Frontiers in Aging Neuroscience最新文献

{"title":"Editorial: Decoding the gut-brain axis: implications for neurodegenerative disease therapies.","authors":"R M Damian Holsinger","doi":"10.3389/fnagi.2026.2015896","DOIUrl":"https://doi.org/10.3389/fnagi.2026.2015896","url":null,"abstract":"","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"2015896"},"PeriodicalIF":5.2,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13739768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased LINE-1 expression is associated with neuronal gene network downregulation in the aged mouse prefrontal cortex.","authors":"Shinya Fujii, Chu Guo, Yutaka Nakachi, Mohammad Mustakim Billah, Yuko Imamura, Emi Kiyota, Miki Bundo, Kazuya Iwamoto","doi":"10.3389/fnagi.2026.1961301","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1961301","url":null,"abstract":"<p><strong>Background: </strong>Aging is associated with epigenetic alterations, neuroinflammation, and progressive decline of neuronal function. Derepression of the retrotransposon LINE-1 (L1) has been implicated in aging and age-related diseases. However, the regional expression of L1 and its relationships with DNA methylation, genomic L1 copy number, and aging-related transcriptional changes in the normal aging brain remain incompletely understood.</p><p><strong>Methods: </strong>We examined L1 expression in the prefrontal cortex (PFC), hippocampus, and nucleus accumbens of young (17-week-old, <i>n</i> = 10) and aged (101-week-old, <i>n</i> = 7) male C57BL/6J mice. L1 expression, DNA methylation, and genomic copy number were quantified by RT-qPCR, pyrosequencing, and genomic qPCR, respectively. Transcriptomic alterations in the PFC were analyzed by RNA-seq, followed by weighted gene co-expression network analysis (WGCNA).</p><p><strong>Results: </strong>L1 expression was significantly increased in the aged PFC across multiple active L1 subfamilies, whereas no significant changes were observed in the other brain regions. Despite elevated L1 expression, no detectable changes were observed in the DNA methylation of active L1 promoters or in genomic L1 copy number between age groups. WGCNA identified three major aging-associated modules. Among these, only the neuronal module showed a significant negative correlation with L1 expression and was enriched for genes involved in synaptic signaling, neuronal development, and neuronal projections.</p><p><strong>Conclusion: </strong>L1 expression increased in the aged mouse PFC and is associated with coordinated downregulation of neuronal gene networks rather than other major aging-associated transcriptional programs. These findings further characterize the molecular context of increased L1 expression during normal brain aging.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1961301"},"PeriodicalIF":5.2,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13739680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial metabolites as modulators of gut-brain communication in neurodegeneration: from intestinal sensing to disease initiation and progression.","authors":"Xi Liu, Sirui Wang, Wei Long, Xinyue Tan, Wanlin Li, LiChen Gao","doi":"10.3389/fnagi.2026.1926883","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1926883","url":null,"abstract":"<p><p>How heterogeneous gut metabolite alterations relate to Parkinson's disease (PD) and Alzheimer's disease (AD) remains unresolved. We propose a framework in which intestinal sensing of indole derivatives, short-chain fatty acids and bile acids links microbial function to barrier regulation and gut-brain communication. Integration denotes tissue-level convergence of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and metabolite-responsive G-protein-coupled receptor responses across epithelial and neighbouring immune cells, rather than an established same-cell receptor complex. Tryptophan metabolism provides an analytical focus connecting microbial indole production with host kynurenine and serotonin pathways; metabolite concentrations alone do not establish pathway flux or receptor activity. We hypothesise that suppressed indole-associated epithelial signalling, barrier hyperpermeability and peripheral immune activation could form a shared gut-derived vulnerability state in subsets of PD and AD. Its co-occurrence and temporal relationship to CNS pathology have not been prospectively demonstrated. Neural, immune and vascular processes may overlap in both diseases, with genotype and cellular context modifying relative susceptibility rather than determining exclusive pathways. Human observational findings are distinguished from experimental mechanisms and proposed interactions. Receptor-directed treatments and metabolite-based biomarkers remain candidates requiring mechanism-specific, safety and clinical validation. Whether a gut-derived intervention window exists, is reversible, or favours earlier treatment requires longitudinal and controlled studies. The framework accommodates bidirectional communication and CNS-intrinsic disease, and generates separate tests of composite gut phenotyping and genotype-metabolite interactions.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1926883"},"PeriodicalIF":5.2,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13741297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An AI-driven model for risk stratification and prototype intervention mapping in motoric cognitive risk syndrome and subjective cognitive decline.","authors":"Zhihan Wang, Dingying Liu, Bosi Zhou, Shuo Chen, Qing Xu, Haonan Ding, Bing Xu, Xue Qin","doi":"10.3389/fnagi.2026.1878389","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1878389","url":null,"abstract":"<p><p>As Alzheimer's disease and other dementias continue their global rise, there is a compelling need for early identification of pre-clinical cognitive decline. Motoric Cognitive Risk Syndrome and Subjective Cognitive Decline represent crucial transition phases to facilitate targeted intervention, and existing unimodal approaches are neither sensitive nor sufficiently multimodal for appropriate risk classification and individualized intervention mapping (prototype). This study introduces a hybrid multimodal CNN fusion framework based on an improved version of light spectrum optimizer as metaheuristic optimizer to address this challenge. The framework fuses multiple modality-specific information through parallel three-dimensional convolutional neural network branches (MRI and PET) and encoders of motor, cognitive, and biomarker information followed by a combination of intermediate and late fusion layers with parameters tuned by the optimized framework. The framework is meticulously assessed on the BIOCARD longitudinally dataset and achieved an accuracy of 93.7% and an area under the ROC curve (AUC) of 0.965. It significantly surpassed seven state-of-the-art methods and revealed clinical interpretability through longitudinal risk trajectories and SHAP attribution of features.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1878389"},"PeriodicalIF":5.2,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13739817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: The role of neurotransmitters: from normal aging to age-related diseases, volume II.","authors":"Yan Zhou, Xiaodan Pan, Yitong Cao, Xuntao Yin","doi":"10.3389/fnagi.2026.2015252","DOIUrl":"https://doi.org/10.3389/fnagi.2026.2015252","url":null,"abstract":"","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"2015252"},"PeriodicalIF":5.2,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13739709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming the gut-brain axis in neurodegeneration: comparative microbiome, metabolite, immunometabolic, polyphenol, probiotic, and epigenetic mechanisms in Alzheimer's and Parkinson's diseases.","authors":"Yu Jie Cheng, Mei Ping Tao, Kexin Qian, Wei Ye","doi":"10.3389/fnagi.2026.1865514","DOIUrl":"https://doi.org/10.3389/fnagi.2026.1865514","url":null,"abstract":"<p><p>The gut-brain axis has emerged as a central mechanistic framework linking dietary bioactives, microbial ecology, and neurodegenerative disease progression. Similar microbiome-related mechanisms have also been implicated in colorectal cancer, suggesting potential shared links between microbial dysbiosis, inflammation, and disease progression. This study synthesizes preclinical evidence examining how polyphenols, polyphenol-derived compounds, and advanced delivery systems, including nanoparticles and synbiotics, modulate Alzheimer's disease (AD) and Parkinson's disease (PD) through microbiome-dependent mechanisms. Evidence from transgenic mice, toxin-induced rodent models, and <i>Drosophila</i> systems was compared across microbiome alterations, microbial metabolites, signaling pathways, epigenetic regulation, and functional outcomes. Across AD and PD models, dietary bioactives consistently promoted restoration of gut microbial homeostasis, characterized by enrichment of beneficial taxa and reduction of dysbiosis-associated microorganisms. These changes were accompanied by alterations in microbial metabolites, particularly short-chain fatty acids (SCFAs), tryptophan-derived metabolites, and lipid-associated signaling molecules. These metabolites provide functional links between microbial ecology and CNS physiology and may regulate epigenetic processes, including histone acetylation, DNA methylation, chromatin remodeling, and non-coding RNA activity. Despite substantial upstream convergence, downstream effects showed disease-specific patterns. In AD models, microbiome modulation predominantly influenced metabolic, amyloidogenic, and neurotrophic pathways, including AKT/GSK3β, NRF2, NF-κB, and BDNF-associated signaling, contributing to reduced amyloid-β deposition, attenuated tau pathology, and improved cognitive outcomes. In PD models, greater emphasis was placed on inflammatory, oxidative, and mitochondrial pathways involving SIRT1/NRF2, TLR4/MyD88/NF-κB, inflammasome signaling, and neuronal survival mechanisms, resulting in reduced neuroinflammation and preservation of dopaminergic neurons and motor function. Epigenetic regulation represents an additional convergence layer through which microbial metabolites and polyphenols may influence inflammatory, metabolic, mitochondrial, and neuronal gene programs in both disorders. Nanoparticle-based delivery systems enhanced bioavailability, tissue targeting, and microbiome-related effects, whereas synbiotic strategies reinforced microbial and metabolic homeostasis. Collectively, these findings support a microbiome-metabolite-epigenome-brain framework in which dietary bioactives modulate neurodegeneration through interconnected microbial, metabolic, immune, redox, mitochondrial, and epigenetic pathways. This framework provides a mechanistic basis for developing disease-tailored and precision-oriented gut-brain interventions for AD and PD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1865514"},"PeriodicalIF":5.2,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13740822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-cohort generalization limitations in gut microbiome-based Alzheimer's disease classifiers: evidence from four supervised cohorts with batch-correction analysis.","authors":"Arhan Chakravarthy","doi":"10.3389/fnagi.2026.1918251","DOIUrl":"10.3389/fnagi.2026.1918251","url":null,"abstract":"<p><p>Gut microbiome dysbiosis has been proposed as an Alzheimer's disease (AD) biomarker, but the transportability of microbiome classifiers across independent cohorts remains uncertain. We reprocessed five public 16S rRNA cohorts (509 samples, China, Kazakhstan, South Korea) with a common DADA2/genus-level pipeline and evaluated logistic regression and LightGBM classifiers using nested within-cohort cross-validation, leave-one-cohort-out (LOCO) transfer, pairwise transfer, permutational multivariate analysis of variance (PERMANOVA), batch adjustment, and out-of-fold SHapley Additive exPlanations (SHAP) analyses. Within four labeled cohorts, using strict training-only genus selection as the primary classifier-performance pipeline (Section 2.5.1), within-cohort area under the receiver operating characteristic curve (AUC-ROC) ranged from 0.611 to 0.996. The near-perfect Li 2019 result was stable across 50 repeated nested-cross-validation (CV) partitions and exceeded a 1,000-permutation label null (<i>p</i> = 0.000999), though a technical metadata confound cannot be excluded (Section 4.3). In LOCO evaluation, AUC ranged from 0.506 to 0.812 (mean decreases of 0.170 for logistic regression and 0.133 for LightGBM); paired bootstrap intervals excluded zero for four of eight cohort-model differences. LOCO estimates agreed closely with a fixed common-universe reference retained for secondary analyses (max |Δ| = 0.066), though one pairwise-transfer cell changed materially (Kazakhstan→Ling 2020, LightGBM: 0.58 → 0.44), reported without smoothing. In the four-cohort marginal PERMANOVA model, cohort-associated compositional variation exceeded diagnosis-associated variation (R² = 0.172 vs. 0.014), decreasing to 0.059 vs. 0.023 when restricted to three more technically comparable Chinese paired-end MiSeq cohorts; dispersion differed significantly among cohorts. Label-blind transductive ComBat-seq and MMUPHin adjustment changed mean LOCO AUC by at most 0.007 and did not recover transferability. Cross-cohort overlap of top predictive taxa was low: logistic regression overlap remained above a prevalence-restricted null, while LightGBM did not. A descriptive coefficient-stability screen identified eight logistic-regression genera with opposite, stable fitted-coefficient directions across cohorts. These findings demonstrate substantial, heterogeneous cross-cohort generalization limitations among the evaluated public 16S datasets and show that, under the tested label-blind transductive design, the two batch-adjustment methods did not restore transferability. Prospective validation in larger, geographically and technically diverse cohorts is needed before microbiome-based AD classifiers can be considered clinically actionable.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1918251"},"PeriodicalIF":5.2,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal fluid neurofilament heavy protein levels associated with domain-specific cognitive decline in Alzheimer's disease.","authors":"Jianjing Zhang, Xiwu Wang, Lingkai Yang, Zhaoting Lv, Suilin Jia, Teng Ye","doi":"10.3389/fnagi.2026.1826215","DOIUrl":"10.3389/fnagi.2026.1826215","url":null,"abstract":"<p><strong>Background: </strong>Neurofilament proteins are fluid biomarkers of neuroaxonal damage in various neurological diseases. However, it remains to be elucidated whether CSF neurofilament heavy (NfH) protein levels correlate with cognitive decline and progression in Alzheimer's disease (AD).</p><p><strong>Methods: </strong>This study included 165 cognitively unimpaired (CU) participants, 385 participants with mild cognitive impairment (MCI), and 128 participants with AD. To examine correlations between CSF NfH levels and baseline cognitive measures, Pearson's correlation was used. Linear mixed-effects models were fitted to assess the relationship between elevated CSF NfH levels and longitudinal cognitive decline in the CU, MCI and AD groups. Kaplan-Meier survival analyses and Cox proportional hazards models were used to assess the clinical progression in the CU and MCI groups separately.</p><p><strong>Results: </strong>In the MCI group, higher CSF NfH levels were significantly associated with poorer performance across global measures (MMSE, CDR-SB, ADAS-Cog-13, and RAVLT immediate recall; <i>p</i> < 0.001) and three cognitive domains (such as memory, language, and executive function), in both cross-sectional and longitudinal analyses. In contrast, the significant associations in the CU and AD groups were observed for a subset of cognitive tests and domains. Kaplan-Meier survival analyses showed that the high CSF NfH group had higher progression rates than the low group in both the CU and MCI groups. In the Cox proportional hazards models, baseline CSF NfH (continuous) remained a significant predictor of clinical progression.</p><p><strong>Discussion: </strong>Higher CSF NfH levels were associated with faster cognitive decline and clinical progression in CU and MCI groups but not in participants with AD, suggesting its potential as a biomarker for tracking early disease progression and cognitive impairment.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1826215"},"PeriodicalIF":5.2,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13735100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced weighted permutation entropy in visual-temporal cortex and altered resting-state brain dynamics in Alzheimer's disease.","authors":"Wenjing Zhao, Yuhong Huang, Hongyi Li, Wei Jian, Ziqi Wang, Tingting Wang, Xue Qiu, Xuemei Chen, Shicai Li, Man Liu, Hui He","doi":"10.3389/fnagi.2026.1921894","DOIUrl":"10.3389/fnagi.2026.1921894","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is increasingly recognized as a disorder of distributed neural dynamics. Resting-state fMRI combined with signal-complexity measures may provide new insights into alterations in spontaneous brain activity. This study investigated whether weighted permutation entropy (WPE), an amplitude-sensitive measure of temporal complexity, could identify regional abnormalities in AD and characterize their temporal and network-level features.</p><p><strong>Methods: </strong>Twenty patients with AD and twenty-four healthy controls underwent resting-state fMRI. Regional WPE was calculated using the Brainnetome atlas. Group comparisons included age, sex, years of education, and mean framewise displacement as covariates. Brainnetome findings were evaluated at an exploratory uncorrected threshold of <i>p</i> < 0.001 and checked against Bonferroni correction across 246 regions. Selected regions were used for secondary seed-based functional connectivity analysis. Four complexity-drop cascade intervals were compared without multiplicity correction. Sensitivity analyses examined window length, AAL parcellation, and cascade recruitment thresholds of 8, 10, and 12 regions; Fourier-surrogate analyses provided an additional model-based assessment.</p><p><strong>Results: </strong>At the exploratory Brainnetome threshold, AD was associated with lower WPE in two right inferior temporal subregions and one left fusiform subregion; these findings did not survive Bonferroni correction across 246 regions. The AAL analysis showed a similar regional pattern under FDR correction (<i>q</i> < 0.05). Secondary seed-based analyses identified increased connectivity with visual, parietal, and sensorimotor regions. Longer Peak-to-End and Start-to-End cascade intervals were observed in AD at nominal <i>p</i> < 0.05, without correction across the four interval tests. The overall pattern of subsequent cascade analyses was retained at the 8- and 12-region thresholds.</p><p><strong>Conclusion: </strong>This small-sample study suggests that AD is associated with regional WPE differences, altered connectivity, and possible prolongation of complexity-drop cascades. The exploratory Brainnetome and temporal findings, together with within-sample AAL convergence, motivate independent replication with prespecified multiplicity control. These measures do not yet establish a clinical biomarker or a specific physiological mechanism.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1921894"},"PeriodicalIF":5.2,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compound heterozygous and digenic inheritance in early-onset Parkinson's disease: a systematic review.","authors":"Victor Flores-Ocampo, Grecia Sevilla-Parra, Fangyuan Cao, Deepak Darshan, Santiago Díaz-Torres, Claudia Gonzaga-Jauregui, Kishore Raj Kumar, Miguel Enrique Rentería, Natalia S Ogonowski","doi":"10.3389/fnagi.2026.1930518","DOIUrl":"10.3389/fnagi.2026.1930518","url":null,"abstract":"<p><strong>Introduction: </strong>Compound heterozygous (CH) genotypes represent an established biallelic autosomal-recessive mechanism in early-onset Parkinson's disease (EOPD), whereas digenic inheritance (DI) has been proposed for variant combinations across two genes but is more difficult to establish. We systematically evaluated the genetic architecture and clinical features of CH cases and cases reported as DI in the published literature.</p><p><strong>Methods: </strong>This PRISMA-compliant systematic review included studies reporting CH or DI EOPD through September 2026. Two reviewers independently screened studies, extracted data, and curated variant- and case-level information. Variants were harmonized using current Human Genome Variation Society nomenclature and classified by gene, variant type, ancestry, and inheritance model.</p><p><strong>Results: </strong>We included 106 studies comprising 304 CH and 16 DI cases. CH was dominated by <i>PRKN</i>, with structural variants present in 85% (205/241) of <i>PRKN</i> cases, predominantly exon-level deletions. <i>PINK1</i> was the second most frequently implicated CH gene, whereas other CH subtypes were rare and genetically heterogeneous. Cases reported as DI involved seven genes, most commonly <i>LRRK2</i>-<i>PRKN</i> and <i>PINK1</i>-<i>PRKN</i>, although most variant combinations were unique. Across the CH and reported-DI groups, patients presented with a core Parkinsonian syndrome but showed substantial variability in age at onset, motor severity, and non-motor manifestations. <i>PRKN</i>-associated CH cases generally had earlier onset and favorable levodopa responsiveness, whereas <i>PLA2G6</i>- and <i>VPS13C</i>-associated cases more often exhibited cognitive impairment, psychiatric features, or structural neuroimaging abnormalities. No reproducible genotype-specific phenotype emerged.</p><p><strong>Conclusion: </strong>Compound heterozygous represents a conventional biallelic recessive mechanism in EOPD and was largely driven by <i>PRKN</i> structural variation. In contrast, cases reported as DI were rare and heterogeneous, and the available evidence generally did not establish causal digenic inheritance. These findings support comprehensive detection of structural and sequence variants while highlighting the need for segregation, functional, and replication evidence to distinguish causal DI from modifier effects or coincidental variant co-occurrence.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 ","pages":"1930518"},"PeriodicalIF":5.2,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149341549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}