammed into iPSC lines. G-band Karyotype, factor loss analyses, genetic finger printing, immunocytochemistry (ICC) and qRT-PCR for intracellular and surface pluripotency markers was confirmed in the iPSC lines. The PSEN1 G206A variant, originating in African ancestry haplotype revealing a founder effect, is an important contributor to AD in an underserved population. Understanding the role of the G206A variant in AD pathogenesis and the factors that influence its effect on AOO will provide insight on AD pathogenesis, age of onset variation and identification of potential novel therapeutic targets.

Patterns of cognitive performance associated with different stages of dementia have been primarily studied in Non-Hispanic White (NHW) populations. This study compares patterns of cognitive performance, on a brief neuropsychological battery, in Caribbean Hispanic (CH) and NHW individuals with mild cognitive impairment, based on Clinical Dementia Rating (CDR) staging scores. Our data included 427 individuals including 299 self-identified CH (mean age = 76.0; 69.6% female; mean education = 11.9) and 128 NHW (mean age = 72.9; 61.7% female; mean education = 13.8) who completed the CDR and a brief neuropsychological battery. Participants with other medical conditions known to impact cognition were excluded. Sex-, age-, and education-adjusted Z-scores were calculated for all cognitive tests (Logical Memory (Immediate and Delayed recall), Digit Span (Forward and Backward), and Verbal Fluency (Animals and Vegetables)). ANOVAs were used to examine the effects of ethnicity (NHW, CH) and CDR Global Score (0.5, 1.0) on the adjusted Z-scores for all cognitive tests. CDR score distribution was adjusted through factorial ANOVA (ethnicity x CDR). Descriptive analyses included independent t-tests to examine differences between ethnicity groups on age, sex, education, percent AD, percent Unclear, and CDR Global Score. There was a main effect of ethnicity on Digit Span Forward (p < 0.001), Digit Span Backward (p < 0.001), and Verbal Fluency – Vegetables (p < 0.01), where CH individuals showed greater impairment regardless of Global CDR score. We found a main effect of Global CDR score on all cognitive tests, where individuals with Global CDR score of 1.0 demonstrated more impairment than individuals with a Global CDR score of 0.5. No ethnicity x CDR interactions were significant. Our sample of older CH and NHW individuals, presumed to have mild cognitive impairments based on CDR staging, did not differ in memory abilities. However, the CH group scored significantly lower on measures of attention and working memory. Finally, semantic fluency performance was variable and possibly influenced by cultural familiarity with different semantic categories. Among older CH individuals with mild dementia, cognitive difficulties may extend beyond memory problems and include attentional and executive function difficulties. These findings have clinical implications for diagnosis and management of CH patients.

Alzheimer disease (AD) is the fourth leading cause of death in Puerto Rico. The Puerto Rican (PR) population has a high proportion of older adults (18%, over > 65), with 12.5% of them suffering from ADThese statistics highlight the need to investigate the genetic risk factors underlying AD in the PR population, as it could lead to the development of targeted treatments and therapies. Moreover, the ancestrally admixed makeup of the PR population provides an opportunity to assess the role of the European (∼67%), African (∼20%) and Amerindian (∼13%) ancestry in AD risk. We performed genome wide association analysis (GWAS) using whole genome sequence data to identify genetic risk/protective factors associated with AD in the PR population. The PR dataset includes WGS and phenotype data from 640 individuals, comprising 335 AD and 305 cognitively unimpaired (CU) controls. To account for the population substructure, we calculated the global ancestry (principal components) using EIGENSTRAT. We performed GWAS analyses with a generalized linear mixed-model using the SAIGE software. The model included genotype, sex, age, and principal components (population substructure) as fixed effects and genetic relationship matrix as a random effect. The genetic relationship matrix was calculated based on genomic data and accounted for the relatedness among the individuals in the dataset. We identified four suggestive significant loci (P<1×10 −6 ) associated with the risk of AD in PRs: NACC2 (pv = 4.8×10 −7 ) on chromosome 9, SCN8A (pv = 9.3×10 −7 ) on chromosome 12, FOXK2 (pv = 9.9×10 −7 ) on chromosome 17, and APOEe4 (pv = 6.8×10 −8 ) on chromosome 19. Eight additional AD loci with the same lead marker from European GWAS study (Bellenquez et al.) showed nominal significance: FERMT2 (pv = 6.2×10 −3 ), TREM2 (pv = 8.0×10 −3 ), CLU (pv = 1.8×10 −2 ), RASGEF1C (pv = 2.4×10 −2 ), ADAM17 (pv = 3.5×10 −2 ), DOC2A (pv = 4.3×10 −2 ), GRN (pv = 4.4×10 −2 ) and SORL1 (pv = 5.1×10 −2 ). This study identified three suggestive novel significant loci (NACC2, SCN8A, and FOXK2) associated with AD risk in PRs. In addition, GWAS study on PRs with a high proportion of European ancestry was able to replicate nine AD loci previously identified in European studies. These findings provide new insights into the genetic architecture of AD in the PR population.

The APOE4 genotype is the main contributor to the risk of developing Late Onset Alzheimer’s Disease (LOAD), while the APOE3 genotype has no effect on LOAD risk. Previously our group has shown that Local Ancestry (LA) surrounding APOE4 regulates APOE expression in adult individuals. As LOAD pathology has been shown to develop decades before the onset of symptoms, we sought to explore if LA has similar or different effect in mitotic cells, and whether the APOE3 genotype modulates the effect of the LA. To answer this question, we generated APOEε3/3 and APOEε4/4 isogenic induced Pluripotent Stem Cells (iPSCs) lines from individuals with either European LA or African LA. PBMCs were derived from APOEε4/4 carrying individuals with either African or European APOE LA. To generate APOE isogenic lines, we formed a ribonucleoprotein (RNP) complex using a previously published APOE sgRNA (Lin et al. 2018) and performed nucleofection using the 4D-Nucleofector system (Lonza). Homozygous APOEε3/3 edited and APOEε4/4 unedited isogenic clones were selected, and confirmed to lack unwanted off-target editing. Isogenic clone pluripotency was confirmed by immunocytochemistry (SOX2, NANOG and OCT4a staining). APOE expression in the isogenic clones was tested by quantitative Real-Time PCR and significance was calculated by Student’s T-test. Isogenic clones were similar in their pluripotency and growth characteristics. Preliminary APOE expression in the iPSC line carrying the African LA was higher (p = 0.0002) in each of the individual APOEε3/3 KI clones (n = 3) compared to each of the individual unedited APOEε4/4 clones (n = 2), showing consistency within each isogenic group. In contrast, the APOE expression in the iPSC line carrying the European LA was not significant in the APOEε3/3 KI clones (n = 2) compared to the parental line. Our data suggests that differences in local ancestry has a direct effect on the expression of APOE isoforms in iPSCs. This finding supports previous reports in frontal cortex suggesting that the regulation of APOE expression differs depending on ancestry.

Puerto Ricans, the second largest US Latino group, are underrepresented in genomic studies of Alzheimer disease (AD). We describe a multi-source ascertainment approach, networking with community and governmental stakeholders, as part of the Puerto Rico (PR) Alzheimer Disease Initiative (PRADI) whose goal is to increase recruitment and retention of PR individuals in genomic research.The National Alzheimer’s disease Action Plan 2015-2025 served as a framework for PRADI group that aims to fill two of the goals of the plan: increase research and education. We developed collaborative relationships with community and governmental organizations that serve the elderly and AD patients from 37/78 (47%) municipalities of PR to identify potential research participants. Trust and transparency were central to our interactions with community groups. We educated patients and caregivers about AD and their possible contribution to science. Bringing academia to the community encouraged participation. Additionally, we established relationships with multiple neurologists across PR caring for AD patients and their families. For recruitment and enrollment PRADI team members visited families in the homes, daycare facilities and clinics. All participants were assigned diagnoses by a clinical adjudication committee comprised of neurologists and neuropsychologists with expertise in AD and related dementias (ADRD) Since 2016 we have enrolled 1, 281 individuals. Among these 752 are unrelated individuals (193 AD, 170 mild cognitive impairment (MCI), 306 cognitively unimpaired (CU) and 83 with other diagnoses (OD). 529 individuals (195 AD, 76 MCI, 178 CU and 80 OD) were part of 155 multiplex AD families. Most families are from Eastern and Northern PR regions, reflecting dense population areas with large cities. Longitudinal follow-up of the first 167 participants for diagnostic updates is complete. 64 individuals were ascertained in the continental US (cUS). Of the 167 individuals in the longitudinal follow-up (3-5 years), 7.2% progressed from either CU to MCI or AD, or MCI to AD. The PRADI group multisource ascertainment approach enabled recruitment and retention of participants both in PR and the cUS. Longitudinal clinical data across the cohort further enriches the impact of genomic studies in a diverse population.

The effect of variants associated with Alzheimer’s disease (AD) can be influenced by ancestry, which determines the genomic regulatory architecture (GRA). A global understanding of GRA in the context of AD is imperative to interpret the variability associated with AD risk genes across populations. Most studies up to date have focused on studying GRA in European ancestry, in this study we aimed at determining the GRA in African, Amerindian, and European ancestries. Since GRA is cell specific, we developed a human induced pluripotent cells (hiPSC) based model for oligodendrocytes (OLs), a cell type which has limited studies focused on AD. Cells from AD patients or non-cognitively impaired controls with >90% of either Amerindian, African or European global ancestry were differentiated using a modified multi-stage protocol that promotes the development and enrichment of oligodendrocytes in neural spheroids. After terminal differentiation, cells were collected and lysed to isolate nuclei for Multiomic profiling of chromatin accessibility and transcriptome using Single Cell ATAC and Single Cell RNA-seq. Additionally, we examined chromatin interactions using Hi-C analyses. We identified oligodendrocyte lineage cells at different stages of development ranging from dividing cells with transcriptional profiles consistent with those of oligodendrocyte precursor cells (OPC) to mature myelinating oligodendrocytes. We compared the oligodendrocytes clusters across ancestries, cases versus controls and APOE genotypes to characterize the genomic landmarks and signatures associated with AD related GWAS loci. Astrocytes and neurons were also derived within our 3D spheroids, allowing us to study ancestry-related cell type specific changes in GRA. Our results provide ancestry-specific insights into oligodendrocyte chromatin structure and gene regulation in the context of AD. These results offer an integrated view of the GRA of a previously overlooked cell lineage that constitute a large population in the central nervous system and is compromised during AD in terms of abundance and function. This will expand the available functional resources for gene identification studies in African American and Hispanic/Latino studies.

Plasma concentrations of phosphorylated threonine-181 of Tau (pTau181) and the ratio of amyloid beta isoforms Ab42/Ab40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, measurement of these biomarkers is mostly from individuals of non-Hispanic, European ancestry. Given differences in AD risk, generalizability of these findings is not assured in individuals of diverse ancestry. This study evaluates the utility of plasma pTau181 and Ab42/Ab40 in discriminating clinically diagnosed AD from cognitively intact, age-matched controls in ancestrally diverse, admixed cohorts. We measured plasma pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3-PLEX A assays, respectively. Our cohorts consisted of: 642 African Americans (162 AD and 480 cognitively intact (CI)), 906 Puerto Ricans (385 AD and 521 CI), 149 Peruvians (49 AD and 100 CI), 60 Cubans (26 AD and 34 CI), and 246 non-Hispanic, European ancestry (22 AD and 224 CI). Linear mixed-effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify differences across AD status. Diagnostic performance and construct receiver operator characteristic (ROC) curves were created from logistic regression models. Plasma pTau181 concentrations were increased in individuals with AD compared to CI (p < 2×10 −16 ) taking into account all individuals and in each cohort separately (African Americans, p = 1.2×10 −9 ; Puerto Ricans, p = 7.6×10 −9 ; Peruvians, p = 0.02), and European ancestry, p = 2.2×10 −8 ) except for the Cubans where there was a trend. There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing concentration in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined. The accuracy varied widely over the individual cohorts with AUC from 0.845 for African Americans to 0.683 for Peruvians. These results suggest AD biomarkers are generalizable across ancestries, though the predictive value may differ depending on specific ancestral backgrounds. Ultimately, combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.

BACKGROUND:Patterns of cognitive performance associated with different stages of dementia have been primarily studied in Non-Hispanic White (NHW) populations. This study compares patterns of cognitive performance, on a brief neuropsychological battery, in Caribbean Hispanic (CH) and NHW individuals with mild cognitive impairment, based on Clinical Dementia Rating (CDR) staging scores. METHOD:Our data included 427 individuals including 299 self-identified CH (mean age = 76.0; 69.6% female; mean education = 11.9) and 128 NHW (mean age = 72.9; 61.7% female; mean education = 13.8) who completed the CDR and a brief neuropsychological battery. Participants with other medical conditions known to impact cognition were excluded. Sex-, age-, and education-adjusted Z-scores were calculated for all cognitive tests (Logical Memory (Immediate and Delayed recall), Digit Span (Forward and Backward), and Verbal Fluency (Animals and Vegetables)). ANOVAs were used to examine the effects of ethnicity (NHW, CH) and CDR Global Score (0.5, 1.0) on the adjusted Z-scores for all cognitive tests. CDR score distribution was adjusted through factorial ANOVA (ethnicity x CDR). Descriptive analyses included independent t-tests to examine differences between ethnicity groups on age, sex, education, percent AD, percent Unclear, and CDR Global Score. RESULT:There was a main effect of ethnicity on Digit Span Forward (p < 0.001), Digit Span Backward (p < 0.001), and Verbal Fluency - Vegetables (p < 0.01), where CH individuals showed greater impairment regardless of Global CDR score. We found a main effect of Global CDR score on all cognitive tests, where individuals with Global CDR score of 1.0 demonstrated more impairment than individuals with a Global CDR score of 0.5. No ethnicity x CDR interactions were significant. CONCLUSION:Our sample of older CH and NHW individuals, presumed to have mild cognitive impairments based on CDR staging, did not differ in memory abilities. However, the CH group scored significantly lower on measures of attention and working memory. Finally, semantic fluency performance was variable and possibly influenced by cultural familiarity with different semantic categories. Among older CH individuals with mild dementia, cognitive difficulties may extend beyond memory problems and include attentional and executive function difficulties. These findings have clinical implications for diagnosis and management of CH patients.

BACKGROUND:Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non-Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary by population in AD. This is likely the result of both sociocultural and genetic ancestral differences. However, the impact of these NPS on AD in different groups is not well understood.METHODS:Self-declared AA, HIW, and NHW individuals were ascertained as part of ongoing AD genetics studies. Participants who scored higher than 0.5 on the Clinical Dementia Rating (CDR) Scale (CDR) were included. Group similarities and differences on Neuropsychiatric Inventory Questionnaire (NPI-Q) outcomes (NPI-Q total score, NPI-Q items) were evaluated using univariate ANOVAs and post hoc comparisons after controlling for sex and CDR stage.RESULTS:Our sample consisted of 498 participants (26% AA; 30% HIW; 44% NHW). Overall, NPI-Q total scores differed significantly between our groups, with HIW having the highest NPI-Q total scores, and by AD stage as measured by CDR. We found no significant difference in NPI-Q total score by sex. There were six NPI-Q items with comparable prevalence in all groups and six items that significantly differed between the groups (Anxiety, Apathy, Depression, Disinhibition, Elation, and Irritability). Further, within the HIW group, differences were found between Puerto Rican and Cuban American Hispanics across several NPI-Q items. Finally, Six NPI-Q items were more prevalent in the later stages of AD including Agitation, Appetite, Hallucinations, Irritability, Motor Disturbance, and Nighttime Behavior.CONCLUSIONS:We identified differences in NPS among HIW, AA, and NHW individuals. Most striking was the high burden of NPS in HIW, particularly for mood and anxiety symptoms. We suggest that NPS differences may represent the impact of sociocultural influences on symptom presentation as well as potential genetic factors rooted in ancestral background. Given the complex relationship between AD and NPS it is crucial to discern the presence of NPS to ensure appropriate interventions.

The vast majority of biomedical data currently available for any disease is derived from studies in non-Hispanic white (NHW) populations. Specifically, clinical information, genetic factors as well as biomarkers for frontotemporal dementia (FTD) have been studied predominantly in those NHW populations. To increase representation in biomedical research, we set out to enroll and characterize a diverse FTD patient cohort enriched for Caribbean Hispanic patients. Our current cohort consists of 89 FTD patients (30% NHW, 67% Hispanic), with continuing enrollment from the University of Miami Hospital Neurology Department in Miami, FL and the Caribbean Center for the Study of Memory and Cognition in San Juan, PR. All patients were evaluated using NACC approved Uniform DataSet (UDS) or equivalent in their preferred language. For ∼65% of the cohort we also completed the NACC FTD module forms. We generated genotyping data (Illumina GDA+Neurobooster array) as well as whole genome sequencing and plasma biomarker data (Quanterix Simoa Neuroplex-3; Ab40, Ab42, and total tau) for a subset of the cohort. Initial genetic analyses showed none of the Hispanic patients are carriers of known FTD mutations originally identified in NHW patients, including the C9orf72 repeat expansion and reported pathogenic variants in MAPT or GRN . We did not identify a significant difference in age-at-onset or Clinical Dementia Rating scores at time of enrollment between NHW and Hispanic patients. Additionally, biomarker data on Aβ40/Aβ42 ratio and total tau levels in a subset of 22 FTD patients (∼12/10 Hispanic/NHW) did not show significantly different levels between patients of both ethnicities. Genetic analyses of FTD in underrepresented population groups is necessary as genetic information from research in NHW is not always generalizable across race/ethnicity. We are currently working to expand our efforts to include identification of novel genetic risk factors for FTD in the Hispanic patients using whole genome sequencing, full evaluation of the Neuroplex as well as p-tau181 and NfL biomarkers in the complete cohort and comparison of clinical presentations between ethnicities. The biomedical characterization of FTD across race/ethnicity will help the understanding of disease mechanisms in all patients ultimately preventing further health disparities.

Depression (DEP) is a known risk factor for . However, DEP symptoms vary by race‐ethnicity (e.g. greater somatization among African Americans). The relationship between DEP and AD progression in underrepresented groups is not well‐understood. We hypothesize that certain DEP symptoms will be associated with earlier AAO, and that this relationship is moderated by race‐ethnicity

Identifying the genes and biological pathways involved in Alzheimer disease (AD) is critical in the effort to develop effective therapies. Significant work has identified genetic variants conferring risk and protection for AD in individuals of diverse ancestries, but identification of downstream functional effects including modulation of gene regulation is lacking, particularly in individuals of diverse ancestries. Therefore, to explore transcriptional changes between clinically diagnosed AD and cognitively intact age-matched controls, herein we analyzed RNA sequencing data from peripheral blood collected from individuals of admixed genetic backgrounds. Total RNA was extracted from peripheral whole blood stored in PAXGene tubes from 47 Cubans (22 AD and 25 controls), 85 Peruvians (41 AD and 44 controls), and 168 Puerto Ricans (88 AD and 80 controls). PolyA selected mRNA was sequenced to more than 40 million paired end read per sample on the Illumina NovaSeq 6000. The bioinformatic pipeline included mapping to the human reference genome (GRCh38), gene quantifications against the GENCODE v35 annotation set, and differential expression was calculated using DESeq2 with sex, age at blood draw, and count of APOEe4 alleles as covariates. Functional categorization was performed by gene set enrichment of gene ontology and KEGG pathways. Across the cohorts, a total of 358 protein-coding genes (FDR ≤ 0.05, Fold change ≥ 1.25) were differentially expressed with 238 down-regulated and 120 up-regulated in AD relative to controls. Despite the few genes overlapping between ethnicities, pathway analysis revealed common pathways including up-regulation of genes involved in inflammation and RNA processing and down-regulation of genes involved in cellular detoxification and lipid transport, among others. Interestingly, while few specific genes overlap in differential expression overlap with a published set of genes from non-Hispanic Europeans and African Americans (Griswold et al, 2018), the pathways identified are similar. Our analysis reveals a signature of gene expression that implicates increased inflammation and decreased cellular detoxification based on gene expression analysis in admixed Latinx AD. Convergence of pathways across these and African American and European cohorts supports the idea of distinct genes but similar underlying pathological processes contributing to AD across individuals of diverse ancestries.