SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimer's disease (AD). Studies suggest that restoring SORLA function or its trafficking pathways, particularly the SORLA-retromer recycling system, may offer a promising strategy to slow or halt AD progression. While both rare and common SORL1 variants have been associated with increased AD risk, recent evidence suggests a potential involvement of SORL1 in other neurodegenerative conditions. This study assessed the contribution of SORL1 genetic variation to the risk of AD, related dementias (RD), and Parkinson's disease (PD) using data from six large-scale biobanks, comprising 15,043 AD, 9,943 RD, and 42,763 PD cases, along with 111,969 controls across 11 ancestries. We identified 53 potentially disease-related SORL1 variants (CADD score > 20, MAC ≥ 2, annotated as protein-altering or splicing, and with the mutated allele present only in cases), including 41 novel and 12 previously reported variants. Three were found across multiple ancestries. Overall, 13 variants were found in AD-related cohorts, 5 in RD cohorts, and 35 in PD cohorts. Association analysis identified 10 nominally significant variants associated with AD and 5 with PD. The replication of multiple SORL1 variants across neurodegenerative diseases and ancestrally diverse populations underscores its potential broad genetic contribution to neurodegeneration and reinforces its relevance across distinct clinical phenotypes. Burden analysis identified a nominal association of SORL1 variants in PD in the South Asian population (P = 0.048). A family-based analysis identified a rare predicted-damaging variant in two East Asian families (11:121478242:G:A, p.R176Q) and two variants in two families of European ancestry (11:121514222:A:C, p.N371T; 11:121545392:G:A, p.V672M) that show some evidence of segregation in PD families. Although these variants were slightly more frequent in unrelated PD cases vs. controls, none of them showed statistically significant enrichment in PD, likely due to their very low frequency. Overall, our results extend the understanding of SORL1 beyond AD, suggesting a broader role in neurodegeneration and emphasizing the need for diverse population studies when evaluating genetic risk.

The 3D brain organoids have been widely used as a tool to study human brain development and disorders. Although angiogenesis and blood vascular endothelial cells play important roles in brain development and pathogenesis in neurological disorders, most 3D brain organoids lack inherent endothelial cells and need either the addition of differentiated endothelial cells or to be transplanted to animals to reconstitute such vascular structures. However, these approaches could miss the developmental interactions between angiogenesis and neurogenesis in the human brain. To reconstitute a 3D organoid mimicking the in vivo development of neural and vascular endothelial cells, we cultured iPSC-derived embryoid bodies and sequentially applied endothelial and neuronal induction media along with Matrigel embedding. The resulting 3D organoid consists of both neural cells and endothelial cells with vascular-like structures, as determined by immunostaining. With scRNA-Seq analysis, the organoid was confirmed to contain neural cell types similar to human brains, including a variety of excitatory and inhibitory neurons and glia. Furthermore, when compared with conventionally generated cerebral organoids without endothelial cells using RNA-Seq analysis, the vascular endothelial-containing neural organoids (EC-neural organoids) showed different gene profiles and favored angiogenesis and vasculogenesis. Of the differentially expressed genes, KRBA2 expression was found to be higher in neural cells and its inhibition by siRNA treatment resulted in decreased transcriptions of a variety of genes specific to neuronal differentiation but not genes specific to pluripotent stem cells such as OCT4. The EC-neural organoids also expressed receptors to SARS-CoV-2 at levels similar to human brains. This 3D EC-neural model provides a useful tool to study the interactions between vascular endothelial cells and neural cells in brain development and potentially for the study of neural infectious disorders where vascular endothelial cells are targets for infection and mediators for neural damage.

Induced pluripotent stem cell (iPSC)-derived neurons are a powerful tool with which to investigate both neuronal development and neurodegenerative diseases. Here, we applied quantitative proteomic and phosphoproteomic analyses to profile the neuronal differentiation of the KOLF2.1J iPSC line, the first reference line of the iPSC Neurodegenerative Disease Initiative (iNDI) project. We developed an automated workflow enabling high-coverage enrichment of proteins and phosphorylated peptides, which revealed molecular signatures during the differentiation of iPSC-derived neurons. Proteomic data highlighted distinct changes in mitochondrial pathways throughout the course of differentiation, whereas phosphoproteomic data revealed specific regulatory dynamics in GTPase-mediated signaling pathways and microtubule proteins. Additionally, phosphosite dynamics were not correlated to changes in protein abundance, particularly in processes related to axon functions and RNA transport. We measured the dynamic changes in kinases that are critical for neuronal development and maturation and developed an interactive web app to visualize the temporal landscape dynamics of protein and phosphosite abundance. By establishing baselines of proteomic and phosphoproteomic profiles for neuronal differentiation, this dataset is a valuable resource for future research into neuronal development and neurodegenerative diseases using this reference iPSC line.

Sex differences in neurodevelopmental, psychiatric, and neurodegenerative disease susceptibility may arise from sex chromosome and hormonal influences on cell type-specific gene expression. We present a single-cell transcriptomic analysis of adult human cortex performed using 169 samples from 15 females and 15 males (age 26 to 78 years) across six regions selected according to their sex-biased volumes. Sex-based analysis identified the strongest differences in the fusiform cortex, glia, and excitatory neurons and among sex-chromosome genes. More than 3000 genes showed sex-biased expression, including 133 with consistent effects across regions and cell types. Core autosomal signatures linked sex differences to cortical architecture, hormone-responsive regulation, and genetic risk for sex-biased brain disorders. This study advances our understanding of sex differences in human brains and provides a valuable resource to support future research.

Somatic differences in mitochondrial DNA (mtDNA) have been observed with aging and between brain regions for mutations, structural variation, and abundance, which are represented by single nucleotide variants (SNVs), large deletions, and copy number, respectively. We used bioinformatic methods to interrogate mtDNA changes and their relation to cortical and cerebellar aging using whole genome sequencing data from the North American Brain Expression Consortium. This dataset contained 292 unpaired postmortem samples from frontal cortex (n = 143) and cerebellum (n = 149), ranging in age from 0.4 to 100 years and without neurological diagnoses (i.e., controls). Our analyses included (a) evaluation of mtDNA copy number using fastMitoCalc; (b) quantification of large mtDNA deletions using Splice-Break2; (c) analysis of homoplasmic and heteroplasmic SNVs; and (d) mitochondrial genome-wide associations between SNVs and large deletions. For mtDNA deletions specifically, we expanded our previous analyses to include the predicted effects on mitochondrial complexes (I-V), mitochondrial-derived microproteins, and tRNAs. MtDNA copy number significantly decreased in the cortex with age. MtDNA deletions increased in both brain regions with age, with a more dramatic slope in the cortex. These large deletions had significantly more effect on mitochondrial Complex I than other mitochondrial-encoded complexes (III-V); likewise, deletions had significantly more effect on mtALTND4 and SHMOOSE than other annotated microproteins. Heteroplasmic SNVs increased with age in cortex but not cerebellum. Finally, three common SNVs (T14798C, G12372A, and C14766T) significantly associated with large mtDNA deletions (7816-14,807, 12,369-14,004, and 8775-14,771) and altered the length of the repeat sequence associated with the 5' or 3' breakpoint.

Transposable elements (TEs) are mobile DNA sequences that shape genome architecture and gene regulation, yet their roles in the human brain remain largely unresolved. Short-read sequencing lacks the resolution to accurately map TE insertions, detect associated structural variants, and resolve highly repetitive regions. Here, we leverage long-read whole-genome sequencing to profile germline TE insertions in postmortem brain tissue from two ancestrally diverse cohorts: the North American Brain Expression Consortium (NABEC; European ancestry, n = 205) and the Human Brain Collection Core (HBCC; African and African-admixed ancestry, n = 146). We identified 2,842 and 1,660 high-confidence non-reference insertions in HBCC and NABEC, respectively, spanning Alu, LINE-1, and SVA elements. We then also further characterized complex short tandem repeat and variable number tandem repeat variation within reference SVA and Alu loci. Reference TEs were also found to mediate complex structural variants at loci implicated in brain development and neurodegenerative disease, with several showing ancestry-specific patterns. Integration of bulk RNA-sequencing data identified TE expression quantitative trait loci, including insertions that modulate neuronal gene expression. Single-nucleus RNA sequencing revealed cell-type-specific effects of TE regulation across cortical populations. Long-read methylation profiling further demonstrated age-associated epigenetic regulation of both reference and non-reference Alu elements. As a community resource, we release a catalog of TE insertions, allele frequencies, and ancestry-specific distributions to enable future functional and disease-focused investigations. Together, these findings highlight the widespread regulatory and epigenetic influence of TEs in the human brain and establish long-read sequencing as a powerful approach for uncovering cell-type- and population-specific TE dynamics.

Aging is an unavoidable part of life, but gaps still remain in the understanding of age-associated molecular changes within the brain. We generated single-nucleus multiome ATAC plus gene expression profiles in 357 human brain samples from European and African admixed ancestry individuals ranging from 15 to 100 years old. The final dataset consisted of paired transcriptomic and epigenomic profiles for over 1.5 million cells. These were classified into seven major cell types using canonical marker genes, and each type was analyzed for features associated with aging. Open chromatin regions were correlated with transcription factor expression to identify age-associated regulatory networks, and co-accessibility identified linked peaks and genes, revealing a catalog of putative cis-regulatory elements by cell type. These multiomic data serve as a resource to characterize transcriptional regulation by cell type and generate hypotheses about how these distinct profiles both influence and are influenced by aging and disease.

Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer’s disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer’s disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer’s disease risk. Alzheimer’s-linked APOE variants affect the composition and plasticity of astrocytic lipid droplets. These fat storage organelles are rapidly turned over with protective APOE2, but clear slowly with Alzheimer's-associated APOE4.

Viral infections are common across the human lifespan, yet their molecular effects on human neurons remain poorly characterized. We present a mass spectrometry (MS)-based proteomic dataset profiling human induced pluripotent stem cell (iPSC)-derived neurons following exposure to five neurotropic viruses: Herpes simplex virus 1 (HSV-1), Human coronavirus 229E (HCoV-229E), Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV), and Influenza A virus (H1N1). Neurons differentiated from the KOLF2.1 J iPSC line were infected at multiple viral doses and sampled at three post-infection time points. Protein abundance was quantified using data-independent acquisition mass spectrometry and a customized human-viral proteome library, enabling simultaneous detection of host and viral proteins. The dataset includes approximately 7,500 human proteins and virus-specific peptides, providing a systematically controlled resource to compare virus- and time-dependent proteomic responses. All raw MS files and processed data are publicly deposited in the PRIDE repository, and an interactive web application supports data exploration and reuse. This dataset is designed to support cross-virus comparisons, hypothesis generation, and integration with transcriptomics and population-scale datasets.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Strategies that directly inhibit the LRRK2 kinase active site have not demonstrated disease-modifying efficacy in recent clinical testing. A naturally occurring protective variant, R1398H, provides an alternative route for understanding how reduced disease risk may be achieved by tuning the regulatory GTPase domain rather than the kinase domain itself. Here, we combine structural, computational, biochemical, and cell-based analyses to define how R1398H alters the Ras of complex proteins (ROC) G domain of LRRK2. Purified ROC carrying R1398H is folded but resolves as a stable homodimer corresponding to the GDP-bound off state previously defined for wild-type ROC. A 2.0 Å A crystal structure shows unambiguous density for H1398 and reveals close superposition with the GDP-bound wild-type ROC dimer. Molecular dynamics modeling predicts that R1398 engages the γ-phosphate of GTP to stabilize switch-region interactions required for activation, whereas histidine at this position weakens γ-phosphate sensing. Consistent with this model, R1398H reduces GTP hydrolysis, selectively weakens GTP-state stabilization while preserving GDP binding, and decreases Rab29-dependent trans-Golgi recruitment of full-length LRRK2. These findings identify R1398 as a γ-phosphate sensor that couples nucleotide chemistry to ROC conformational switching and suggest a genetics-anchored strategy for stabilizing a protective off-state conformation of LRRK2.

INTRODUCTION: Understanding concordance across biofluids and platforms is critical for understanding neurodegenerative biomarkers results and translating them into clinical use; yet systematic comparisons remain limited. To address this gap, we performed large-scale proteomic profiling of patient-paired plasma and CSF to characterize cross-modal relationships. METHODS: We profiled paired plasma and CSF from 67 individuals using SomaScan 11K and NULISAseq CNS panels. Disease severity was assessed with the CDR+NACC FTLD-M Global Score. RESULTS: We identified 269 SomaScan and 18 NULISA proteins with significant cross-biofluid correlation. Cross-platform concordance within biofluids was strong. NEFL, NPTX2, TREM2, and CHIT1 demonstrated consistent cross-platform agreement. Associations with disease severity were compartment-specific, with decreased NPTX2 in CSF, increased NEFL and GFAP in plasma, and decreased TREM2 across biofluids. DISCUSSION: Cross-platform consistency supports biomarker robustness, while limited cross-biofluid concordance highlights compartmental biology. Given additional clinical correlations despite varying underlying pathology, these findings may point to shared neurodegenerative disorder pathways. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03225144 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of the National Institutes of Health gave ethical approval for this work. clinicaltrials.gov identifier: [NCT03225144][1] I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03225144&atom=%2Fmedrxiv%2Fearly%2F2026%2F09%2F06%2F2026.09.02.26361977.atom

DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if age-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to reprogram to iPSCs. After reprogramming, the resulting iPSCs were evaluated for DNA methylation signatures to determine if they reflect the confounding factors of aging and environmental effects. Data from genome-wide DNA methylation arrays in both cell types showed that age-related methylation measured by epigenetic clocks is largely reset to an early methylation age after reprogramming of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS) and identified a set of methylation Quantitative Trait Loci in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are modified by population-level genetic variation.

ABSTRACT Mutations in the protein DJ-1 are linked to familial forms of Parkinson’s disease (PD). The protein has been well-documented to exert a role in energy metabolism and antioxidant defense, contributing to the maintenance of mitochondrial homeostasis. We and others have previously observed that DJ-1 can also influence autophagy, but the mechanisms are still incompletely defined. In this study, using complementary cellular and animal models, we characterize the impact of DJ-1 loss on the autophagic pathway. Our data demonstrate that DJ-1 deficiency impairs autophagosome-lysosome fusion and lysosomal degradation, resulting in the accumulation of dysfunctional autolysosomes and the subsequent buildup of autophagic substrates. Mechanistically, we show that elevated reactive oxygen species (ROS) in DJ-1-null models inhibit the energy-sensing AMP-activated protein kinase (AMPK), thereby activating the autophagy suppressor mechanistic target of rapamycin 1 (mTORC1). Collectively, these findings delineate a novel signaling axis linking oxidative stress to autophagic dysfunction, providing new insights into the cellular mechanisms underlying autophagic dysfunction in PD.

Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer’s disease and Parkinson’s disease genome-wide association studies (GWAS), such as apolipoprotein E ( APOE ), and leucine-rich repeat kinase 2 ( LRRK2 ) in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/ Graphical Abstract *Created using Biorender.com Highlights Establishment of a single nuclei atlas of human aging in four brain regions Each region and cell type exhibits a unique aging-associated transcriptome signature Gene expression changes occur in absence of overt cell loss and are categorically unique across cell types Neurological disease-associated genes have age-associated expression patterns in specific cell types in the context of healthy aging

The APOE gene encodes a lipid transport protein central to Alzheimer's disease (AD) pathogenesis. Three common alleles-ε2 (rs7412(C > T)), ε3 (reference), and ε4 (rs429358(T > C))-arise from two coding variants in exon 4 and confer distinct AD risk profiles, with ε4 increasing risk and ε2 being protective. The ε3-linked APOE variant rs769455[T] has also been associated with increased AD risk among individuals of African ancestry who also carry the APOE ε4 allele. Determining how genetic variation influences CpG methylation requires methQTL-type analyses, but conventional bisulfite and array-based approaches offer limited resolution for distinguishing allele-specific effects. Here, we use high-accuracy long-read sequencing to generate haplotype-resolved methylation profiles across the APOE locus in 332 postmortem brain tissue samples from ancestrally diverse cohorts, including 201 samples from individuals of European ancestry and 131 samples from individuals of African and African admixed ancestry. Treating each haplotype as an independent observation, OLS regression identified 18 novel differentially methylated CpG sites associated with ε2, ε4, and rs769455[T] across the APOE locus (TOMM40, APOE, APOC1, and APOC4-APOC2 genes). These findings reveal distinct allele-specific methylation signatures and demonstrate the utility of long-read sequencing for resolving epigenetic variation relevant to AD risk.

The genomic locus that encodes the Leucine-rich repeat kinase 2 (LRRK2) gene is highly pleiotropic and associated with Parkinson’s disease (PD). Coding variants associated with risk of PD act as gain of function kinase mutations increasing phosphorylation of RAB substrates, and non-coding variants in the promoter region of LRRK2 increase expression of the gene, notably in immune cells. If regulation of LRRK2 expression is a causal contributor to PD, it is important to understand the mechanism(s) by which LRRK2 is regulated, particularly in the context of inflammation. Here, we show that interferon-ɣ exposure induces robust LRRK2 activation in human iPSC-derived microglia through signaling of the Janus-activated Kinase complex to phosphorylate STAT1, which then binds to the LRRK2 promoter and is associated with remodeling of chromatin structure in this genomic locus. Additional regulatory mechanisms include the stress-induced transcription factor and long non-coding RNA encoded at the same locus, resulting in increased LRRK2 mRNA levels. We also show evidence of the same effect in acutely cultured human brain slices. While we were unable to demonstrate any induction of Lrrk2 mRNA in the mouse brain, the introduction of a human bacterial artificial chromosome transgene into the mouse genome recapitulated sensitivity to interferon-ɣ in microglia. A comparative genomic analysis across mammals suggests that these species differences are driven by regulatory regions upstream of LRRK2 that are specific to anthropoid primates. These results demonstrate that there are differences between species in how genes associated with human diseases are regulated and provide important information that should be incorporated in disease modeling.

Purpose of Research:The generation of iPSC lines expressing 21, 56 and 79 glutamine repeats within the HTT protein and homozygous KO of HTT in the KOLF2.1J background as an additional disease series within the iPSC Neurodegenerative Disease Initiative (iNDI) collection. Major Findings:All iPSCs, even those expressing long repeats of 79Q or HTT KO, were capable of differentiating to striatal and cortical neurons, astrocytes and microglia using established protocols. General quality control stains and morphological analyses are described for each differentiation. A selected set of assays were carried out on differentiated cells; expanded repeat expressing astrocytes showed altered expression of astrocyte protein markers and morphological characteristics, and striatal neurons showed altered DARPP-32/CTIP2 colocalization. mRNAseq carried out for striatal neurons showed high similarities in gene expression changes between 79Q and KO lines compared to the unexpanded repeat. Conclusions:The KOLF2.1J isogenic CAG repeat series serves as a community resource to study HD mechanisms with the potential for direct comparison across other neurodegenerative diseases through the iNDI collection.

While induced pluripotent stem cells (iPSCs) have gained popularity in studying neurodegenerative diseases, the heterogeneity of stem cells used across studies impacts cross-study comparison. The iPSC Neurodegenerative Disease Initiative (iNDI) selected the KOLF2.1J cell line and prioritized its use as a reference standard for studying the effects of pathogenic variants on cell biology due to its stability and neutral neurodegenerative disease genetic risk. This cell line, and its derivatives expressing over 100 variants related to Alzheimer's disease, Parkinson's disease, and other neurological diseases, are available for academic and industry access. Current genomic data analyses are limited by the use of a human reference genome that does not capture the complete genetic background of a given iPSC line. While in the future this issue may be partially mitigated by the creation of a comprehensive human pangenome, previous work has shown that generating custom genomes is of value both to characterize the variation present and to serve as a more appropriate genomic reference. Here, we generated and characterized a custom complete genome assembly from KOLF2.1J. Mapping of sequencing reads to a personalized diploid assembly results in more comprehensive mapping compared to traditional linear references (i.e GRCh38). In addition, we provide a comprehensive custom gene annotation along with isoform expression and differential methylation analyses across multiple cell types. The assembly and all additional data is browsable and publicly available. This resource will enable more accurate investigation of the KOLF2.1J cell line and any genomics data generated compared to using traditional generalized references, while also serving as a foundational approach for establishing custom reference assemblies for other high-value iPSC lines.

ObjectivesEmerging evidence suggests that the genetic architecture of Alzheimer disease (AD) and Parkinson disease (PD) risk varies across ancestries. This study seeks to explore distinct and universal genetic targets across individuals of Latino, African/African-admixed, East Asian, and European populations by implementing population attributable risk (PAR) comparisons using summary statistics from genome-wide association studies (GWASs). MethodsPAR was calculated for the most significant disease variants using summary statistics derived from select multi-ancestry GWAS meta-analyses, followed by fine-mapping analysis to validate genetic contribution of disease variants to European, African/African-admixed, East Asian, and Latino individuals. ResultsFor AD, APOE4 PAR estimates were universally high across all ancestries, with TSPAN14 and PICALM emerging as other common targets. Attributable risk varied across PD-related major risk loci, including variation nearby GBA1 and LRRK2. By contrast, SNCA, MCCC1, VPS13C, and MAPT loci demonstrated comparable attributable risk across ancestries. DiscussionThis cross-ancestry evaluation of PAR reinforces the genetic heterogeneity of AD and PD. In consideration of the complex etiology of these diseases, these findings may inform the strategic prioritization of therapeutic targets and improve global health outcomes.

In Parkinson’s disease and dementia with Lewy bodies, aggregated and phosphorylated α-synuclein appears in select neurons throughout cortical and subcortical regions, but little is currently known about why certain populations are selectively vulnerable. Here, using imaging spatial transcriptomics (IST) coupled with downstream immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn) in the same tissue sections, we identified neuronal subtypes in the cortex and hippocampus of transgenic human α-synuclein-overexpressing mice that preferentially developed pSyn accumulation. Additionally, we investigated the transcriptional underpinnings of this vulnerability, pointing to expression of Plk2, which phosphorylates α-synuclein at Ser129, and human SNCA (hSNCA), as key to pSyn development. Finally, we performed differential expression analysis, revealing gene expression changes broadly downstream of hSNCA overexpression, as well as pSyn-dependent alterations in mitochondrial and endolysosomal genes. Overall, this study yields new insights into the formation of phospho-α-synuclein and its downstream effects in a synucleinopathy mouse model.