MitoH3: Mitochondrial Haplogroup and Homoplasmic/Heteroplasmic Variant Calling Pipeline for Alzheimer's Disease Sequencing Project.

Background: Mitochondrial DNA (mtDNA) is a double-stranded circular DNA and has multiple copies in each cell. Excess heteroplasmy, the coexistence of distinct variants in copies of mtDNA within a cell, may lead to mitochondrial impairments. Accurate determination of heteroplasmy in whole-genome sequencing (WGS) data has posed a significant challenge because mitochondria carrying heteroplasmic variants cannot be distinguished during library preparation. Moreover, sequencing errors, contamination, and nuclear mtDNA segments can reduce the accuracy of heteroplasmic variant calling. Objective: To efficiently and accurately call mtDNA homoplasmic and heteroplasmic variants from the large-scale WGS data generated from the Alzheimer's Disease Sequencing Project (ADSP), and test their association with Alzheimer's disease (AD). Methods: In this study, we present MitoH3-a comprehensive computational pipeline for calling mtDNA homoplasmic and heteroplasmic variants and inferring haplogroups in the ADSP WGS data. We first applied MitoH3 to 45 technical replicates from 6 subjects to define a threshold for detecting heteroplasmic variants. Then using the threshold of 5% ≤variant allele fraction≤95%, we further applied MitoH3 to call heteroplasmic variants from a total of 16,113 DNA samples with 6,742 samples from cognitively normal controls and 6,183 from AD cases. Results: This pipeline is available through the Singularity container engine. For 4,311 heteroplasmic variants identified from 16,113 samples, no significant variant count difference was observed between AD cases and controls. Conclusions: Our streamlined pipeline, MitoH3, enables computationally efficient and accurate analysis of a large number of samples.

APOE genotype-specific methylation patterns are linked to Alzheimer disease pathology and estrogen response.

The joint effects of APOE genotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in an APOE genotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood. Additionally, we identified seven CpG sites in the APOE region containing TOMM40, APOE, and APOC1 genes with P < 5 × 10-8 between APOE ε4 carriers and non-carriers in brain or blood. In brain, the most significant CpG site hypomethylated in ε4 carriers compared to non-carriers was from the TOMM40 in the total sample, while most of the evidence was derived from AD cases. However, the CpG site was not significantly modulating expression of these three genes in brain. Three CpG sites from the APOE were hypermethylated in APOE ε4 carriers in brain or blood compared in ε4 non-carriers and nominally significant with APOE expression in brain. Three CpG sites from the APOC1 were hypermethylated in blood, which one of the 3 CpG sites significantly lowered APOC1 expression in blood using all subjects or ε4 non-carriers. Co-methylation network analysis in blood and brain detected eight methylation networks associated with AD and APOE ε4 status. Five of the eight networks included genes containing network CpGs that were significantly enriched for estradiol perturbation, where four of the five networks were enriched for the estrogen response pathway. Our findings provide further evidence of the role of APOE genotype on methylation levels associated with AD, especially linked to estrogen response pathway.

A comparative study of structural variant calling in WGS from Alzheimer's disease families.

Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins. We developed a novel metric, D-score, to evaluate caller specificity for deletions. The accuracy of deletions was evaluated by Sanger sequencing. We generated a high-quality call set of 152,301 deletions of diverse sizes. Sanger sequencing validated 114 of 146 detected deletions (78.1%). Scalpel excelled in accuracy for deletions ≤100 bp, whereas Parliament was optimal for deletions >900 bp. Overall, 83.0% and 72.5% of calls by Scalpel and Parliament were validated, respectively, including all 11 deletions called by both Parliament and Scalpel between 101 and 900 bp. Our flexible protocol successfully generated a high-quality deletion call set and a truth set of Sanger sequencing-validated deletions with precise breakpoints spanning 1-17,000 bp.

Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of the leading causes of disability worldwide. The apolipoprotein E4 gene (APOE4) is the strongest genetic risk factor for AD. In 2023, the APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data and discuss the question of whether to reduce or increase APOE4 as a therapeutic intervention for AD. It was the unanimous consensus that cumulative data from multiple studies in humans and animal models support that lowering APOE4 should be a target for therapeutic approaches for APOE4 carriers. ANN NEUROL 2024;95:625-634.

DNA from multiple viral species is associated with Alzheimer's disease risk.

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.

Sex-specific genetic architecture of late-life memory performance.

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.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

INTRODUCTION: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. METHODS: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. RESULTS: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. DISCUSSION: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. HIGHLIGHTS: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.

Comparison of Commonly Measured Plasma and Cerebrospinal Fluid Proteins and Their Significance for the Characterization of Cognitive Impairment Status.

BACKGROUND: Although cerebrospinal fluid (CSF) amyloid-ß42 peptide (Aß42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer's disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). OBJECTIVE: This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. METHODS: This cohort study included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. RESULTS: We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aß42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aß42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aß42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aß42)]. These results were adjusted for age, sex, education, and APOEϵ4 genotype. CONCLUSIONS: This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN.

Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness, and elucidating its underlying disease mechanisms is vital to the development of appropriate therapeutics. We identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue, the macular retina pigment epithelium (RPE)/choroid and the macular neural retina within the same eye. We utilized 27 deeply phenotyped donor eyes (recovered within a 6 h postmortem interval time) from Caucasian donors (60-94 years) using a standardized published protocol. Significant findings were then validated in an independent set of well-characterized donor eyes (n = 85). There was limited overlap between DEGs and DSGs, suggesting distinct mechanisms at play in AMD pathophysiology. A greater number of previously reported AMD loci overlapped with DSGs compared to DEGs between disease states, and no DEG overlap with previously reported loci was found in the macular retina between disease states. Additionally, we explored allele-specific expression (ASE) in coding regions of previously reported AMD risk loci, uncovering a significant imbalance in C3 rs2230199 and CFH rs1061170 in the macular RPE/choroid for normal eyes and intermediate AMD (iAMD), and for CFH rs1061147 in the macular RPE/choroid for normal eyes and iAMD, and separately neovascular AMD (NEO). Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1, validated between the iAMD vs. normal comparison, and AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292, validated between the NEO vs. normal comparison, revealed an intricate regulatory network with transcription factors and miRNAs identifying potential upstream and downstream regulators. Findings regarding the complement genes C3 and CFH suggest that coding variants at these loci may influence AMD development via an imbalance of gene expression in a tissue-specific manner. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes, potential splice variation, and allelic imbalance), which may open new avenues for AMD diagnostics and therapies specific to iAMD and NEO.

APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry.

Importance: Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. Objective: To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. Design, Setting, Participants: This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. Main Outcomes and Measures: The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. Results: Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). Conclusion and Relevance: Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

The impact of blood MCP-1 levels on Alzheimer's disease with genetic variation of UNC5C and NAV3 loci.

Background: Previous study shows that monocyte chemoattractant protein-1 (MCP-1), which is implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption, modulates the genetic risks of AD in established AD loci. Methods: In this study, we hypothesized that blood MCP-1 impacts the AD risk of genetic variants beyond known AD loci. We thus performed a genome-wide association study (GWAS) using the logistic regression via generalized estimating equations (GEE) and the Cox proportional-hazards models to examine the interactive effects between single nucleotide polymorphisms (SNPs) and blood MCP-1 level on AD in three cohorts: the Framingham Heart Study (FHS), Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study/Memory and Aging Project (ROSMAP). Results: We identified SNPs in two genes, neuron navigator 3 (NAV3, also named Unc-53 Homolog 3, rs696468) (p < 7.55×10- 9) and Unc-5 Netrin Receptor C (UNC5C rs72659964) (p < 1.07×10- 8) that showed an association between increasing levels of blood MCP-1 and AD. Elevating blood MCP-1 concentrations increased AD risk and AD pathology in genotypes of NAV3 (rs696468-CC) and UNC5C (rs72659964-AT + TT), but did not influence the other counterpart genotypes of these variants. Conclusions: NAV3 and UNC5C are homologs and may increase AD risk through dysregulating the functions of neurite outgrowth and guidance. Overall, the association of risk alleles of NAV3 and UNC5C with AD is enhanced by peripheral MCP-1 level, suggesting that lowering the level of blood MCP-1 may reduce the risk of developing AD for people with these genotypes.

Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease.

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

INTRODUCTION: The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease.Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects.

Structural variations (SVs) are important contributors to the genetics of numerous human diseases. However, their role in Alzheimer's disease (AD) remains largely unstudied due to challenges in accurately detecting SVs. Here, we analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP, N=16,905 subjects) and identified 400,234 (168,223 high-quality) SVs. We found a significant burden of deletions and duplications in AD cases (OR=1.05, P=0.03), particularly for singletons (OR=1.12, P=0.0002) and homozygous events (OR=1.10, P<0.0004). On AD genes, the ultra-rare SVs, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1, were associated with AD (SKAT-O P=0.004). Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, e.g., a deletion (chr2:105731359-105736864) in complete LD (R2=0.99) with rs143080277 (chr2:105749599) in NCK2. We also identified 16 SVs associated with AD and 13 SVs associated with AD-related pathological/cognitive endophenotypes. Our findings demonstrate the broad impact of SVs on AD genetics.

Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project.

Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near APOE, BIN1, and LINC00320 significantly associated with AD (p < 5×10-8). Population-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5×10-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2×10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.

Extended genome-wide association study employing the African Genome Resources Panel identifies novel susceptibility loci for Alzheimer's Disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimer's Disease (AD) genomics efforts. METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis of RNAseq and whole-genome sequencing data. RESULTS: A novel AD risk locus was identified in MPDZ on chromosome 9p23 (rs141610415, MAF=.002, P =3.68×10 -9 ). Two additional novel common and nine novel rare loci approached genome-wide significance at P <9×10 -7 . Comparison of association and LD patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 ( ASCL1 ), suggesting that the association is modulated by regional origin of local African ancestry. DISCUSSION: Increased sample sizes and sample sets from Africa covering as much African genetic diversity as possible will be critical to identify additional disease-associated loci and improve deconvolution of local genetic ancestry effects.

Bulk brain tissue cell-type deconvolution with bias correction for single-nuclei RNA sequencing data using DeTREM.

BACKGROUND: Quantifying cell-type abundance in bulk tissue RNA-sequencing enables researchers to better understand complex systems. Newer deconvolution methodologies, such as MuSiC, use cell-type signatures derived from single-cell RNA-sequencing (scRNA-seq) data to make these calculations. Single-nuclei RNA-sequencing (snRNA-seq) reference data can be used instead of scRNA-seq data for tissues such as human brain where single-cell data are difficult to obtain, but accuracy suffers due to sequencing differences between the technologies. RESULTS: We propose a modification to MuSiC entitled 'DeTREM' which compensates for sequencing differences between the cell-type signature and bulk RNA-seq datasets in order to better predict cell-type fractions. We show DeTREM to be more accurate than MuSiC in simulated and real human brain bulk RNA-sequencing datasets with various cell-type abundance estimates. We also compare DeTREM to SCDC and CIBERSORTx, two recent deconvolution methods that use scRNA-seq cell-type signatures. We find that they perform well in simulated data but produce less accurate results than DeTREM when used to deconvolute human brain data. CONCLUSION: DeTREM improves the deconvolution accuracy of MuSiC and outperforms other deconvolution methods when applied to snRNA-seq data. DeTREM enables accurate cell-type deconvolution in situations where scRNA-seq data are not available. This modification improves characterization cell-type specific effects in brain tissue and identification of cell-type abundance differences under various conditions.

Genetics of Alzheimer's Disease in the African American Population.

Black/African American (AA) individuals have a higher risk of Alzheimer's disease (AD) than White non-Hispanic persons of European ancestry (EUR) for reasons that may include economic disparities, cardiovascular health, quality of education, and biases in the methods used to diagnose AD. AD is also heritable, and some of the differences in risk may be due to genetics. Many AD-associated variants have been identified by candidate gene studies, genome-wide association studies (GWAS), and genome-sequencing studies. However, most of these studies have been performed using EUR cohorts. In this paper, we review the genetics of AD and AD-related traits in AA individuals. Importantly, studies of genetic risk factors in AA cohorts can elucidate the molecular mechanisms underlying AD risk in AA and other populations. In fact, such studies are essential to enable reliable precision medicine approaches in persons with considerable African ancestry. Furthermore, genetic studies of AA cohorts allow exploration of the ways the impact of genes can vary by ancestry, culture, and economic and environmental disparities. They have yielded important gains in our knowledge of AD genetics, and increasing AA individual representation within genetic studies should remain a priority for inclusive genetic study design.

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults.

Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, Setting, and Participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main Outcomes and Measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (ß = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (ß = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and Relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

Novel loci for Alzheimer's disease identified by a genome-wide association study in Ashkenazi Jews.

INTRODUCTION: Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). METHODS: We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene-based analyses were performed using aggregated rare variants. RESULTS: In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10-9 ), rs541586606 near RAB3B (p = 5.01 × 10-8 ), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10-8 ). In EW analyses (1504 cases and 2047 controls), study-wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10-7 ). A significant gene-based association was identified with GIPR (p = 7.34 × 10-7 ). DISCUSSION: Our results highlight the efficacy of founder populations for AD genetic studies.