Citations

Abstract INTRODUCTION The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized. METHODS Over 7500 total whole‐genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool. RESULTS Low PathSeq scores for human herpesvirus 6 (HHV‐6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV‐6 genome integration. DISCUSSION This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV‐6 may play a role in a subset of these patients. Highlights Over 7500 whole‐genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV‐6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1 , PLEKHM1 , LRP2 , P2RX1 , and HAP1. Subsequent analysis of these genes in Parkinson’s disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

Objectives Multiple system atrophy (MSA) is classified into parkinsonian (MSA‐P) and cerebellar (MSA‐C) phenotypes based on predominant motor features, with corresponding pathological classifications of striatonigral (SN) degeneration and olivopontocerebellar (OPC) atrophy; however, disease progression patterns remain poorly understood. We aimed to identify novel MSA subtypes based on neuronal loss patterns using unsupervised machine learning. Methods We applied the Subtype and Stage Inference (SuStaIn) algorithm to analyze neuronal loss patterns in 167 autopsy‐confirmed MSA. Neuronal loss was semi‐quantitatively assessed in 5 brain regions: putamen, substantia nigra, pontine nucleus, inferior olivary nucleus, and cerebellar Purkinje cells. Obtained subtypes were validated by clinicopathological information. Results Three distinct subtypes were identified: SN‐early subtype (54% [86/160]) with initial SN neuronal loss, OPC‐early subtype (28% [44/160]) with early OPC involvement, and SN‐OPC‐synchronous subtype (19% [30/160]) with concurrent early neuronal loss in both systems. These subtypes corresponded well with clinical phenotypes. The SN‐OPC‐synchronous subtype exhibited significantly shorter survival (median 6.2 years vs 6.9 and 7.4 years in SN‐early and OPC‐early subtypes; p = 0.0049), more frequent rapid progression (57% vs 24% and 41% in SN‐early and OPC‐early subtypes; p = 0.0048), and more frequent early falls (70% vs 36% and 50% in SN‐early and OPC‐early subtypes; p = 0.0039). Immunohistochemical validation confirmed extensive α‐synuclein pathology in both SN and OPC systems in the SN‐OPC‐synchronous subtype. Interpretation The SN‐OPC‐synchronous subtype provides insights into α‐synuclein propagation mechanisms, suggesting multiple initial seeding sites rather than unidirectional spread. This computational approach uncovered disease heterogeneity undetectable by conventional methods, potentially benefiting clinical trials through patient stratification. ANN NEUROL 2026;99:989–1000

Abstract Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a usually prodromal manifestation of neurodegenerative disorders with α-synuclein pathology: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Clinical trials in the iRBD population face substantial barriers: limited access to well-characterized cohorts, inconsistent assessment protocols across centers, and the absence of validated biomarkers of disease burden. The North American Prodromal Synucleinopathy (NAPS) Consortium was established to address these challenges and facilitate clinical trials for neuroprotective therapies targeting synucleinopathy at the earliest known stages. In this multi-site, longitudinal, observational study, nine academic centers across North America will enroll and follow over 500 individuals with iRBD from existing sleep centers. Sixty control participants, matched for age, sex, and race will also be recruited. A harmonized protocol—including a standardized clinical battery assessing motor, cognitive, autonomic, psychiatric, sensory, and sleep function; structured diagnostic adjudication; biospecimen collection; and centralized analysis of both polysomnography and neuroimaging data—is outlined herein and reflects NAPS Stage 2. Each participants completes these assessments annually, and are replaced in the event of phenoconversion. By unifying assessments and expanding geographic reach, NAPS lays the groundwork for efficient, well-powered clinical trials designed to delay or prevent progression of iRBD to overt PD, DLB, or MSA—ultimately enabling earlier, more effective therapeutic intervention for neurodegenerative disease. Registered at clinicaltrials.gov (NCT05826457).

Abstract Background Isolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF). Method We included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests. Result Compared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance ( T = 2.0, p < 0.05, Figure 2). Conclusion Our study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

Abstract Background Plasma phosphorylated‐tau217 (pTau217) is a blood‐based biomarker of Alzheimer's Disease (AD) pathology. Cognitive resilience describes the presence of neurodegenerative pathology and preserved cognition. Cognitive resistance describes avoidance of neurodegeneration. This post hoc analysis of the Post‐Operative Delirium Belfast (PODB) cohort aimed to define cognitive resilience using plasma pTau217 and Mini Mental State Examination (MMSE) measures. Methods PODB was an observational cohort study, investigating people aged 65 and over, without a diagnosis of dementia, undergoing elective hip and knee replacement between 2012‐2014 with subsequent long‐term follow‐up. In this analysis, pre‐operative plasma pTau217 was used as a marker of neuropathology. A cutoff of 0.42 pg/mL was used (Ashton NJ et al. 2024). Pre‐operative and 8‐year follow‐up MMSE scores were used as a marker of cognition. A score of ≥24 was considered preserved. Definitions used were: Cognitive resilience = pTau217 ≥0.42 pg/mL plus MMSE ≥24. Cognitive resistance = pTau217 <0.42pg/mL plus MMSE ≥24. Affected = pTau217 ≥0.42 pg/mL plus MMSE <24. Those with normal markers plus poor cognition were defined as pTau217 <0.42pg/mL plus MMSE <24. These four groups were identified at baseline and follow‐up, respectively. In this analysis, 231 participants were included at baseline, 104 at follow‐up. Results Of the n = 231 participants included at baseline, n = 147/231 (64%) were cognitively resilient, n = 65/231 (28%) resistant, n = 17/231 (7%) affected, and n = 2/231 (<1%) had normal markers and MMSE <24. Of the n = 104 participants with follow‐up information included in this analysis, n = 61/104 (59%) were cognitively resilient, n = 33/104 (32%) were resistant, n = 8/104 (8%) affected, and n = 2/104 (<1%) had normal markers and MMSE <24. Cognitively resilient participants at baseline were younger ( p = 0.011) and tended to be female ( p = 0.977) compared to affected participants. At follow‐up, those who were cognitively resilient tended to be younger ( p = 0.196) and female ( p = 0.212) compared to affected participants (Table 1). Of those cognitively resilient at follow up, n = 59/61 (97%) of these participants were also cognitively resilient at baseline. Conclusions Using pTAu217, at the cut‐off quoted, we found a high incidence of cognitive resilience in an older elective surgical cohort.

Abstract Pick’s disease (PiD) is a rare cause of sporadic frontotemporal dementia, neuropathologically defined by the presence of Pick bodies consisting of aggregates of 3-repeat tau. Given the genetic aetiology of PiD remains unresolved, we assembled the Pick’s disease International Consortium (PIC) to identify susceptibility loci through a genome-wide association study (GWAS). A GWAS was conducted in 294 autopsy confirmed PiD cases and 1,055 controls. Lead variants were annotated using the Functional Mapping and Annotation of GWAS (FUMA) platform, followed by co-localisation analyses using the METABRAIN dataset and statistical finemapping using FINEMAP and SuSiE. After exclusion of 3 cases of MAPT mutations, no variants were associated with risk of PiD at genome-wide significance ( p < 5 × 10 -8 ). The strongest association was on chromosome 4 (4p13, lead SNP rs112161979, OR = 7.53, 95% Confidence Interval (CI) = 3.62-15.65, p = 6.37 × 10 -8 ) followed by chromosome 11 (11p15.4, lead SNP rs66481907, OR = 2.10, 95% CI = 1.54-2.84, p = 1.83 × 10 -6 ). rs112161979 is an intronic SNP in the KCDT8 gene, encoding a potassium channel tetramerization domain that acts as an auxiliary subunit for GABA B receptors, whilst rs66481907 is an intronic SNP in TRIM22 , encoding an E3 ubiquitin-protein ligase. Our GWAS provides the first evidence of possible genetic risk for PiD that implicate the modulation of GABA B receptor signalling and inflammation, in disease pathogenesis. Replication of these findings will be important, but our results suggest that, if present, the genetic risk of PiD beyond MAPT mutations is low.

Abstract INTRODUCTION Visual hallucinations (VHs) represent one of the core clinical features of dementia with Lewy bodies (DLB); however, their underlying pathology remains unclear. METHODS We employed proximity ligation assay (PLA) and phosphorylated α‐synuclein (αSYN) immunohistochemistry to compare αSYN oligomers and Lewy‐related pathology across brain regions along the ventral visual pathway in patients with and without VHs (five patients each). RESULTS Greater αSYN oligomer burden in the parahippocampal cortex was observed in patients with VHs compared to those without ( p = 0.041), whereas the burden of Lewy‐related pathology was similar between groups. DISCUSSION Our findings suggest that αSYN oligomers, rather than conventional Lewy‐related pathology, may be more closely associated with VHs in DLB. This provides novel evidence linking αSYN oligomers to a core clinical feature in DLB and suggests potential therapeutic targets for managing VH in these patients. Highlights Visualization of αSYN oligomers by PLA and quantitative neuropathologic analysis. Abundant αSYN oligomers in parahippocampal cortex of DLB with VHs. First human brain study linking αSYN oligomers to VHs. Potential oligomer‐targeted therapy for managing VH in DLB.