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Although large-scale genetic association studies have proven useful for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients., Competing Interests: Declaration of interests H.L.L., D.V., H.I., and M.A.N.’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is a scientific founder at Neuron23 Inc, he also owns stocks.

Alzheimer's disease (AD) and Parkinson's disease (PD) are influenced by genetic and environmental factors. Using data from UK Biobank, SAIL Biobank, and FinnGen, we conducted an unbiased, population-scale study to: 1) Investigate how 155 endocrine, nutritional, metabolic, and digestive system disorders are associated with AD and PD risk prior to their diagnosis, considering known genetic influences; 2) Assess plasma biomarkers' specificity for AD or PD in individuals with these conditions; 3) Develop a multi-modal classification model integrating genetics, proteomics, and clinical data relevant to conditions affecting the gut-brain axis. Our findings show that certain disorders elevate AD and PD risk before AD and PD diagnosis including: insulin and non-insulin dependent diabetes mellitus, noninfective gastro-enteritis and colitis, functional intestinal disorders, and bacterial intestinal infections, among others. Polygenic risk scores revealed lower genetic predisposition to AD and PD in individuals with co-occurring disorders in the study categories, underscoring the importance of regulating the gut-brain axis to potentially prevent or delay the onset of neurodegenerative diseases. The proteomic profile of AD/PD cases was influenced by comorbid endocrine, nutritional, metabolic, and digestive systems conditions. Importantly, we developed multi-modal prediction models integrating clinical, genetic, proteomic and demographic data, the combination of which performs better than any single paradigm approach in disease classification. This work aims to illuminate the intricate interplay between various physiological factors involved in the gut-brain axis and the development of AD and PD, providing a multifactorial systemic understanding that goes beyond traditional approaches. Further, we have developed an interactive resource for the scientific community [https://gut-brain-nexus.streamlit.app/] where researchers can investigate components of the predictive model and can investigate feature effects on a sample level., Competing Interests: Competing interests: KSL, HLL, HI, and MAN’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. MAN also currently serves on the scientific advisory board at Clover Therapeutics and is an advisor and scientific founder at Neuron23 Inc. All other authors declare they have no competing interests.

Background: Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations., Objective: We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies., Methods: We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples. This novel platform includes approximately 10,000 tagging variants to facilitate imputation and analyses of neurodegenerative disease-related genome-wide association study loci across diverse populations., Results: In this article, we describe NBA's potential as an efficient means for researchers to assess known and novel disease genetic associations in a multi-ancestry framework. The NBA can identify rare genetic variants and accurately impute more than 15 million common variants across populations. Apart from enabling sample prioritization for further whole-genome sequencing studies, we envisage that NBA will play a pivotal role in recruitment for interventional studies in the precision medicine space., Conclusions: From a broader perspective, the NBA serves as a promising means to foster collaborative research endeavors in the field of neurological disorders worldwide. Ultimately, this carefully designed tool is poised to make a substantial contribution to uncovering the genetic etiology underlying these debilitating conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Immunity acquired by vaccination following infection, termed hybrid immunity, has been shown to confer enhanced protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by enhancing the breadth and potency of immune responses. Here, we assess Fc-mediated humoral profiles in hybrid immunity and their association with age and vaccine type. Participants are divided into three groups: infection only, vaccination only, and vaccination following infection (i.e., hybrid immunity). Using systems serology, we profile humoral immune responses against spikes and subdomains of SARS-CoV-2 variants. We find that hybrid immunity is characterized by superior Fc receptor binding and natural killer (NK) cell-, neutrophil-, and complement-activating antibodies, which is higher than what can be expected from the sum of the vaccination and infection. These differences between hybrid immunity and vaccine-induced immunity are more pronounced in aged adults, especially for immunoglobulin (Ig)G1, IgG2, and Fcγ receptor-binding antibodies. Our findings suggest that vaccination strategies that aim to mimic hybrid immunity should consider age as an important modifier., Competing Interests: Declaration of interests G.A. is currently an employee of Moderna Therapeutics and holds equity in Leyden Labs and Seromyx Systems. P.K. is currently an employee of Moderna Therapeutics. J.S.-L.L. is currently an employee of Moderna Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The under-representation of non-European cohorts in neurodegenerative disease genome-wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non-European or multi-ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non-European or multi-ancestry studies. Notably, only six of the loci have been replicated. The significant under-representation of non-European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. HIGHLIGHTS: Eighty-two percent of neurodegenerative genome-wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations., Methods: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity., Findings: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10 -14 ) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity., Interpretation: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease., Funding: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research., Competing Interests: Declaration of interests DV, HI, HLL, KSL, CXA, and MAN's participation in this project was part of a competitive contract awarded to Data Tecnica International by the US National Institutes of Health (NIH) to support open science research. MAN also currently serves on the scientific advisory board for Character Biosciences and Neuron 23. KH is employed by 23andMe and holds stock or stock options in 23andMe. AS, MBM, PAJ, CB, KD, MJK, JJK, and PWC are employed by the NIH. AS also declares funding for the present work from the Michael J Fox Foundation (MJFF) and Aligning Science Across Parkinson's (ASAP); royalties for a diagnostic for stroke (unrelated to the current work); honoraria for associate editorial work for the journals Movement Disorders and npj Parkinson's Disease; and travel support from the Chan Zuckerberg Initiative to attend annual investigators’ meeting, MJFF to attend Parkinson's Progression Marker Initiative annual meeting, and Weill Cornell to give grand rounds. The spouse of AS is an employee of GeneDx. OOk, IE, HI, JHK, and DV declare funding from the NIH (1ZIA AG000534-04). HI also declares honoraria from GP2 for a steering committee meeting and from MJFF for a data community meeting. DGS declares support for the present work from ASAP (for the BLAAC-PD study); research support from the NIH (P50 108675), the MJFF, the Parkinson Foundation of the National Capital Area, the American Parkinson Disease Association, AbbVie, and Genentech; book royalties from McGraw Hill; consulting fees from AbbVie, Curium Pharma, F Hoffman-La Roche, Appello Pharma, and Blue Rock Therapeutics; participation on a data safety monitoring board or advisory board for Sanofi-Aventis, Theravance, and Alnylam Pharmaceuticals; being Deputy Editor of the journal Movement Disorders; and being Chair of the Scientific Advisory Board of the American Parkinson Disease Association. DAH declares support for the present work from the NIH, the MJFF, the CHDI Foundation, Parkinson's Foundation, Lundbeck, Uniqure, and Neurocrine. TX declares research funding from the MJFF, the American Parkinson's Disease Association, and the NIH; and consulting fees from Parkinson's Foundation and CVS Caremark. HH and JH declare research funding by the Medical Research Council (UK), the Wellcome Trust, the MSA Trust, NIHR University College London Hospitals Biomedical Research Centre (NIHR-BRC), the MJFF, the Fidelity Trust, the Rosetrees Trust, the Guarantors of Brain, SOLVE-RD, and the Dolby Family Fund. HRM declares support from the MJFF related to this work; grants not related to this work from PSP Association, CBD Solutions, Drake Foundation, and Cure Parkinson's Trust; consulting fees from Roche, Amylyx, and Aprinoia; speaker's honoraria from Kyowa-Kirin, the British Medical Journal, and the Movement Disorders Society; travel support from the MJFF and the Movement Disorders Society; and being on the advisory board for Cure PSP Association, the Association of British Neurologists Movement Disorders special interest group, and the Association of British Neurologists Neurogenetics advisory group. HRM is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). ES declares funding for the present work from the US National Human Genome Research Institute (NHGRI) Intramural Research Program; grants from ASAP and MJFF; and a cooperative research and development agreement with Roche. EAS declares funding for the present work from the MJFF; and travel support from the MJFF. MND declares funding for the present work from MJFF; grant support from ASAP; speaker's honoraria from the Parkinson's Foundation; and is a member of the Parkinson's Foundation Gulf Coast advisory board. Z-HF declares salary support from the MJFF. OOOj declares a study grant from the NIHR; honoraria for educational courses from the International Parkinson and Movement Disorder Society (IPMDS); travel support from P2 for an annual investigators’ meeting and from the IPMDS for congress attendance; and is a member of the executive committee of the IPMDS. NUO declares a study grant from the NIHR; travel support and honoraria for educational courses from the IPMDS; and being Chair of the IPMDS Africa Section. UA declares a study grant from the NIHR. RA declares grant support from the NIH (U01HG010273, U19AG074865), the UK Royal Society and the African Academy of Sciences Future Leaders—African Independent Research (FLR/R1/191813, FCG/R1/201034), and the Global Brain Health Institute, Alzheimer's Association, and Alzheimer's Society UK (GBHI ALZ UK-21- 24204). TF declares speaker's honoraria from Roche; travel support from the Alzheimer's Association; and is a member of the Alzheimer's Disease International medical and scientific advisory panel. CB declares support from ASAP. KD declares a Japan Society for the Promotion of Science Research Fellowship. JJK declares participation in the graduate school programme for Queen Mary University London (London, UK). PAJ declares participation in the graduate school programme for University College London (London, UK). MBM declares participation in a summer internship at Genentech/Roche (unrelated to the current work). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer's disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease., Competing Interests: Declaration of interests K.S.L., H.L.L., H.I., N.J., F.F., and M.A.N.’s participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc., (Published by Elsevier Inc.)

Radiation-induced apoptosis can be mediated through pathways initiated by either DNA damage or ceramide-induced Fas signaling. Glioblastoma multiforme is a primary brain tumor that is highly resistant to irradiation, and U-87 MG, SF126, and T98G are glioblastoma-derived cell lines that mimic this characteristic. We found that these radioresistant glioma cells are susceptible to Fas-mediated cell death induced by treatment with either anti-Fas antibody or exogenous ceramide. Fas-mediated cell death in these cell lines is p53-independent. These data demonstrate that apoptosis can be induced by ceramide and mediated through the Fas pathway in glioma cells, although high-dose ionizing radiation fails to trigger this pathway.

Surgical resection followed by radiation therapy is the mainstay of treatment for glioblastoma multiforme (GBM), the most aggressive of the malignant gliomas. The poor clinical response of GBM and the intrinsic radiation resistance of this tumor type have prompted clinical investigations seeking to define the role of chemotherapy in the treatment of GBM. In this study, we examined the cytotoxic response of GBM-derived cell lines to treatment with both radiation and chemotherapy. We observed that the sensitivity of glioma cells to cisplatin- and FAS-induced apoptosis was diminished by prior treatment with ionizing radiation. Radiation conferred resistance to cisplatin and FAS cytotoxicity in a dose- and time-dependent manner. Radiation diminished the cisplatin-induced cytotoxicity of malignant glioma cells but failed to alter the cisplatin susceptibility of normal primary human astrocytes. Given the role of p53 in the response of cells to irradiation, we evaluated whether p53 function affects the observed radiation-induced resistance to cisplatin. By examining isogenic cell lines differing only in p53 function, we demonstrated that radiation conferred resistance to cisplatin independently of p53. Current clinical strategies in the treatment of astrocytic tumors, which include combined modality therapy, have been empirically derived from limited clinical experience. Further understanding of the molecular determinants of apoptosis associated with combined modality therapy may guide the design of more efficacious multimodality protocols.