Announced in this Comment and in collaboration with Nature Medicine is the convening of the Brain Health for Economic Resilience Commission, a global, transdisciplinary effort to define, measure and operationalize brain health and cognitive capacity as foundational drivers of economic resilience.

The Davos Alzheimer’s Collaborative (DAC) Egypt Cohort (DAC-Egypt) is a newly established longitudinal study of cognitive aging in a community-based convenience sample of older Egyptian adults. The cohort’s purpose is to characterize trajectories of cognitive decline and dementia risk factors in an understudied population, filling a critical gap in aging research in the Middle East. Participants (n = 1,530) aged 55 and above were recruited via regionally diverse convenience sampling, with detailed baseline data collected on demographics, health status, lifestyle, and cognitive function. Cognitive assessments included both traditional neuropsychological testing and innovative digital tools (digital voice/speech & olfactory-sensory assessments) to enable comprehensive monitoring. Key preliminary findings indicated a high prevalence of chronic diseases and notable socioeconomic disparities in cognitive performance among older Egyptians. Blood samples were collected from 98% of participants, and dried blood spot (DBS) cards were obtained for 88% of participants to facilitate future biomarker and genetic research. This study seeks to enrich the scientific field of dementia and Alzheimer’s disease and related disorders (ADRD) for early detection and intervention strategies for cognitive health in aging populations.

Background:Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms. Sub-Saharan Africa (SSA) with its rapidly rising ageing population is experiencing a surge in the burden of PD in clinical care. Delayed diagnosis and treatment initiation, coupled with socioeconomic and healthcare barriers, may uniquely contribute to the population of PD with advanced clinical disease in SSA. This study aimed to clinically characterize Ghanaian PD patients, and identify predictors of mid-to-advanced disease. Methods:A hospital-based cross-sectional study was conducted at Komfo Anokye Teaching Hospital, Ghana (May 2023 - March 2024). Consecutive adults meeting UK Brain Bank criteria for PD diagnosis were neurologist-confirmed and evaluated using structured interviews including Hoehn and Yahr (H&Y) staging, and MDS-UPDRS. Data were analyzed using Graph Pad Prism, with logistic regression identifying predictors of mid-to-advanced PD defined by H&Y stages 3-5. Results:Of 161 participants (mean age 64.0 ± 9.1 years; 114 males), 98 (60.9%) were in early-stage PD (H&Y stages 1-2). Mid-to-advanced stages (H&Y stages 3-5) had higher motor scores (19.9 vs 15.4; p = 0.003) but lower non-motor scores (p < 0.001). Medication use was universal in mid-to-advanced stages vs 42.9% in early stages (p = 0.001). Male patients, those who had lost employment due to PD, and those with moderate UPDRS severity were more likely to have mid-to-advanced disease, whereas higher income and urinary symptoms were less likely. Conclusion:Mixes of socio-demographic and clinical features are associated with mid-to-advanced stages of PD among this Ghanaian sample of PD patients. Integrating socioeconomic determinants into prognostic models may enable earlier identification of patients with mid-to-advanced PD and guide targeted interventions such as social support systems to improve their quality of life in resource-limited settings.

Introduction Genome-wide association studies (GWAS) have identified over 130 risk loci for Parkinson's 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. Methods We conducted GWAS in AFR and AAC populations by integrating individual-level genotype data from the Global Parkinson's 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. Results The 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). Conclusions This 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was supported by the Global Parkinsons Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinsons (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinsons Research (MJFF). For a complete list of GP2 members see https://doi.org/10.5281/zenodo.7904831. This research was supported by the Aligning Science Across Parkinson's Initiative, the Intramural Research Program, National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949, and the Michael J. Fox Foundation for Parkinson's Research. This work utilized the computational resources of the NIH STRIDES Initiative (https://cloud.nih.gov) through the Other Transaction agreement - Azure: OT2OD032100, Google Cloud Platform: OT2OD027060, Amazon Web Services: OT2OD027852. We would like to thank the research participants, Paul Cannon, and employees of 23andMe Research Institute for making this work possible. We would also like to thank Dario Alessi and his team for their valuable contributions in functionally contextualizing this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data used in the preparation of this article were obtained from GP2. Specifically we used Tier 2 data from GP2 (release 11: DOI 10.5281/zenodo.17753486). GP2 data can be accessed through AMP PD (https://amp-pd.org). For the MVP dataset, PD summary statistics from the Million Veterans Program (MVP) were downloaded from dbGAP (accession number: phs002453.v1.p1; analysis accession: pha010400.1). Summary statistics from 23andMe were shared under a collaborative agreement submitted at https://research.23andme.com/collaborate/. All code generated for this article, and the identifiers for all software programs and packages used, are available on GitHub (https://github.com/GP2code/GP2-AFR-AAC-metaGWAS) and were given a persistent identifier via Zenodo (DOI: 10.5281/zenodo.7888140)

Abstract INTRODUCTION The apolipoprotein E (APOE) gene is the strongest known genetic risk factor for late‐onset Alzheimer's disease (AD), particularly the ε4 allele. Evidence suggests that women carrying at least one APOE ε4 allele have a higher risk of developing AD compared to men. However, data addressing genetic risk and sex‐specific effects in Middle Eastern and North African populations remain limited. METHODS To address this gap, we evaluated APOE allele frequencies, their association with AD risk, and their contribution to sex‐specific variability in a cohort of 63 clinically diagnosed AD patients and 201 cognitively healthy controls recruited across Egypt. RESULTS The APOE ε3 allele was the most prevalent in both AD cases (83.3%) and controls (83.6%). The ε4 allele was more frequent among AD patients (12.7%) than controls (8.0%) (adjusted odds ratio [OR] = 1.09, 95% confidence interval [CI]: 0.46 to 2.49, p = 0.85), while the ε2 allele was less frequent in AD patients (4.0%) compared to controls (8.5%) (adjusted OR = 0.82, 95% CI: 0.24 to 2.36, p = 0.73). However, neither association reached statistical significance after Benjamini–Hochberg false discovery rate correction. Sex‐stratified analyses revealed no significant sex‐specific effects of APOE alleles. CONCLUSION This pilot study provides the first characterization of APOE genotype and allele frequencies in Egyptians with clinically confirmed AD. No statistically significant association was observed between APOE status and AD risk in either males or females. Larger, geographically representative studies are needed to further elucidate the role of APOE in AD susceptibility within the Egyptian population and to explore potential alternative genetic or environmental contributors.

Determinants of long-term disability in multiple sclerosis (MS) remain incompletely understood, with clinical course varying greatly among individuals. Recent integrative genetic models have identified genomic clusters associated with divergent disability trajectories. Here, we integrated clinical, genetic, and postmortem neuropathological data from 291 MS brain donors from the UK MS Society Tissue Bank to test whether genomic severity clusters converge on distinct tissue phenotypes. Consistent with prior stratification, donors in genomic cluster 2 had lower age-adjusted disease duration score (ADDS) than cluster 3 (β = − 0.195, P = 0.023) and a shorter interval from progression to death than cluster 1 (β = − 0.225, P = 0.049). However, this adverse clinical profile did not reflect greater active or chronic active lesion burden. Instead, chronic active broad-rim lesions were more frequent in cluster 1 than clusters 2 and 3 (37.3

Emerging genomic studies across Africa are revealing how decades of population bias have constrained understanding of disease mechanisms. New evidence in Parkinson disease genetics illustrates how overlooking Africa’s vast genetic diversity not only limits scientific insight but also slows the development of medical and biotechnological innovations that are vital for advancing global health.

Objectives Rapid advances in transcriptomics have driven efforts to identify deregulated pathways in multiple sclerosis (MS) tissues, though many detected differentially expressed genes are likely false positives, with only a small fraction reflecting actual pathological events. Robust, integrative methods are essential for accurately understanding the molecular mechanisms underlying MS pathology. Methods We conducted a gene prioritization analysis of MS white matter pathology transcriptomic studies. Articles were sought in Scopus and PubMed up to July 31, 2024. Potentially eligible publications were those that provided either transcriptomics datasets (deposited in GEO) or lists of differentially expressed genes comparing MS white matter to control white matter. Results Applying a vote‐count strategy to search for the intersection of genes reported in multiple independent studies with a consistent fold‐change direction, followed by a Monte Carlo simulation, we identified 528 highly significant differentially expressed multi‐study genes ( p < 0.0001; 10,000 simulations). Functional enrichment analysis revealed deregulation of the folate pathway in MS normal‐appearing white matter, and tumor necrosis factor (TNF) ‐related and complement‐related pathways in active and chronic active lesions, respectively. Network analysis identified 6 key signaling hubs: PTPRC, HLA‐B, MYC, MMP2, COL11A2, MAG. The major nodes identified revealed mechanistic concordance with published in vivo MS models, supporting their value as potential therapeutic targets. Interpretation Our strategy provides a robust framework for integrating gene expression data, effectively identifying the intricate pathways altered in human diseased tissues. This method holds potential for translating findings into drug development strategies. ANN NEUROL 2025

BackgroundThe apolipoprotein E (APOE) gene, encompassing three alleles (ε2, ε3, ε4), is a critical player in lipid metabolism and has been extensively studied for its role in neurodegenerative diseases. This study examines APOE genetic variability and its association with PD in an Egyptian cohort.MethodsA total of 891 participants, including 422 PD patients and 469 healthy controls, were included in this study. APOE genotyping was performed using Kompetitive Allele Specific PCR (KASP) to detect the rs429358 and rs7412 SNPs, which define the APOE alleles. APOE alleles were categorized based on the genotypes into ε2, ε3, and ε4 groups. Clinical assessments of PD patients included age at onset, disease severity (MDS-UPDRS), and demographic factors. Statistical analyses compared APOE distributions between PD and control groups and examined associations with clinical variables.ResultsThe ε3 allele was the most prevalent in the cohort (77.3%), aligning with global and African trends. The ε2 allele was observed in 11.4%, and the ε4 allele in 11.3%, with both frequencies being lower than reported African estimates. The ε3/ε3 genotype was predominant in both PD patients (72.51%) and controls (72.07%). The ε4/ε4 genotype was absent in PD cases and rare among controls (0.64%). No significant association was found between APOE genotypes and PD risk, age at onset, or disease severity.ConclusionOur findings do not support a significant role for APOE in PD susceptibility or severity in Egyptians.

Africa stands at a decisive moment in which urgent action is essential to safeguard its brain health and economic stability. While Africa's population remains predominantly young, it is expanding and aging rapidly. This demographic shift is projected to drive a sharp rise in neurodegenerative diseases, including Alzheimer's, with profound health and economic costs-but brain health research, policy, funding and care across the continent remain critically underdeveloped. In this Perspective, we examine key trends in aging and brain health across Africa and introduce the 6 × 5 Plan-a 5-year strategic framework developed through collective multi-stakeholder insights-to address this pressing challenge. The plan targets six high-impact priorities: strengthening advocacy and health literacy, positioning brain health as a socioeconomic driver, breaking down silos of people and data, repurposing local resources, investing in artificial intelligence and digital health, and boosting research funding. To ensure effective implementation and long-term sustainability, the plan will be executed through a pan-African, multisectoral task force. This initiative seeks to accelerate Africa's response to the needs of a changing population and position the continent as a global leader in brain health innovation.

Huntington Disease-like (HDL) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. We review the different phenocopies of HDL in Africa from a clinical and genetic perspective through published cases. A literature review through PubMed and Google Scholar of all clinically and genically described cases of HDL until the end of December 2022 was performed and a descriptive analysis was carried out. Fifteen papers were published from 2000 to 2022 in Africa on HDL. Only HD phenocopies caused by mutation of the following genes (JPH3, ATXN2, VPS13A, VPS13D, PRNP, NBIA, ATN1, ATM) were described. The most representative phenocopies was HDL2 (JPH3) described in case series and families in South Africa. Other phenotypes and genotypes are described either as case series or isolated clinical cases. This review clarifies some aspects of the phenotype and genotype of HDL, mainly HDL2, and highlights others in Africa that require further research.

The 2024 Lancet Commission Report on dementia prevention has identified 14 modifiable risk factors that account for approximately 45% of global dementia cases. We used a global multidimensional approach that integrates gender equity considerations, poverty, wealth shocks, income inequality and HIV infection rates to identify additional risk factors beyond those reported in 2024 report. This methodological framework aims to enhance equitable prevention strategies to mitigate the global burden of dementia. We demonstrate that adding four additional risk factors: poverty, wealth shocks, income inequality, and HIV, while also considering the influences of sex and gender will improve the global applicability of the 2024 report. This is important because, despite dementia primarily affecting women, 57% of the risk factors identified in the 2024 report are more prevalent in men. Our analysis suggests that incorporating these four additional factors could potentially increase the proportion of preventable dementia cases to about 65%. This approach would also reshape the understanding of dementia risk, indicating that around 56% of modifiable risks disproportionately impact women. Expanding risk models in this manner is crucial for developing equitable and effective global dementia prevention strategies, particularly in underrepresented regions. We present these considerations as enhancements to the Commission's significant work.

BACKGROUND:Information comparing healthcare access and utilization between Black and White patients with Parkinson's disease (PD), particularly for deep brain stimulation (DBS) and supplementary care, remains sparse due to the lack of large Black population in a majority of healthcare facilities and limited scope of information in electronic datasets. We hypothesized that Black PD patients are less likely to have implantation for DBS due to many reasons, including ones not explored yet such as a lower likelihood of being assessed for DBS and/or acceptance for DBS when indicated, but more likely to have supplementary care. METHODS:We searched electronic medical records in our tertiary center between January 1, 2006 and October 1, 2021, followed by chart reviewing and extracting demographics, socioeconomic status, comorbidities, and healthcare access and utilization, including medications, DBS and supplementary care. Of 2827 patients in records, 1211 were assessed by movement neurologists here, who verified the diagnosis in 882 of them (72.8 %). We included 846 patients (95.9 %) (Black/White 255/591) with needed information for analysis. RESULTS:Compared to White patients, Black patients lacked male predominance, had lower socioeconomic status, more comorbidities, and frequent care in emergency/inpatient settings. There was no difference in overall medication use, but Black patients were less likely to have implantation and evaluation for DBS, and to accept DBS when indicated, and more likely to have supplementary care. CONCLUSIONS:Black patients are less likely to have DBS implantation, evaluation, and acceptance but more likely to have supplementary care compared to White patients. These new findings could help improve healthcare.

Background:Olfaction has enabled humans to survive and reproduce throughout their evolutionary history. Certain odors have been historically associated with danger while others, pleasure. Further, olfactory impairment is one of the earliest manifestations of neurodegeneration, such as Alzheimer's disease. Therefore, olfactory tests have the potential to reveal insights into a person's brain health. The landscape of orthonasal olfactory tools is vast, and many have been adapted for populations living in low- and middle-income countries, but challenges remain in the awareness of the utility of olfactory testing, effective deployment, and scalability. Objective:This report explores the current landscape of olfactory tests, the potential for digital tests to provide scalable data in low-resource settings, and their potential applicability in the Alzheimer's disease and brain health space. We also describe the ScentAware digital odor identification test and present some preliminary findings from its use in Egypt, a site for the Davos Alzheimer's Collaborative's Global Cohorts Program. Methods:The American University in Cairo in partnership with University College London collected olfactory data using the ScentAware test from 125 participants from the North African Dementia Registry, a longitudinal study of community dwelling adults over age 55 in Egypt and the surrounding Middle East and North Africa region. Results:Participants' olfactory function measured by the culturally adapted ScentAware test somewhat correlated with language and memory, as assessed by the Egyptian Harmonized Cognitive Assessment Protocol battery. Conclusions:Our adaptation of the ScentAware test suggests that digital olfactory assessment holds promise for cost-effective deployment at scale in a low-resource setting.

REM sleep behavior disorder (RBD), is a prodromal synucleinopathy affecting a subset of Parkinson’s disease (PD) patients and associated with neuropsychiatric symptoms. This study compared the genetic profiles of 13,020 PD patients with probable RBD (PD + RBD) and 5403 without (PD-RBD) using genome-wide association study (GWAS). RBD was assessed by questionnaires or self-reporting. Potential genetic correlations between neuropsychiatric traits and PD + RBD were assessed using linkage disequilibrium score regression. The top variant in the SNCA locus was associated with PD + RBD (rs10005233-T, OR = 1.21, 95% CI = 1.16–1.27, p = 1.81e−15). PD risk variants in SNCA (rs5019538-G, OR = 0.85, 95% CI = 0.81–0.89, p = 2.46e−10; rs356182-G, OR = 0.89, 95% CI = 0.84–0.95, p = 0.0001) and LRRK2 loci (rs34637584, OR = 0.41, 95% CI = 0.28–0.61, p = 1.04e−5) were associated with reduced PD + RBD risk. A suggestive genetic correlation between attention deficit hyperactivity disorder and PD + RBD was observed but was not statistically significant after correction. These findings highlight genetic distinctions between PD + RBD and PD-RBD, offering insights into PD stratification and potential subtype-specific treatments.

Risk prediction models play a crucial role in advancing healthcare by enabling early detection and supporting personalized medicine. Nonetheless, polygenic risk scores (PRS) for Parkinson's disease (PD) have not been extensively studied across diverse populations, contributing to health disparities. In this study, we constructed 105 PRS using individual-level data from seven ancestries and compared two different models. Model 1 was based on the cumulative effect of 90 known European PD risk variants, weighted by summary statistics from four independent ancestries (European, East Asian, Latino/Admixed American, and African/Admixed). Model 2 leveraged multi-ancestry summary statistics using a p-value thresholding approach to improve prediction across diverse populations. Our findings provide a comprehensive assessment of PRS performance across ancestries and highlight the limitations of a "one-size-fits-all" approach to genetic risk prediction. We observed variability in predictive performance between models, underscoring the need for larger sample sizes and ancestry-specific approaches to enhance accuracy. These results establish a foundation for future research aimed at improving generalizability in genetic risk prediction for PD.

BACKGROUND:Leucine-rich repeat kinase 2 (LRRK2) p.L1795F variant was proposed as a genetic risk factor for Parkinson's disease (PD). However, its prevalence, phenotype, and origin remain unknown. OBJECTIVE:The aim was to evaluate the frequency and phenotype of p.L1795F in early-onset PD (EOPD) and familial PD compared to healthy controls (HC) in Central Europe. METHODS:Whole-exome sequencing was used to screen 219 EOPD and familial PD patients of Central Europeans compared to HC. Sanger sequencing assessed segregation. Detailed clinical phenotype was evaluated for all positive carriers. RESULTS:p.L1795F was identified in 1.37% (3/219) and 3.23% of familial cases (3/93), with no carriers among HCs (0/303). Segregation analysis confirmed association with PD. Carriers were traced to the eastern Slovak-Hungarian region. It also appears to be associated with a more aggressive phenotype. CONCLUSION:Our data indicate that p.L1795F contributes to PD in Central Europe. Further exploration in larger cohorts is warranted to establish its contribution to global PD risk.