Jia Nee Foo

It is hypothesised that peripheral immune states responding to regional environmental triggers contribute to central neurodegeneration. Region-specific genetic selection pressures require this hypothesis to be assessed in an ancestry-specific manner. Here, we utilise genome-wide association studies and expression quantitative trait loci from African, East Asian and European ancestries to show that genes causally-implicated in neurodegeneration are preferentially expressed in innate rather than adaptive immune cells. Using colocalisation and Mendelian randomisation analyses, we show that in addition to known colocalising signals in microglia, genetic variants associated with neurodegenerative disease risk also regulate the expression of these genes in peripheral monocytes across ancestries.

Parkinson's disease (PD) exhibits pronounced sex differences, yet the underlying genetic and molecular mechanisms remain poorly understood. We performed the largest-to-date meta-analysis of sex-stratified genome-wide association studies of PD followed by brain proteogenomics-based causal inference analyses. We nominated 10 candidate proteins that appear important to sex-biased PD risk, of which 2 female-biased, GALC and PSMG1, and 3 male-biased, ACTR1B, WDR41, and CD151, were most robustly prioritized. Together, our findings provide evidence for genetic sex differences in PD, prioritizing sex-biased proteins implicated in lysosomal regulation, neuroinflammation, lipid biology, and other PD-relevant mechanisms, and highlighting potential sex-informed therapeutic opportunities.

Objective: The extent of neuronal loss in Parkinson's disease (PD) and the pathogenic processes underlying neuronal dysfunction and loss remain poorly understood. Here, we analyzed the expression of key molecules representing different cell death signaling pathways and their association with Lewy pathology, dopaminergic (DA) neuron loss and stage of PD progression in human postmortem brain tissue. Methods: We performed neuropathological and molecular analyses on 47 postmortem substantia nigra (SN) tissue samples from PD cases and healthy controls to investigate neuronal cell death pathways. Results: An average loss of 54% of dopaminergic neurons was found in the SN of PD cases, which correlated strongly with PD Braak staging. The apoptosis markers, cleaved subunits of caspases 3 and 8, were absent. Levels of the active necroptosis kinase, phosphorylated RIPK3 (pRIPK3), were significantly increased in advanced‐stage PD. Although phosphorylated MLKL (pMLKL) levels were not significantly different, both active markers were detected in small numbers of PD neurons by immunofluorescence, suggesting focal necroptotic pathway activation. In contrast, evidence for ferroptosis was more pronounced, particularly in advanced‐stage PD. This was supported by significantly increased transferrin receptor 1 (TFR1) protein levels and significantly decreased glutathione peroxidase 4 (GPX4) RNA and protein levels. Interpretation: Our findings implicate ferroptosis, and to a lesser extent necroptosis, in PD neuronal death, with ferroptosis potentially playing a larger role in advanced disease. We propose a “2‐hit” model where early synucleinopathy‐driven insults are amplified in advanced disease by a neuromelanin‐iron‐driven feedback loop, establishing ferroptosis as the predominant cell death mechanism. This stage‐dependent shift provides critical insights into PD pathogenesis and suggests distinct therapeutic windows for neuroprotection. ANN NEUROL 2026;99:1415–1427

The differentials for rapidly progressive dementia are broad, encompassing structural, infectious, inflammatory, neoplastic, and neurodegenerative etiologies. The presence of abnormal movements further complicates the diagnostic approach. We describe a 69-year-old man presenting with a diverse array of neurologic symptoms, starting with rapidly progressive cognitive impairment, later developing abnormal movements, sleep disruption, and constitutional symptoms. Despite extensive investigations and empirical treatment, the diagnosis remained elusive until postmortem evaluation. This case highlights the challenges inherent in neurologic diagnostic odysseys, offering insight into the diagnostic reasoning process and unveiling novel clinical findings that may aid earlier recognition of this rare disorder.

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations. We investigated the p.A419V variant across multiple ancestry cohorts comprising over 200,000 individuals. In cases of East Asian ancestry, the variant was significantly associated with increased risk (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), It lies on rare EAS haplotypes, and was not in linkage disequilibrium with other LRRK2 coding variants. Although not significant, meta-analysis of age of onset in EAS cases show a suggestive trend (β = –0.89 years; SE = 1.01; p = 0.380). LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB10, RAB29 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling pathway.

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.

Genome-wide association studies of Parkinson’s disease (PD) have identified multiple genetic variants across populations, but the biological mechanisms remain largely unknown. To investigate ancestry-specific disease pathways, we performed a series of Mendelian randomisation analyses, integrating GWAS results with ancestry-specific protein quantitative trait loci data. For Europeans, we utilised the UK Biobank plasma proteomics (UKB-PPP) dataset alongside a European PD GWAS. For East Asians, we combined plasma proteomic data from Han Chinese and the East Asian subset of UKB-PPP with an East Asian PD GWAS. We identified 21 protein-encoding genes causally associated with PD in Europeans and 8 in East Asians, with BST1 common to both (Europeans: OR=1.04, 95% CI 1.02-1.06; East Asians: OR=1.18, 95% CI 1.10-1.27). Ancestry-specific associations included PRSS53 and TXNDC15 in Europeans, and HDGF , PM20D1 , and TOP1 in East Asians. These findings highlighted ancestry-related differences in gene-protein-PD associations and have implications for biomarker development and targeted therapeutic strategies.

LRRK2-related Parkinson’s disease (LRRK2-PD) is the most frequent form of monogenic PD worldwide, with important therapeutic opportunities, exemplified by the advancement in LRRK2 kinase inhibition studies/trials. However, many LRRK2 variants, especially those found in underrepresented populations, remain classified as variants of uncertain significance (VUS). Leveraging on Malaysian, Singaporean, and mainland Chinese PD datasets (n = 4901), we describe 12 Chinese-ancestry patients harboring the LRRK2 p.Arg1067Gln variant, more than doubling the number of previously reported cases (total n = 23, 87% East Asian, mean age of onset: 53.9 years). We determine that this variant is enriched in East Asian PD patients compared to population controls (OR = 8.0, 95% CI: 3.0–20.9), and provide supportive data for its co-segregation with PD, albeit with incomplete penetrance. Utilizing established experimental workflows, this variant showed increased LRRK2 kinase activity, by ~2-fold compared to wildtype and higher than the p.Gly2019Ser variant. Taken together, p.Arg1067Gln should be reclassified from a VUS to pathogenic for causing LRRK2-PD.

Genome-wide association studies have identified SV2C as a Parkinson's disease (PD) risk locus, with a common missense variant p.Asp543Asn in the synaptic vesicle glycoprotein 2C (SV2C) protein significantly associated with PD. We examined if other rare SV2C variants also influence PD risk. We analyzed sequencing data of 9810 East Asian individuals comprising 4298 patients and 5512 controls and identified 55 rare nonsynonymous variants. There was no significant association of rare nonsynonymous or loss-of-function variants with PD. Our findings show that besides p.Asp543Asn, other rare coding variants in SV2C do not play a major role in PD susceptibility in East Asia.