Citations

Abstract INTRODUCTION The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized. METHODS Over 7500 total whole‐genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool. RESULTS Low PathSeq scores for human herpesvirus 6 (HHV‐6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV‐6 genome integration. DISCUSSION This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV‐6 may play a role in a subset of these patients. Highlights Over 7500 whole‐genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV‐6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance ( p <5×10 ‐8 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ‐5 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ‐6 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ‐6 ) was linked to diffuse plaques. All three SVs associated with AD ( p <5×10 ‐6 ) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

Objective Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α‐synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically‐defined series of LBD cases. Methods We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High‐resolution whole‐genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes. Results Our analysis identified 1 significant ( P < 3.43 × 10 −5 ) and 4 suggestive ( P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA‐mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA‐DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus ( P = 3.30 × 10 −5 ), with weaker and suggestive associations observed in the middle frontal ( P = 1.80 × 10 −4 ) and inferior parietal gyrus ( P = 6.33 × 10 −4 ). Additionally, although only suggestive, HLA‐DRB1*11:01 correlated with a lower Thal amyloid phase ( P = 1.56 x 10 −4 ), and HLA‐B*15:01 correlated with an increased risk of diffuse LBD ( P = 7.58 x 10 −4 ). Interpretation This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune‐related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AbstractBackgroundLate‐Onset Alzheimer’s Disease (LOAD) is characterized by genetic heterogeneity and there is no single model explaining the genetic mode of inheritance. To date, more than 70 genetic loci associated with AD have been identified but they explain only a small proportion of AD heritability. Structural variants (SVs) may explain some of the missing AD heritability, and specifically, their segregation in AD families has yet to be investigated.MethodWe analyzed WGS data from 197 NHW families (926 subjects, 58.5% affected) and 214 CH families (1,340 subjects, 59.17% affected). Manta, Absinthe, and MELT were used for large insertions/deletions calling from short‐read WGS, combined with Sniffles2 calls from 4 ONT‐sequenced genomes and an external SV call set from HGSVC on 32 PacBio‐sequenced genomes from the 1000 Genomes Project. Genotyping produced a unified project‐level VCF. We identified 45,251 insertions and 76,566 deletions genome‐wide. Variants were tested for segregation and pathogenicity using Annot‐SV, cadd‐SV, and Variant Effect Predictor. Segregation required SV presence in all affected family members and only in unaffected members five years younger than average disease onset.ResultWe identified 453 insertions and 598 deletions segregating in 78.68% and 87.31% of NHW families, respectively. In CH families, 432 insertions and 460 deletions were segregating in 75.23% and 72.90% of the families, respectively. Genes overlapping with the SVs exhibited high expression levels in brain tissues. Notably, around 93% of insertions and 76% of deletions segregating in NHW and CH families were less than 1 kilobase pair (1kbp) in length. A total of 79 insertions and 96 deletions were found to be segregating in both NHW and CH families. Interestingly, a segregating insertion was observed in CH families overlapping within the CACNA2D3 gene, which was previously reported in a CH GWAS for clinical AD. A deletion segregating in NHW overlapped with the PSEN1, and another in a CH family overlapped with the PTK2B gene.ConclusionOur findings suggested that there are several SVs associated with familial AD across CH and NHW families. Prioritizing the SVs based on their effects on gene function and expression will be helpful in understanding their contributions in AD.

AbstractBackgroundAPOEε4 significantly increases the risk of developing Alzheimer’s disease (AD). Cognitively healthy APOEε4‐carriers exist, suggesting potential protective mechanisms against APOEε4. We hypothesized that some APOEε4‐carriers may have genetic variations protecting them from developing APOEε4‐mediated AD pathology. We aim to identify these protective genetic variants.MethodsWhole genome sequencing (WGS) and cerebrospinal fluid (CSF) proteomics were performed from human cohorts to identify potential protective variants segregating exclusively among APOEε4 carriers. Bioinformatic analyses were performed to select candidate target genes. Immunohistochemistry on postmortem human brain tissues and mouse models expressing human APOE variants were performed along with in‐vivo functional studies in adult zebrafish AD model.ResultWGS analyses revealed 510 potential gene variants segregating exclusively among APOEε4 carriers, which included rare and loss‐of‐function (LOF) variants. Pathway analysis of these genes showed significant enrichment in extracellular matrix (ECM)‐related processes, suggesting protective effects of LOF in ECM proteins. This was further validated by CSF proteome profiling and subsequent analyses in APOEε4 carriers and non‐carriers. Fibronectin‐1 (FN1) and Collagen‐6A2 (COL6A2) were prioritized as candidate target genes for postmortem validation and in‐vivo functional studies. FN1 protein was increased in APOEε4 carriers resulting in thickened ECM at the basement membrane around the blood vessels, potentially impairing pathology‐induced responses such as clearance and immune system activity. This observation is validated in human brains, mouse models and zebrafish model; therefore, the pathological association of FN1 to AD is evolutionarily conserved. Supporting this hypothesis, in‐vivo functional study in zebrafish model with LOF mutations in fn1b revealed that fibronectin LOF enhanced gliovascular remodeling and microglial activation while reducing astrogliosis, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF.ConclusionThe vascular deposition of the ECM components FN1 and COL6A2 are increased in APOEε4 carriers. Rare variant in FN1 protect against APOEε4‐mediated pathogenesis in AD. We propose a new disease mechanisms and potential therapeutic intervention targets for vascular contribution to dementia to mitigate the risk of developing AD.

AbstractBackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder involving pathological deposition of tau that includes glial inclusions and specific regional vulnerability patterns. Therapeutic developments are hampered by incomplete understanding of disease mechanisms. Few studies have examined its cell type‐specific effects. We performed RNA‐sequencing in a large cohort of PSP patients and controls to understand molecular pathways disrupted across prefrontal cortex and caudate nucleus in PSP. We also performed multi‐omic single‐nucleus sequencing to deconvolute cell type‐specific changes.MethodRNA‐sequencing was conducted in 250 PSP patients and age‐ and sex‐matched controls, with a subset (N = 23) undergoing multi‐omic single‐nucleus RNA‐sequencing and ATAC‐sequencing (10x Genomics). Sequencing data was aligned to GRCh38 and quantified using STAR and RSEM (RNA‐seq) and CellRanger (single‐nucleus) and corrected for technical and biological covariates. Differential expression was calculated with Dream (RNA‐seq) and Dreamlet (single‐nucleus sequencing), and co‐expression network analysis (WGCNA) used to extract disease‐relevant gene modules.ResultRNA‐sequencing analysis identified ∼4000 differentially expressed genes in both brain regions. Despite differences in cellular composition and degree of disease impact, both regions share patterns of dysregulation related to protein folding and processing, indicating common pathological mechanisms. Differences between the regions includes disruption of cellular homeostasis and intracellular trafficking in caudate, while prefrontal cortex shows suppression of metabolic processes and immune response. Preliminary findings from the single cell genomic analyses suggest the greatest changes occur in neurons of both regions, where there is a shared pattern of protein processing dysregulation and a distinct enrichment in metabolic processing within prefrontal cortex interneurons.ConclusionWe identified thousands of dysregulated genes in two impacted brain regions in PSP and show that this dysregulation is reflected in specific neuronal populations in these regions. Identifying regional and specific cell type‐specific mechanisms related to PSP will further our understanding of causative disease mechanisms and provide new avenues for therapeutic developments.

Abstract BACKGROUND Few rare variants have been identified in genetic loci from genome‐wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS Eighty‐six rare missense or loss‐of‐function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E ( APOE)‐ 𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. Highlights Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE‐𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non‐Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non‐Hispanic families.

AbstractBackgroundStructural variants range from simple loss or gain of genetic material to complex events that restructure entire chromosomes. This heterogeneity coupled with variant size greater than sequencing read‐length makes structural variant mapping from short‐read sequencing data difficult and error‐prone. Consequently, the role of structural variants is poorly explored in many phenotypes, including dementia.MethodWe used the GATK‐SV pipeline that combines four external structural variant mapping algorithms with machine‐learning to build high‐quality consensus structural variant calls. We applied GATK‐SV to short‐read whole‐genome sequencing data of 2,601 frontotemporal dementia‐amyotrophic lateral sclerosis spectrum (FTD/ALS) patients, 2,612 Lewy body dementia (LBD) patients, and 4,132 neurologically unaffected participants.ResultAfter stringent quality‐control, we performed genome‐wide association studies on 2,307 ALS/FTD patients versus 3,677 controls with 4,699 common structural variants and 2,355 LBD patients versus 3,700 controls with 4,889 common structural variants. In the FTD/ALS cohort, we identified well‐known risk variants at the C9orf72 (p‐value = 4.99×10‐18, OR = 14.47, 95% CI = 7.90–26.49) and MAPT loci (p‐value = 3.48×10‐6, OR = 0.77, 95% CI = 0.68–0.86) corroborating the ability of our pipeline to identify disease‐associated structural variants. Moreover, we discovered, replicated, and validated TPCN1 as a novel risk locus for LBD (p‐value = 9.18×10‐6, OR = 1.43, 95% CI = 1.22–1.67). Further, we identified rare exonic variants with known pathogenic or likely pathogenic effects, such as an SNCA gene duplication in LBD and a deletion of exons 1 and 2 in CHCHD10 in FTD/ALS. We additionally observed structural variants in regulatory regions, e.g. a deletion of a key PSEN2 enhancer, which resulted in an approximate 0.70 fold‐change in PSEN2 expression in LBD. Finally, we built an interactive web app where structural variants can be visualized and explored (https://ndru-ndrs-lng-nih.shinyapps.io/non_ad_dementias_sv_app/).ConclusionCommon and rare structural variants play a role in LBD and FTD/ALS. Our structural variant resource is publicly available and can be used to further explore the role of structural variants in LBD and FTD/ALS.