Neurology Genetics

INTRODUCTIONThe amyloid cascade hypothesis predicts that amyloid-beta (A{beta}) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between A{beta}40 and A{beta}42 and total Tau (t-Tau) plasma biomarkers. METHODSPlasma A{beta}40, A{beta}42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between A{beta}s and t-Tau. RESULTSNo clear evidence that A{beta}40 or A{beta}42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the A{beta} biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSIONPlasma A{beta}40 or A{beta}42 do not appear to have a direct causal impact on t-Tau. In contrast, A{beta} aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

BackgroundParkinsons disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors. We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. MethodsWe performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. ResultsUsing exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. ConclusionsIntegrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

BackgroundLarge-scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise. To support identification of Parkinsons disease (PD) risk and disease-causing variants, we developed an open-access, summary-level genomic data browser. MethodsWe performed uniform joint variant calling to harmonize whole-genome sequencing (WGS) data from AMP-PD Release 4, GP2 Data Releases, and additional controls from the Alzheimers Disease Sequencing Project. Clinical exome sequencing (CES) data from GP2 Release 8 was also included. ResultsThe integrated dataset includes 31,665 WGS and 9,559 CES samples, spanning eleven ancestries and over 300 million variants. ConclusionThe GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene- and variant-level summaries with ancestry-stratified allele frequencies and functional annotations. It is open source and freely accessible at https://gp2.broadinstitute.org, enabling broad access to PD genomic data and supporting global research efforts.

The identification of Parkinsons Disease (PD) from post-mortem brain slices is time consuming for highly trained neuropathologists, often taking many hours per case. In this study, we demonstrate fully automatic PD detection, from single 1000um regions, from sections spanning from the dorsal motor nucleus of the vagus nerve to the frontal cortex. This is achieved via image processing and statistical methods, with improved accuracy demonstrated when using machine learning. Digitised stained brain sections were processed via a deep neural network to produce re-coloured, or synthetically stained, images which were then filtered and passed to a secondary network for classification. We demonstrate state-of-the-art PD detection (>90% accuracy on single 1000um regions), with the ability to perform binary classification on high resolution sections within minutes, in addition to demarcating regions of interest to the pathologist for manual visual verification. Executive SummaryThe identification of Parkinsons Disease (PD) from post-mortem brain slices is time consuming for highly trained neuropathologists, often taking many hours per case. Accurate classification and stratification of PD is critical for the confirmation that the brain donor suffered from PD and to maximise the potential usefulness of the brain in research studies to better understand the causes of PD and foster drug development. Parkinsons UK Brain Bank, at Imperial College London, has produced a dataset containing digitised images of brain sections immunostained for the protein alpha-synuclein (-syn), the pathological marker of PD; along with control cases from healthy donors. This dataset is much larger (over 400 cases), more consistent, and of higher quality (all have been stained with the same protocol and imaged within the same laboratory) than has been documented elsewhere in the literature; including those found in a meta-analysis study on detection of neurological disorders containing over 200 papers (Lima et al., 2022). The project team, consisting of neuroscientists and subject matter experts from: Imperial, NHS AI Lab Skunkworks, Parkinsons UK, and Polygeist have undertaken a 12 week project to examine the possibility of producing a Proof-of-Concept (PoC) tool to automatically load, enhance and ultimately classify those brain sections containing -syn. The initial focus of the project was to make a tool that could make a biomarker of PD, -syn, more visible to the pathologist; saving time in searching for the protein manually. This goal was quickly reached, producing a tool that could synthetically stain the -syn, marking regions of interest in a high-contrast bright green, making them quickly identifiable for the pathologist. Statistical analysis of the synthetically stained images showed that very few regions in the control group were stained compared to the PD group, raising the possibility that an automatic classifier could be developed, which became a stretch goal for the project. A bespoke neural network model was designed that processed the synthetically stained segments of each immunostained section and produced a binary judgement (whether a segment contains PD pathology or not). The model achieved >90% sensitivity for PD detection, much higher than is reported for neuropathologists (~60% sensitivity when searching for -syn patches across all stages, Signaevsky et al., 2022). While expert raters are still more precise (~6% better than the model), the model performed ~20% better than expert raters when considering precision and recall. The key output of the project is an open-source PoC tool that can automatically classify PD from digitised images of brain sections with accuracy that is approaching viability for real world applications. An MIT Licensed code repository has been released, containing all of the model development code, along with associated documentation, to allow others to build on the project teams work. This report summarises the scientific and engineering process undertaken through the development of the PoC tool.

BackgroundKnown pathogenic variants in Parkinsons disease (PD) contribute to disease development but have yet to be fully explored by arrays at scale. ObjectivesThis study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries. MethodWe analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinsons Genetics Program dataset. Of these, 25 were genotyped on NBA and cluster plots were used to assess their quality. ResultsGenes previously predicted to have high or very high confidence of causing PD tend to have more pathogenic variants and are present across ancestry groups. Twenty-five of the 34 pathogenic variants were typed by the NBA array and classified "good" (n=12), "medium" (n=4), and "bad" (n=9) variants. ConclusionOur results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for genotyping of rare variants for PD.

BackgroundChitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimers disease (AD). Few studies have examined the spatial expression of chitinase expressing cells with respect to neuropathologic hallmarks of disease. MethodsRNA-sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal cord and motor cortex. Immunohistochemistry was used to characterize the distribution of Chit-1 and CHI3L1 expressing cells in ALS, C9-ALS, FTLD, AD, and non-neurologic disease controls. Immunofluorescence confocal microscopy was used to correlate distribution of Chit-1 and CHI3L1 expressing cells to TDP pathology. ResultsChit-1 gene expression was increased in the spinal cord, and CHI3L1 expression was increased in both the spinal cord and motor cortex of sALS and C9-ALS patients when compared to controls. Highest levels of Chit-1+ glia were in cortical regions that contain hallmark neuropathology for each neurodegenerative disease. CHI3L1+ glia were only significantly increased in sALS. Neither Chit-1+ nor CHI3L1+ glia were in close proximity to pTDP containing neurons in the motor cortex gray matter; however, there was a significant co-localization of glial pTDP with Chit-1 and CHI3L1 in the motor cortex white matter. ConclusionsChit-1 and CHI3L1 expressing cells were most abundant in the white matter of cortical regions affected by each neurodegenerative disease and the spinal cord. Chit-1 or CHI3L1 expressing cells in the white matter also contained phosphorylated TDP-43. We also observed correlations between levels of Chit-1 or CHI3L1 expressing cells in the white matter to disease duration. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSPrior studies identified elevated levels of Chit-1 and CHI3L1 proteins in the CSF of various neurodegenerative conditions, though few studies examined levels of Chit-1 and CHI3L1 expressing cells both spatially and in relation to disease pathology. What this study addsWe performed an extensive spatial characterization of Chit-1 and CHI3L1 protein levels across multiple regions and neurodegenerative conditions. This study also correlates Chit-1 and CHI3L1 expression to TDP pathology and other clinical parameters of disease duration. How this study might affect research, practice or policyOur findings indicate that the majority of Chit-1 and CHI3L1 expressing glia are located in the cortical subpial layer and the white matter, suggesting a role for chitinases in modulating neuroinflammatory mechanisms or reparative/regenerative responses in the white matter of ALS and other neurodegenerative diseases. This study suggests new therapeutic opportunities for targeting chitinase expressing cells in neurodegenerative diseases.

Although adult Huntingtons disease (HD) studies have significantly advanced our understanding of the course of degeneration, they may underrepresent critical neurodevelopmental aspects of the disease. Significant gaps remain in understanding how mutant huntingtin affects early neurodevelopment, its long-term impact, as well as potential implications for treatment outcomes. The Childhood to Adult Neurodevelopment in Gene-Expanded Huntingtons Disease (ChANGE-HD; NCT01951588) study aims to evaluate brain structure and function in premanifest, at-risk children and young adults, and explore HDs developmental origins. Here, we introduce the ChANGE-HD study protocol, which will investigate and integrate the neurodevelopmental and neurodegenerative aspects of HD. The ChANGE-HD study is a prospective, multi-site observational trial with an accelerated longitudinal design. Four hundred participants aged 6-30 years who are at risk for HD will be recruited and asked to return for multiple visits (if possible). At each visit, cognitive, motor, behavioral, blood, and MRI data are collected. ChANGE-HD represents the first prospective multi-site study to systematically document brain structure and function during the premanifest phase of HD in children and young adults. Data collection is ongoing with first results anticipated in 2026-2027. The ChANGE-HD approach is likely to provide novel pathophysiological insights and guide the development of therapeutic strategies tailored to both the developmental and degenerative phases of the disease.

Background/AimsThe Parkinson Progression Markers Initiative (PPMI) is an international, longitudinal, observational study that acquires comprehensive clinical, imaging and genetic data, as well as cerebral spinal fluid (CSF) and blood biological samples from individuals in all stages of Parkinsons disease (PD) to develop biomarkers that accelerate therapeutic development. The effort to enroll a large population of prodromal individuals (participants with PD biomarkers and/or early symptoms) presents an opportunity to share insights for overcoming specific challenges unique to enrollment prior to the onset of typical symptoms. MethodsPaid and earned media, referral cohorts, and individual and community ambassadors were leveraged as recruitment strategies to attract and enroll a broad study population. The success of each strategy was measured as conversion to (i) informed consent, (ii) smell test completion, and (iii) identification of hyposmic individuals. Participants completed an eConsent and questionnaire online, followed by remote smell test screening for Parkinsons risk. Participants with hyposmia were invited to complete dopamine transporter (DAT) imaging. Those who continued to meet eligibility criteria were invited to enroll in the PPMI clinical study, for comprehensive longitudinal follow-up. ResultsOver 1.2 million visits to the smell test website were recorded and 79,837 participants consented to remote hyposmia screening. A smell test was sent to 57,754 participants and completed by 38,419; 6,649 were identified to be hyposmic (as defined by PPMI study cutoffs). DAT imaging was completed by 1,720, with 1,120 identified as eligible for longitudinal follow-up. The greatest number of participants who consented to smell testing came from paid media and social media ads, referral networks (commercial and study partners), and the MJFF community. Overall, 14.4% of participants who completed smell testing were confirmed to be hyposmic. The highest rates of conversion from completed UPSIT to confirmed case of hyposmia occurred with promoted online search results, earned press coverage, and radio ads. ConclusionPPMI provides a useful example of overcoming challenges to enrollment of participants with biomarkers and/or early symptoms (but without typical symptoms) of disease. Important lessons from these data for this study team, and other researchers alike, are to be agile in recruitment strategies, to utilize effective participant engagement approaches, and to prioritize centralized study teams/resources to offload site burden and streamline participant experience.

BackgroundReliable detection and accurate genotyping of structural variants (SVs) and insertion/deletions (indels) from whole-genome sequence (WGS) data is a significant challenge. We present a protocol for variant calling, quality control, call merging, sensitivity analysis, in silico genotyping, and laboratory validation protocols for generating a high-quality deletion call set from whole genome sequences as part of the Alzheimers Disease Sequencing Project (ADSP). This dataset contains 578 individuals from 111 families. MethodsWe applied two complementary pipelines (Scalpel and Parliament) for SV/indel calling, break-point refinement, genotyping, and local reassembly to produce a high-quality annotated call set. Sensitivity was measured in sample replicates (N=9) for all callers using in silico variant spike-in for a wide range of event sizes. We focused on deletions because these events were more reliably called. To evaluate caller specificity, we developed a novel metric called the D-score that leverages deletion sharing frequencies within and outside of families to rank recurring deletions. Assessment of overall quality across size bins was measured with the kinship coefficient. Individual callers were evaluated for computational cost, performance, sensitivity, and specificity. Quality of calls were evaluated by Sanger sequencing of predicted loss-of-function (LOF) variants, variants near AD candidate genes, and randomly selected genome-wide deletions ranging from 2 to 17,000 bp. ResultsWe generated a high-quality deletion call set across a wide range of event sizes consisting of 152,301 deletions with an average of 263 per genome. A total of 114 of 146 predicted deletions (78.1%) were validated by Sanger sequencing. Scalpel was more accurate in calling deletions [≤]100 bp, whereas for Parliament, sensitivity was improved for deletions > 900 bp. We validated 83.0% (88/106) and 72.5% (37/51) of calls made by Scalpel and Parliament, respectively. Eleven deletions called by both Parliament and Scalpel in the 101-900 bin were tested and all were confirmed by Sanger sequencing. ConclusionsWe developed a flexible protocol to assess the quality of deletion detection across a wide range of sizes. We also generated a truth set of Sanger sequencing validated deletions with precise breakpoints covering a wide spectrum of sizes between 1 and 17,000 bp.

BackgroundMen with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis. MethodsThis study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. ResultsLongitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS. ConclusionsThese findings suggest that executive function changes represent a prodrome of the later movement disorder.

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimers disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.

BackgroundHeterozygous variants in the GBA1 gene cause Parkinsons disease (PD) with variable penetrance and have been classified into severe, mild, and PD-specific risk variants based on their association with Gauchers disease (GD; mild and severe) or PD (risk variants). Polygenic risk scores (PRS) further modify PD susceptibility and may influence the age of onset in GBA1 variant carriers. Our study investigates the interaction between a genome wide PRS and pathogenic GBA1 variants (GBA1PVs), focusing on how established combined PD risk polymorphisms may influence GBA1-related PD risk across different levels of GBA1-mediated pathogenicity. MethodsGBA1 variants were identified from whole exome sequencing data in the UK Biobank (UKB) cohort and from GBA1-targeted PacBio sequencing in the Luxembourg Parkinsons Study (LuxPark). PRSs were calculated for all participants using established genome-wide significant SNPs, excluding variants within the GBA1 locus, and then categorized based on both PRS levels and GBA1PVs carrier status. Carriers of GBA1PVs were further divided into severe (Gaucher-related) +mild (PD-related) and risk groups. To evaluate the relationship between PRS, GBA1PVs carrier status or severity, and PD risk, logistic regression and Cox proportional hazards regression were conducted with disease presence as the dependent variable. ResultsWe identified GBA1PVs in 8.8% of PD patients in the UKB discovery cohort and 9.9% in the LuxPark replication cohort. GBA1PVs carriers had consistently higher PD risk compared to non-carriers across all PRS categories. In UKB, GBA1PVs carriers in the highest PRS category had a 2.3-fold increased risk of PD (OR: 2.34; 95% CI, 2.08-2.63) and cumulative incidence of 67% by the age of 75, while those in LuxPark had a 1.6-fold higher risk (OR: 1.64; 95% CI, 1.52-1.76), and cumulative incidence of 81% at the age of 75. Carriers of "severe+mild" GBA1 variants had nearly double the risk of PD compared to "risk" variant carriers, with ORs ranging from 2.05 to 3.69 in UKB and 1.73 to 1.98 in LuxPark. The interaction between the PRSs and GBA1PVs severity was similar in the two cohorts. ConclusionsOur findings demonstrate that GBA1PVs carrier status and severity significantly impact PD risk, with severe variants conferring higher risk than risk ones. Additionally, PRS consistently increases both PD risk and GBA1PVs penetrance in an additive manner across all variant types, defining a genetic background that influences PD penetrance in GBA1PVs carriers. The presence of additional PD-associated risk variants in GBA1 carriers defines new avenues to incorporate PRS and genetic risk data into future clinical trial design and genetic counselling in GBA1-associated PD.

BackgroundBarth syndrome is an inherited disorder that results from pathogenic mutations in TAZ, the gene responsible for encoding tafazzin, an enzyme that remodels the mitochondrial phospholipid cardiolipin. Barth syndrome is characterized by heart and skeletal muscle myopathy, growth delay, and neutropenia among other features. The TAZPOWER clinical trial investigated the effects of the mitochondria-targeting peptide elamipretide in patients with Barth syndrome. Methods and findingsTAZPOWER included a randomized, double-blind, crossover study of 12 weeks treatment with elamipretide or placebo in 12 patients with Barth syndrome. A broad spectrum of plasma and urine metabolites were measured using liquid chromatography-tandem mass spectrometry at baseline and after 12 weeks treatment with elamipretide or placebo. Of 51 "energy-linked" metabolites analyzed, we highlight here the effects of elamipretide on the plasma and urinary concentrations of several metabolites previously observed to be abnormal in patients with Barth syndrome. Elamipretide treatment was associated with significantly lowered medium- and short-chain acylcarnitines in plasma and urine, respectively (p < 0.05). Acetylcarnitine, 3-hydroxybutyrate, and 3-methylglutaconate trended to decrease after 12 weeks of elamipretide, but these trends did not reach statistical significance. After 12 weeks of treatment, elamipretide had no discernible effect on four amino acids previously characterized as having abnormal concentrations in patients with Barth syndrome. Lastly, elamipretide caused a significant rise in plasma taurine concentrations, an amino acid which has been observed to be decreased in patients with Barth syndrome. ConclusionsAs evidenced by reduced plasma and urinary content of acylcarnitines and trends for lowered ketone body 3-hydroxybutyrate, fat metabolism in Barth syndrome appears to be modified after 12 weeks of elamipretide treatment. Overall, these data are consistent with the improved mitochondrial function that may precede functional benefits with a longer duration of therapy with elamipretide in patients with Barth syndrome. Trial registrationClinicalTrials.gov NCT03098797. Summary pointsO_LIExploratory targeted metabolomic analyses of plasma and urine were performed after a double-blind, crossover trial in patients with Barth syndrome receiving elamipretide or placebo for 12 weeks. C_LIO_LIAmong 51 "energy-linked" metabolites analyzed in both plasma and urine, prominent changes were observed in metabolites associated with fat metabolism. C_LIO_LICollectively, plasma medium-chain (C6-C12) acylcarnitines were reduced after 12 weeks of elamipretide treatment in patients with Barth syndrome. C_LIO_LIUrinary acylcarnitine concentrations were also lowered with elamipretide in Barth syndrome patients, most prominently for shorter chain acylcarnitines. C_LIO_LIElamipretide for 12 weeks also trended to lower 3-methylglutaconate and the ketone body 3-hydroxybutyrate, although these decreases did not reach statistical significance. C_LIO_LIElamipretide also caused a significant rise in plasma taurine, which has been previously reported to be low in Barth syndrome patients. C_LIO_LIThese metabolite changes may be consistent with improved mitochondrial function that precedes the functional benefits observed in patients with Barth syndrome after longer-term therapy. C_LI

Parkinsons disease (PD) is a complex neurodegenerative disorder with environmental and genetic influences. Using genotyping array data of 661 South African PD cases and 737 controls, a polygenic risk score (PRS) analysis was conducted using PRSice-2. Summary statistics were used from two PD association studies as base datasets. The target dataset was split into training (70%; n=979) and validation (30%; n=419) cohorts. Various clumping window sizes, linkage disequilibrium thresholds, and p-value thresholds were tested to determine the optimal combination for risk prediction. Additionally, we investigated the variance explained by different combinations of covariates. Finally, top contributing variants were identified and cross-referenced with inferred local ancestry to assess ancestry-specific effects. Overall, modest predictive performance was observed (AUC: 0.6307-0.6311). Age at recruitment was the strongest individual predictor, while sex contributed the least. Local ancestry analysis indicated that the top contributing variants were not ancestry-specific risk variants. These findings provide the first evaluation of PRS performance for PD in a highly admixed South African cohort, underscoring the importance of including underrepresented populations in genetic risk prediction.

ImportanceThis study identifies and quantifies diverse pathological tau isoforms in the retina of both early and advanced-stage Alzheimers disease (AD) and determines their relationship with disease status. ObjectiveA case-control study was conducted to investigate the accumulation of retinal neurofibrillary tangles (NFTs), paired helical filament (PHF)-tau, oligomeric tau (oligo-tau), hyperphosphorylated tau (p-tau), and citrullinated tau (Cit-tau) in relation to the respective brain pathology and cognitive dysfunction in mild cognitively impaired (MCI) and AD dementia patients versus normal cognition (NC) controls. Design, setting and participantsEyes and brains from donors diagnosed with AD, MCI (due to AD), and NC were collected (n=75 in total), along with clinical and neuropathological data. Brain and retinal cross-sections-in predefined superior-temporal and inferior-temporal (ST/IT) subregions-were subjected to histopathology analysis or Nanostring GeoMx digital spatial profiling. Main outcomes and measureRetinal burden of NFTs (pretangles and mature tangles), PHF-tau, p-tau, oligo-tau, and Cit-tau was assessed in MCI and AD versus NC retinas. Pairwise correlations revealed associations between retinal and brain parameters and cognitive status. ResultsIncreased retinal NFTs (1.8-fold, p=0.0494), PHF-tau (2.3-fold, p<0.0001), oligo-tau (9.1-fold, p<0.0001), CitR209-tau (4.3-fold, p<0.0001), pSer202/Thr205-tau (AT8; 4.1-fold, p<0.0001), and pSer396-tau (2.8-fold, p=0.0015) were detected in AD patients. Retinas from MCI patients showed significant increases in NFTs (2.0-fold, p=0.0444), CitR209-tau (3.5-fold, p=0.0201), pSer396-tau (2.6-fold, p=0.0409), and, moreover, oligo-tau (5.8-fold, p=0.0045). Nanostring GeoMx quantification demonstrated upregulated retinal p-tau levels in MCI patients at phosphorylation sites of Ser214 (2.3-fold, p=0.0060), Ser396 (1.8-fold, p=0.0052), Ser404 (2.4-fold, p=0.0018), and Thr231 (3.3-fold, p=0.0028). Strong correlations were found between retinal tau forms to paired-brain pathology and cognitive status: a) retinal oligo-tau vs. Braak stage (r=0.60, P=0.0002), b) retinal PHF-tau vs. ABC average score (r=0.64, P=0.0043), c) retinal pSer396-tau vs. brain NFTs (r=0.68, P<0.0001), and d) retinal pSer202/Thr205-tau vs. MMSE scores (r= -0.77, P=0.0089). Conclusions and RelevanceThis study reveals increases in immature and mature retinal tau isoforms in MCI and AD patients, highlighting their relationship with brain pathology and cognition. The data provide strong incentive to further explore retinal tauopathy markers that may be useful for early detection and monitoring of AD staging through noninvasive retinal imaging.

BackgroundDNAJC13 was initially linked to autosomal dominant (AD) Parkinsons disease (PD) in a European Mennonite family carrying the p.N855S variant. However, imperfect segregation and conflicting reports of pathogenicity raised uncertainty of DNAJC13s role in the disease. ObjectivesExplore the association between common and rare variants in DNAJC13 and Parkinsons disease. MethodsWe leveraged the largest available PD genetics data from the Accelerating Medicines Partnership - Parkinson Disease (AMP-PD) and the diverse ancestry available through the Global Parkinsons Genetics Program (GP2), consisting of 2,471 patients and 3,098 controls, and 44,186 patients and 27,066 controls, respectively, to perform burden tests and association tests for rare and common variants, respectively. ResultsBurden analysis showed no association between rare variants in DNAJC13 and PD. However, association analysis within common non-synonymous variants nominated 5 variants within DNAJC13. Nevertheless, these associations require further validation since the analyses are still underpowered. DiscussionOur analysis did not find further evidence supporting DNAJC13 involvement in PD. However, studies of even larger cohorts and AD-PD families may bring definite answers about DNAJC13s role in PD.

INTRODUCTIONWidespread language complaints in the cognitively unimpaired (CU) may reflect Alzheimers Disease (AD) pathology and future objective impairments. METHODS138 CU, 45 mild cognitive impairment and 28 dementia participants from the TRIAD cohort underwent 18F-MK-6240 tau-PET and 18F-AZD-4694 amyloid-PET. Word-finding complaints, confrontation naming, semantic and phonemic fluency and word-knowledge were evaluated. Covariance, direct and stepwise discriminant, and voxel-wise regression analyses were conducted. RESULTSWord-finding complaints appeared in early tau stages (Braak 1-2), followed by naming difficulties (Braak 3-4), and widespread language impairments in later stages (Braak 5-6). Complaints over forgetting the names of objects, naming, and APOE significantly improved classification of early AD pathology. In CU, complaints over forgetting names of objects were linked to left fusiform and inferior temporal gyri tau accumulation. DISCUSSIONLanguage measures are useful in detecting and tracking AD-related pathophysiologies. Results encourage refinement of clinical tools for early detection and disease monitoring. HighlightsLanguage decline parallels tau buildup across PET-based Braak stages of AD. Subjective anomia marks earliest tau-related language symptom (Braak 1-2). Objective naming deficits emerge in the middle tau spread stages (Braak 3-4). Advanced tau spread reflects significant and widespread language impairments. Word-finding complaints correlate with left fusiform and inferior temporal tau. Research in contextSystematic review: The literature was reviewed using traditional sources. The core biological definition of Alzheimers disease (AD) has recently been linked to its defining cognitive clinical features of episodic memory impairments. Widespread subjective language complaints amongst cognitively unimpaired (CU) older adults and objective language impairments observed across the AD continuum suggests these measures and the further bridging of biological and clinical definitions of AD could play a critical, cost-effective role in disease detection and monitoring. Interpretation: Results extend to tau previous findings describing language changes in AD and related to amyloid status and grey-matter atrophy. They also establish the likely staging of language impairments across the biological AD continuum. Future directions: The manuscript contextualises the use of subjective word-finding complaints, alongside genetic risks to significantly enhance the prediction of underlying AD related pathology in CU. Languages measures used in clinical practice remain limited however and better test should be utilized and developed.

INTRODUCTIONMitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genomes per nucleated cell, has an unclear causal relationship with AD and PD. We integrate genetic correlation, Polygenic Risk Scores (PRS), and Mendelian Randomization (MR) to assess whether mtDNAcn influences the risk of AD and PD, and evaluate how study-specific factors in mtDNAcn genome-wide association studies (GWAS) may distort these causal estimates. METHODSUsing GWAS of four mtDNAcn measures, AD, AD/dementia, and PD, we evaluated genetic correlations, generated ancestry-normalized PRS in the AD Genetics Consortium (N=27,383), and applied MR methods including Latent Heritable Confounder MR (LHC-MR). RESULTSAcross the four mtDNAcn GWAS, only one was consistently associated with AD/dementia and PD, with genetic correlations and PRS analysis showing negative correlations and MR indicating that higher mtDNAcn reduced AD/dementia and PD risk. DISCUSSIONHigher blood-based mtDNAcn was causally associated with reduced risk of AD/dementia and PD, with limited evidence to suggest a bidirectional effect. Research In ContextO_ST_ABSSystematic ReviewC_ST_ABSMitochondrial dysfunction, measured by mitochondrial DNA copy number (mtDNAcn), has been linked to Alzheimers disease (AD) and Parkinsons disease (PD). However, Mendelian randomization (MR) studies on this relationship have shown inconsistent results, have not applied advanced MR methods that address prior limitations, or examined study-specific biases. InterpretationUsing genetic correlations, polygenic scores, and Mendelian Randomization, we triangulated evidence across complementary methods. We found that results varied depending on the dataset (e.g., clinically diagnosed AD vs. family history of AD) and study design factors such as mtDNAcn measurement techniques. Despite these biases, higher mtDNAcn was consistently associated with a lower risk of AD and PD, supporting a mitochondrial mechanism in both diseases. Future directionsOur findings highlight mtDNAcn as a potential biomarker for AD/PD, emphasizing the importance of measurement methods. Future research is needed to explore the biological pathways underlying this relationship. HighlightsO_LIGenetically predicted higher mtDNAcn is causally associated with lower AD and PD risk C_LIO_LIAD genetic liability is causally associated with higher mtDNAcn, possibly as a compensatory response C_LIO_LImtDNAcn is a potential early biomarker of mitochondrial dysfunction in AD/PD C_LI

Background3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behavior. However, the full profile of adaptive function in 3q29del has not been described, nor has it been compared to other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes. MethodsIndividuals with 3q29del (n=32, 62.5% male) were evaluated using the Vineland Adaptive Behavior Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behavior and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del to published data on Fragile X syndrome, 22q11.2 deletion syndrome, and 16p11.2 deletion and duplication syndromes. ResultsIndividuals with 3q29del had global deficits in adaptive behavior that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behavior, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behavior, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behavior deficits in 3q29del was distinct from previously published data on comparable genomic disorders. ConclusionsIndividuals with 3q29del have significant deficits in adaptive behavior, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behavior than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.

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.