Neurology Genetics

Parkinsons disease (PD) is a disabling neurodegenerative disorder with a substantial heritable component. Despite major advances in genome-wide association studies (GWAS), polygenic risk scores (PRS) show reduced predictive performance outside European populations, limiting equitable translation. Latin American populations represent a particularly difficult case because of their characteristic three-way admixture. We evaluated the cross-ancestry transferability of PD PRS in 1,872 PD cases and 1,443 controls of Latin American ancestry using data from the Global Parkinsons Genetics Program (GP2). PRS were constructed using summary statistics from a large European-ancestry GWAS, a moderately sized mixed-ancestry GWAS meta-analysis, and a small ancestry-matched Latin American GWAS. We benchmarked two single-ancestry approaches (PRSice-2 and SBayesRC) against two multi-ancestry methods (PRS-CSx and BridgePRS) that explicitly model cross-population genetic architecture. Across all performance metrics, SBayesRC performed best. PRS derived from large European GWAS achieved the highest effect size (odds ratio = 2.02; pseudo-R{superscript 2} = 0.031) while PRS derived from mixed ancestry GWAS meta-analysis yielded the highest discriminative ability (AUC=0.67). Our findings demonstrate that, under current sample size imbalances, well-powered European discovery GWAS outperform ancestry-matched but underpowered datasets in three-way admixed populations. Incorporating functional annotations, as implemented in SBayesRC, improves portability across ancestries. However, the full potential of multi-ancestry PRS methods will require substantially larger ancestry-matched discovery GWAS, underscoring the urgent need to expand genetic studies in underrepresented populations.

IntroductionGenome-wide association studies (GWAS) have identified over 130 risk loci for Parkinsons disease (PD), yet the majority derive from studies performed in European ancestry populations. African (AFR) and African admixed (AAC) ancestry individuals remain underrepresented in PD genetics research, limiting our understanding of ancestry-specific genetic architecture and the generalizability of known risk factors. MethodsWe conducted GWAS in AFR and AAC populations by integrating individual-level genotype data from the Global Parkinsons Genetics Program (GP2) with summary statistics from 23andMe Research Institute and the Million Veterans Program. The combined dataset included 3,975 cases and 319,883 controls, representing a 64% increase in total sample size compared with prior analyses. We performed separate GWAS for AFR and AAC cohorts as well as a combined AFR/AAC meta-analysis. ResultsThe intronic GBA1 variant rs3115534 was the most significant association across all analyses, reaching genome-wide significance in AAC individuals for the first time. In the AFR-only analysis, five loci achieved genome-wide significance: GBA1 (rs3115534), the SNCA signal previously reported in European ancestry GWAS (rs356182), a new protein-coding association at LRRK2 (rs72546327, p.T1410M), a non-coding RPL10P13 variant (rs12302417), and a novel signal on chromosome 16 (rs113244182). The combined AFR/AAC meta-analysis identified four genome-wide significant associations at GBA1 (rs3115534), SNCA (rs356182), SCARB2 (rs11547135), and LRRK2 (rs139283662, which is in LD with p.T1410M). ConclusionsThis study reports the largest GWAS of PD in AFR and AAC populations to date. Our findings confirm trans-ancestry risk loci (GBA1 and SCARB2) and identify an ancestry-enriched coding variant at LRRK2. This convergence of evidence around genes involved in glucocerebrosidase (GCase) trafficking and alpha-synuclein clearance supports current therapeutic strategies targeting this pathway and provides critical targets for developing precision medicine in African ancestry populations. Importantly, the identification of a novel association between a LRRK2 coding variant with disease in the AFR and AAC populations opens up a traditionally underrepresented population for ongoing LRRK2 targeted trials. Furthermore, the identification of novel ancestry-specific loci, including those that are directly relevant to current therapeutic deployment, underlines the importance of understanding the basis of disease in all populations.

ObjectiveBrain branks preserve extensive material relevant to neurodegenerative disease research. As these collections age, tissue becomes archival, raising the question of whether long-term fixed and stored human brain tissue remains suitable for contemporary immunohistochemical analyses. Materials and MethodsForty-one autopsy brains collected between 1946 to 1980 were examined. For each case, midbrain and hippocampus were available both as original paraffin-embedded blocks and as tissue stored long term in fixative. New paraffin blocks were prepared from the long-term fixated tissue. Sections from original and newly prepared blocks were immunohistochemically stained for -synuclein, hyperphosphorylated tau and amyloid-{beta}. Immunoreactivity was assessed using semi-quantitative scoring. ResultsOriginal blocks consistently showed good staining intensity and morphological preservation for each protein pathology. Newly prepared blocks showed slightly lower semi-quantitative scores for Lewy-related pathology, without statistically significant differences, except for astrocytic -synuclein in the substantia nigra in cases from the 1960s. Tau pathology displayed modestly reduced labelling, particularly of the neuropil threads and neurofibrillary tangles, most evident in cases from the 1950s. Amyloid-{beta}-positive senile plaques showed similar or slightly higher scores in newly prepared blocks, with no significant differences across regions. ConclusionHuman brain tissue preserved as paraffin-embedded blocks or stored in fixative for up to 78 years remains suitable for immunohistochemical analyses. Adequate-to-good detection of aggregated of -synuclein, hyperphosphorylated tau and amyloid-{beta} is achievable, indicating preserved pathological hallmarks of Lewy Body Disease and Alzheimers Disease in archival tissue.

Structured AbstractO_ST_ABSObjectiveC_ST_ABSSTXBP1-Related Disorders (STXBP1-RD) and SYNGAP1-Related Disorder (SYNGAP1-RD) are two common genetic synaptopathies, leading to epilepsy, developmental delay, and intellectual disability. Both STXBP1-RD and SYNGAP1-RD are potential targets for disease-modifying therapies, but there is limited information in the literature describing the natural history of either disorder, which impedes outcome selection for future clinical trials. The objective of this study is to develop a framework to better define and outline the clinical spectrum and longitudinal trajectories of STXBP1-RD and SYNGAP1-RD natural history, including development, behavior, seizure histories, and electrophysiology. MethodsHere, we describe a protocol, regulatory structure, and supportive preliminary data for multi-center, prospective natural history studies of STXBP1-RD (STARR) and SYNGAP1-RD (ProMMiS). The protocols incorporate gold-standard clinician-assessed outcome measures including the Bayley Scales of Infant and Toddler Development 4th edition, Gross Motor Function Measure-66, and fine motor domains of the Peabody Developmental Motor Scales 3rd Edition, parent reported outcome measures (PROMs), epilepsy histories, and biomarker exploration. To date, the study has enrolled 164 individuals with STXBP1-RD and 159 with SYNGAP1-RD, with ongoing longitudinal assessments every 6 months in a subset of approximately 200 total individuals across both disorders. ResultsOur data support that existing developmental measures are feasible, informative, and show minimal floor or ceiling effects. Furthermore, we demonstrate that medical record-based seizure history reconstruction reveals unique epilepsy trajectories while minimizing burden to families. We observe disease-specific patterns of developmental performance and distinct longitudinal seizure dynamics, highlighting the need for data generation in a gene/disorder-specific manner for clinical trial readiness. SignificanceIn summary, we present a feasible natural history protocol with prospective data for two complex neurodevelopmental disorders with natural histories that have previously been incompletely characterized, within a regulatory framework that will support the use of these data to expedite clinical trial development. Key PointsO_LISTXBP1-Related Disorder (STXBP1-RD) and SYNGAP1-Related Disorder (SYNGAP1-RD) are two common genetic causes of epilepsy, developmental delay, and intellectual disability. C_LIO_LISTXBP1-RD and SYNGAP1-RD are potential targets for drug and gene therapy, but there is limited information in the literature describing the natural history of either disorder which impedes the development of possible therapeutics. C_LIO_LIThe current paper is a description of a prospective natural history study of STXBP1-RD and SYNGAP1-RD which will assess the clinical spectrum of each disorder through detailed developmental assessments, seizure histories, behavioral assessments, and electronic medical record reconstruction. C_LIO_LIBy studying STXBP1-RD and SYNGAP1-RD with both cross sectional and longitudinal assessments, we aim to improve clinical trial readiness so that potential treatments can be assessed expeditiously. C_LI

BackgroundThe SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinsons disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited. ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB). MethodsWe examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied Summary-data-based Mendelian Randomization (SMR) to evaluate whether genetically regulated expression of SLC25A46 shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerated Medicines Partnership: Parkinsons Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal Sequence Kernel Association test (SKAT-O) and meta-analysis were used to assess rare variants. ResultsNo associations were observed between SLC25A46 variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between SLC25A46 expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses. ConclusionSLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.

ATP1A3-related syndromes represent a continuously expanding clinical spectrum and present with an extraordinarily wide range of symptoms. New phenotypes continue to emerge, posing ongoing challenges for both diagnosis and development of treatments. In this context, telemedicine offers a unique opportunity to greatly expand outreach to patients. Remote, high-resolution assessments help refine phenotypic characterization and the identification of novel and intermediate phenotypes. In this study we aimed to determine completion rates and practicality of conducting motor, speech, and neuropsychological assessments entirely via virtual visits. Although the broader recruitment included several ATP1A3-related disorders, this virtual battery was specifically developed for subjects with RDP. Participants with other ATP1A3 phenotypes enrolled in the study contributed to evaluating the overall feasibility of the workflow but were not the target population for the full battery. We recruited individuals with suspected or confirmed diagnosis of ATP1A3-related disorders, along with familial controls, from three participant clinical sites. Participants completed all study procedures through scheduled telemedicine visits using their personal devices (tablets, laptops, smartphones). A total of 59 participants were enrolled, including 46 individuals with suspected or confirmed ATP1A3 variants and 13 family member controls. Among affected patients, 18 had RDP, 12 AHC (Alternating Hemiplegia of Childhood), 4 CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss), 10 were categorized as "uncertain" and 2 with "mixed" phenotype (RDP/CAPOS and RDP/AHC). The virtual assessment battery included: (i) patient history questionnaire (PHQ), (ii) structured neurological examination adapted for virtual visits, (iii) speech recording, and (iv) extensive neuropsychological assessment. Feasibility was evaluated based on completion rates for each assessment component. Remote neurological, speech and neurocognitive/psychiatric assessments were completed by most participants with ATP1A3 phenotypes, with completion rates of 78% for motor examination and 87% for speech evaluation. The observed pattern of motor and speech impairments were consistent with prior in-person evaluations, supporting the validity and feasibility for both motor and nonmotor features of remote assessment in complex genetic neurological disease.

BackgroundNiemann-Pick disease, type C1 (NPC1), is a rare, fatal, neurodegenerative lysosomal disorder caused by pathological variants in NPC1. Defects in lysosomal cholesterol transport result in the accumulation of unesterified cholesterol within the endo-lysosomal compartments. Delayed diagnosis, limited treatment options, and phenotypic heterogeneity characterized by a broad range of signs/symptoms underscore the urgent need for effective biomarkers to facilitate diagnosis, monitor disease progression and assess therapeutic response. The goal of this study was to identify serum protein biomarkers for NPC1. MethodsProximal Extension Assays (PEA) were used to determine relative protein expression levels from 68 serum samples from NPC1 individuals and 20 age-appropriate control serum samples. Statistical models identified NPC1 disease-specific effects after adjusting for covariates. Selected proteins were orthogonally validated by ELISA and correlated with assessments of both disease severity (Age of Neurological Onset (ANO) and Annual Severity Increment Score (ASIS)) and disease burden (NPC Neurological Severity Score (NSS). ResultsQuantifiable data was obtained on 2888 proteins, revealing 186 increased (adjusted log2FC [&ge;] 1) and 286 decreased (adjusted log2FC [&le;] -1) proteins with adj. p-value < 0.1 when comparing NPC1 individuals not being treated with miglustat versus control serum samples. Using orthogonal assays, we confirmed significant elevations for seven proteins: TREM2, AgRP, CCL18, Cathepsin L, GPNMB, NPY, and HSD17B14, and a significant decrease of BDNF. We further identified 100 proteins whose abundance levels were significantly altered towards normal by miglustat treatment. We found the 17-domain NPC NSS to be correlated with protein levels in the PEA data. Orthogonally validated data correlated with the age of neurological onset. We also identified 25 differentially abundant serum proteins in NPC1 baseline samples which are predominantly expressed in brain regions. ConclusionsThe statistical analysis pipeline developed in this study is flexible and scalable and supports application to high-dimensional proteomic datasets. This study identified and validated serum proteins with altered expression in individuals with NPC1, responded to miglustat therapy, and correlated with disease severity or burden. These proteins may have clinical utility as biomarkers and provide insights into cellular mechanisms contributing to NPC1 disease pathology. Trial RegistrationsNCT00344331 (Registration on 2006-06-23)

SORL1, the gene encoding the SORLA protein, has arisen as a potential therapeutic target for Alzheimers 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 Parkinsons 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 [&ge;] 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. Gene-based burden analysis did not reveal any significant cumulative effect of SORL1 variants in the populations tested. 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.

BackgroundVariants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinsons disease (PD). While several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. ObjectiveTo determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. MethodsWe performed a meta-analysis of case-control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open-access resources, and large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. ResultsAcross 67,484 patients and 124,079 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). Enzymatic data showed reduced glucocerebrosidase activity in carriers. ConclusionsThe GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials.

BackgroundQuantitative genome-wide association studies (GWAS) primarily rely on additive linear models that compare average phenotypic differences between genotype groups. While effective for detecting common variants of moderate effect in large sample sizes, such approaches inherently reduce high-resolution phenotypic data to summary statistics (group averages), potentially limiting the detection of subtle genotype-phenotype relationships. Genomic Informational Field Theory (GIFT) is a recently developed methodology that preserves the fine-grained informational structure of quantitative traits by analysing ranked phenotypic configurations rather than relying solely on mean differences. MethodsWe applied GIFT to genetic and neuropathological data from the Brains for Dementia Research cohort, a well characterised dataset of 563 individuals, and compared its performance with conventional GWAS. Principal component analysis (PCA) derived matrix was used to derive independent quantitative traits linked to from Alzheimers disease (AD) neuropathology measures (CERAD, Thal, Braak staging), with and without inclusion of age at death. Principal component analyses were performed using GWAS and GIFT frameworks on the same filtered genotype dataset. ResultsBoth GWAS and GIFT identified genome-wide significant associations (pvalue<10-6) within the APOE locus (NECTIN2-TOMM40-APOE-APOC1), demonstrating concordance with established AD genetic variants. However, GIFT detected additional significant 19 SNPs beyond those identified by GWAS. Variants associated with AD pathology implicated genes involved in amyloid processing, neuronal apoptosis, synaptic function, neuroinflammation, and metabolic regulation. Notably, GIFT identified 29 loci associated with age at death-related variation that were not detected by GWAS, highlighting genes linked to lipophagy, mitochondrial quality control, sphingolipid metabolism, frailty, and aging-related processes. ConclusionsGIFT recapitulates canonical GWAS findings while uncovering additional biologically relevant associations. By preserving the fine-grained structure of phenotypic data distributions and detecting non-random genotype segregation across ranked trait values, GIFT enables the identification of associations that remained undetected by traditional average-based GWAS approaches. These results demonstrate that rethinking analytical representation, rather than solely increasing sample size, can expand discovery potential of genetic association studies, offering a transparent and complementary framework for quantitative genomics in deeply phenotyped datasets.

ImportanceAccurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features and a delay in the emergence of pathognomonic features. ObjectiveTo evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multi-ancestry brain bank cohort. DesignMulticentre retrospective autopsy cohort study on donors enrolled between 1985 - 2024. Setting11 academic brain banks in the UK, US and Australia ParticipantsBrain donors identified from participating brain banks with available brain tissue and a clinical diagnosis of Parkinsons disease, Parkinsons disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls. ExposureGenetic variant carrier status and clinical diagnostic category. Main outcomeClinical diagnostic accuracy; Lewy body and Alzheimers disease pathology burden; survival; association with genetic variants and genetically inferred ancestry. ResultsWe studied 3,353 brain donors (1281 [38.2%] female, mean [SD] age at death, 76.8 [10.6] years). Misdiagnosis rates for movement disorders ranged approximately from 10% - 20%. Clinical diagnoses of dementia with parkinsonism (PDD/DLB) were more strongly associated with Lewy body pathology than Parkinsons disease without dementia (OR = 1{middle dot}96, 95% CI = 1{middle dot}30 - 3{middle dot}04, p = 7{middle dot}2e-04). Lewy pathology was identified in 4% of neurologically normal controls. Alzheimers disease co-pathology was present in 40% of cases with Lewy body disease. GBA1 variant carriers exhibited greater Lewy body burden compared with noncarriers (OR = 1{middle dot}94, 95% CI = 1{middle dot}24 - 3{middle dot}03, p = 0{middle dot}01) or LRRK2 carriers (OR = 7{middle dot}44, 95% CI = 2{middle dot}16 - 25{middle dot}64, p = 0{middle dot}01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (p < 0.0001), independent of GBA1 and LRRK2 mutation status. Conclusion and RelevanceOur findings highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimers disease co-pathology and ancestry-related differences in pathology point to the need for biologically informed diagnostic tools. These results support the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials. FundingMedical Research Council, Global Parkinsons Genetic Program/Aligning Science Across Parkinsons Key PointsO_ST_ABSQuestionC_ST_ABSHow do genetic variants and neuropathology influence clinical features and diagnostic accuracy in movement disorders? FindingsIn this multi-ancestry brain bank series including over 3000 individuals, clinical misdiagnosis was common. Dementia with parkinsonism was more strongly associated with Lewy body (LB) pathology than Parkinsons disease without dementia, and Alzheimers disease co-pathology was frequent. Genetic variation was associated with pathological differences. GBA1 carriers had greater LB burden, while LRRK2 pathogenic variant carriers had a lower LB burden and longer survival. Pathological diagnosis differed by ancestry. MeaningIntegrating genetics and neuropathology may improve diagnosis and support pathology-informed therapeutic trials.

ImportanceDementia is common in Parkinsons disease (PD), causing greater disability than other symptoms, but varies in timing. Although visual deficits are linked with PD dementia, how these interact with genetic factors to predict PD dementia has not been characterised. ObjectiveTo investigate whether visual deficits and genetic factors predict PD dementia. DesignLarge prospective longitudinal case-control study, mean follow-up 32.7 (SD=12.3) months. SettingCases were recruited between 2017-2020 at 35 UK PD clinics. ParticipantsPeople with PD without dementia at baseline were included. Main outcomes and measuresVisual function was measured using a web-based platform. The main outcome measure was global cognition, measured as the Montreal Cognitive Assessment (MoCA). Blood samples were collected for genetics. Results450 patients with PD were included. Mean age of PD patients was 71.7 (SD=7.8), 68% male. Mean baseline MoCA was 27.7 (SD=1.7). 263 patients with PD were classed as poor-vision based on baseline visual tests: mean age 74.4 (SD=6.8) compared to 69.7 (SD=7.5) with good-vision. Poor-vision PD patients had higher rates of progression to mild cognitive impairment (PD-MCI) (HR=2.34, CI=1.58-3.48, pFDR=0.00062, age- and sex-corrected). The combination of genetic factors together with vision influenced outcomes. In good-vision PD patients, high-risk GBA1 gene variants were linked with greater progression to PD-MCI (HR=4.61, CI=1.73-12.28, pFDR=0.0068). Polygenic Risk Score (PRS) for both PD and Alzheimers disease (AD) also modified cognitive survival when combined with vision status. High PD-PRS was associated with greater progression to PD-MCI in good-vision patients (HR=2.66, CI=1.21-5.81, pFDR=0.0381); and high AD-PRS with greater progression to PD-MCI in poor-vision PD patients (HR=1.91, CI=1.10-3.32, pFDR=0.04999). Combining high PD- and AD-PRS, compared to low PD- and AD-PRS in good-vision PD showed even higher progression to PD-MCI (HR=6.14, CI=1.36-27.83, pFDR=0.046). Simulations showed that adding visual and genetic stratification reduced sample size from n=705 to n=160 for clinical trials. Conclusions and relevancePoor vision in PD predicts progression to PD-MCI and dementia. This combines with the effects of genetic factors including GBA risk variants and PD- and AD-PRS. These findings can enable enrichment of clinical trials for patients at higher risk of PD dementia, for more efficient trial design for interventions to slow progression. Key pointsO_ST_ABSQuestionC_ST_ABSDo clinical factors, measured by performance on visual tests, and genetic factors help predict which patients are more likely to develop cognitive involvement in Parkinsons disease? FindingsThis prospective longitudinal study of 450 Parkinsons patients, based in Parkinsons clinics, with mean follow-up 32.7 months, found that Parkinsons patients with poor vision are more likely to develop cognitive impairment; and that genetic factors in combination with poor vision further predict poor prognostic groups for Parkinsons dementia. MeaningThese data could enable selection of Parkinsons patients at highest risk of dementia for clinical trials aimed at slowing Parkinsons dementia.

Background and objectivesA pathogenic GGC repeat expansion in the zinc finger homeobox 3 (ZFHX3) gene, encoding a pure polyglycine tract, is the cause of spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci contribute to the risk of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease involving the progressive loss of motor neurons. There is increasing awareness of the role of short tandem repeat (STR) motif composition and configuration in disease pathogenicity. Given the genetic pleiotropy between ALS and SCA, this study aimed to evaluate whether ZFHX3 GGC expansions were associated with ALS and to characterise repeat motif composition. MethodsExpansionHunter v5 was used to genotype ZFHX3 GGC repeat sizes in short-read whole genome sequencing data from people with ALS and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer v2. Repeat motif configurations of Australian ALS cases were manually derived from REViewer images. Receiver operating characteristic (ROC) curve analysis and Youdens J statistic were performed to find a candidate repeat size threshold for association testing using Fishers exact test. ResultsAnalysis of 5,785 people with ALS and 7,982 healthy controls found no association between ZFHX3 GGC repeat expansions and disease risk. However, more than 30 unique repeat motif compositions were identified across 802 people with ALS. Of these, seven distinct configurations coded a pure polyglycine tract which, when expanded, is canonical to SCA4. DiscussionAlthough no association was observed between ZFHX3 GGC repeat expansions and ALS, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Unique motif compositions were identified both within and between repeat sizes, including the presence of pure polyglycine repeats in ALS. Consideration of repeat motif composition and configuration, in addition to repeat allele length, may be important for assessing neurodegenerative disease risk.

In the Global Parkinson's Genetics Program (GP2) we aim to advance precision medicine by integrating large-scale clinico-genetic data from diverse populations worldwide. We investigated potentially trial-eligible carriers of pathogenic and high-risk GBA1 and LRRK2 variants and conducted a global precision-medicine survey across GP2 sites. Among 65,509 individuals with Parkinson's disease, we identified 9,019 (13.8%) potentially trial-eligible genetic variant carriers, including 6,789 GBA1, 2,084 LRRK2, and 146 dual GBA1-LRRK2 carriers. Individuals were distributed across multiple global regions, many of which currently lack active gene-targeted trials, highlighting a global disparity between relevant variant carriers and the availability of disease modifying treatment trials. GP2's unified framework supports equitable recruitment for gene-targeted therapeutic studies and helps address critical gaps in Parkinson's disease genetics and future therapeutic development.

BackgroundRecent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimers disease (AD) and related dementias (ADRD). MethodsWe performed a CNV analysis using genotyping data (Axiom 815K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n=20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8,275 controls and 7,818 dementia cases were selected for gene-level case/control associations. ResultsWe identified 43,833 CNVs with deletions (47%) and duplications (53%). No genome-wide significant associations were found, but nominal associations were observed in PKP3-SIGIRR and FBRSL1 loci. CNVs in 2,970 genes were exclusive to dementia cases, enriched in vascular-related pathways. Notable findings included 14q11.2 duplication and VPS13B deletions in ADRD cases, the latter confirmed by optical genome mapping. ConclusionOur findings suggest potential novel genes associated with ADRD in the Spanish population. However, the limited resolution of array-based technologies in detecting CNVs warrants further investigation.

BackgroundWhole-genome sequencing (WGS) has improved the diagnosis of rare genetic disorders, yet interpretation of non-coding variants that affect splicing remains challenging. In silico predictions alone are insufficient, and short-read RNA sequencing may fail to capture complex or low-abundance splicing events. Targeted amplicon-based long-read RNA sequencing (Amp-LRS) offers a cost-effective approach for functional validation of candidate splice-altering variants. MethodsWe applied Amp-LRS to five patients with neurological disorders (central nervous system, peripheral nervous system, or muscle) harbouring candidate non-coding variants predicted to alter splicing. RNA was extracted from fibroblasts or peripheral blood, and full-length transcript amplicons were sequenced using Oxford Nanopore Technologies. Nonsense-mediated decay (NMD) inhibition was performed on fibroblast cultures using cycloheximide. ResultsAmp-LRS validated all five candidate variants, including intronic and UTR variants in POLR3A, OPA1, PYROXD1, GDAP1, and SPG11. Aberrant splicing events included exon skipping, intron retention, cryptic splice site activation, and pseudoexon inclusion, often resulting in frameshifts and premature termination codons. For POLR3A and OPA1, multiple abnormal isoforms arose from single variants, highlighting the complexity of splicing disruption. Some pathogenic effects were detectable only in a minority of reads and variably enriched by NMD inhibition, consistent with being hypomorphic. The approach was successfully applied using accessible tissues and enabled multiplexed sequencing at low per-sample cost. ConclusionsAmp-LRS is a sensitive, versatile, and cost-effective method for functional assessment of non-coding splice-altering variants identified by WGS. By enabling full-length transcript analysis from accessible tissues, this approach improves interpretation of variants of uncertain significance and could enhance molecular diagnosis in rare neurological diseases.

BackgroundHuntingtons disease (HD) causes progressive loss of function, cognition, and motor control, with no approved therapy yet shown to slow disease progression. In the PROOF-HD phase 3 trial, pridopidine did not meet the primary or key secondary outcomes in the overall population, but participants who remained off antidopaminergic medications (ADMs) showed benefits compared to placebo during the double-blind phase. Whether such benefits continue with longer duration treatment and how they compare with expected natural-history trajectories remains unknown. MethodsWe evaluated outcomes through Week 104 from baseline in participants who received continuous pridopidine (45 mg twice daily) and remained off-ADMs throughout the double-blind and open-label extension period (n=90). External comparators from ENROLL-HD and TRACK-HD were constructed using propensity-score weighting methods. Least-squares mean changes from baseline to Week 104 were estimated using mixed-effects models for repeated measures across outcomes. ResultsAt two-years, pridopidine treatment was associated with benefits versus propensity-score weighted natural-history comparators across multiple outcomes. Relative to ENROLL-HD, participants receiving pridopidine showed slowing of progression over 104 weeks, expressed as percent slowing across cUHDRS, TFC, SWR, SDMT, and TMS outcomes (39.5-88.3% slowing). Similar patterns were observed relative to TRACK-HD across the same measures (48.5 - 81.5% slowing), including quantitative motor performance assessed by Q-Motor FT-IOI (77.8% slowing). Exploratory analyses including participants receiving concomitant ADMs showed similar directional patterns as the primary analyses. ConclusionsIn a two-year follow-up, continuous pridopidine treatment in participants remaining off-ADMs was associated with slower clinical progression relative to expected natural-history trajectories. (Clinical Trials Identifier: NCT04556656)

BackgroundParkinsons disease (PD) is a multifactorial neurodegenerative disorder shaped by, amongst others, high-impact variants and common polygenic factors. The Personalized Parkinson Project (PPP) offers deep phenotyping and longitudinal follow-up of Dutch people with PD. Here, we characterize the genetic landscape and its interaction with lifestyle factors within PPP. MethodsWe utilized three complementary approaches in N=507 persons with PD: 1) short-read PD gene panel sequencing of eight PD genes, 2) genome-wide genotyping array, and 3) targeted long-read sequencing of the GBA1 gene. Additionally, we calculated the mitochondrial-function polygenic score (MGS). Associations between genetic factors, smoking status, and age at onset (AAO) were assessed using non-parametric tests, correlation analyses, and multiple regression models. ResultsGenetic screening of the participants revealed N=79 GBA1 ([~]15%), N=3 LRRK2, N=1 CHCHD2, N=1 SNCA variant carrier, and N=9 heterozygous PRKN/PINK1 variants. We also observed an interaction between MGS and smoking: MGS was associated with earlier AAO in non-smokers in persons with iPD (N=414, {beta}=-1.87, p=0.038). ConclusionOur findings corroborate previously reported frequencies of variants in PD-associated genes in European populations, and suggest a potential association between smoking and a mitochondrial dysfunction signature in PD. Thus, even in persons without rare variants (iPD subgroup), complex genetic contributions remained relevant. Our study supports future downstream stratification and personalized medicine approaches with high-impact variants and polygenic risk scores.

BackgroundLRRK2-Parkinsons disease (LRRK2-PD) is biologically heterogeneous with approximately 30% lacking aggregated alpha synuclein (Syn) in cerebrospinal fluid by seed amplification assay (SAA). Prior work has suggested slower progression in LRRK2-PD compared to sporadic PD (sPD). ObjectiveWe aimed to assess how LRRK2-PD with Syn aggregates on SAA (S+ LRRK2-PD) compares to S+ sPD. MethodsData from the Parkinsons Progression Markers Initiative were used to compare S+ LRRK2-PD and S+ sPD cohorts propensity score-matched on age, disease duration, sex and levodopa equivalent dose (N = 79 per cohort). Baseline clinical and biological features and 4-year longitudinal features were assessed. ResultsAt baseline, S+ LRRK2-PD participants had lower motor scores and dopaminergic deficit. Among measures showing within group progression, longitudinal trajectories did not differ significantly between groups. ConclusionsLongitudinal clinical progression of S+ LRRK2-PD and sPD in the PPMI study is similar despite differences in baseline features.

ObjectivesWith the expected demographic shift toward those [&ge;]65 years of age in the United States, late-onset epilepsy (LOE) poses a significant public health issue, yet it has been historically understudied. We are undertaking an effort in the Epilepsy-Cog study to pool individual participant data from six US-based prospective cohort studies. In this paper, we outline the process for ascertaining epilepsy, harmonizing, and pooling individual participant data across the six cohorts. MethodsThe Epilepsy-Cog study includes individual participant data from six US-based longitudinal cohort studies: ARIC, CHS, MESA, NOMAS, REGARDS, and WHICAP. In all cohorts except NOMAS, prevalent and incident epilepsy were ascertained using Medicare claims-based algorithms. In NOMAS, epilepsy cases were identified through cohort-based reporting and medical record review. To perform cross-cohort harmonization of variables, we used the lowest common denominator approach, assigning response categories or value levels in common across all cohorts. ResultsFrom a total of 68,544 participants across six cohorts, 43,753 participants met eligibility criteria for Epilepsy-Cog. Among them, we identified 551 (1.3%) participants with prevalent epilepsy and 1,500 (3.4%) participants with incident epilepsy. We have harmonized demographic characteristics, health behaviors, vascular risk factors (VRFs), one genetic variable, medication use, subjective health status measures, incident events, and cause-of-death variables. ConclusionThe Epilepsy-Cog pooled cohort of 43,753 participants with and without epilepsy, combined with harmonized demographic, VRFs, and event data, offers a unique resource to yield new insights into LOE.