Citations

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

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.

Objective Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α‐synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically‐defined series of LBD cases. Methods We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High‐resolution whole‐genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes. Results Our analysis identified 1 significant ( P < 3.43 × 10 −5 ) and 4 suggestive ( P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA‐mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA‐DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus ( P = 3.30 × 10 −5 ), with weaker and suggestive associations observed in the middle frontal ( P = 1.80 × 10 −4 ) and inferior parietal gyrus ( P = 6.33 × 10 −4 ). Additionally, although only suggestive, HLA‐DRB1*11:01 correlated with a lower Thal amyloid phase ( P = 1.56 x 10 −4 ), and HLA‐B*15:01 correlated with an increased risk of diffuse LBD ( P = 7.58 x 10 −4 ). Interpretation This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune‐related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501

Abstract INTRODUCTION The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)‐Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)‐derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures. METHODS The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD‐M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants. RESULTS Both CDR + NACC FTLD‐M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation. DISCUSSION With a motor domain, CDR + NACC FTLD‐M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD‐ALS spectrum and improves clinical trial efficiency. Highlights CDR + NACC FTLD‐M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.

Abstract Bioinformatics methods can be used to quantify mitochondrial DNA copy number from whole genome sequencing (WGS) data. We evaluated mitochondrial DNA copy number from human brain-derived WGS data using the fastMitoCalc tool. 341 Parkinson’s Disease cerebellum samples were compared with 74 age-matched controls from the North American Brain Expression Consortium. Parkinson’s Disease cerebellum had significantly higher mitochondrial DNA copy number compared with controls (P = 4.15e–7), and this effect was reproducible in four of five brain banks when analysis was restricted to each resource that contributed Parkinson’s Disease samples to this genetic dataset. Follow-on analyses of 128 Parkinson’s Disease cerebellum samples and 33 controls that had paired neuropathology data and clinical scores demonstrated a significant increase in mitochondrial DNA copy number with Unified Staging System for Lewy Body disorders stages and Unified Parkinson’s Disease Rating Scale (off meds) motor scores. Analysis of Lewy Body scores from ten brain regions showed cerebellum mitochondrial DNA copy number increased upon pathological infestation of α-synuclein aggregates in the brainstem and limbic system but did not increase after late-stage neocortical involvement. This genetics dataset supports previous observations of cerebellum activation in Parkinson’s Disease and suggests mitochondrial DNA copy number may increase to support this regional activation as a compensatory mechanism to pathology or motor symptoms.

AbstractBackgroundStructural variants range from simple loss or gain of genetic material to complex events that restructure entire chromosomes. This heterogeneity coupled with variant size greater than sequencing read‐length makes structural variant mapping from short‐read sequencing data difficult and error‐prone. Consequently, the role of structural variants is poorly explored in many phenotypes, including dementia.MethodWe used the GATK‐SV pipeline that combines four external structural variant mapping algorithms with machine‐learning to build high‐quality consensus structural variant calls. We applied GATK‐SV to short‐read whole‐genome sequencing data of 2,601 frontotemporal dementia‐amyotrophic lateral sclerosis spectrum (FTD/ALS) patients, 2,612 Lewy body dementia (LBD) patients, and 4,132 neurologically unaffected participants.ResultAfter stringent quality‐control, we performed genome‐wide association studies on 2,307 ALS/FTD patients versus 3,677 controls with 4,699 common structural variants and 2,355 LBD patients versus 3,700 controls with 4,889 common structural variants. In the FTD/ALS cohort, we identified well‐known risk variants at the C9orf72 (p‐value = 4.99×10‐18, OR = 14.47, 95% CI = 7.90–26.49) and MAPT loci (p‐value = 3.48×10‐6, OR = 0.77, 95% CI = 0.68–0.86) corroborating the ability of our pipeline to identify disease‐associated structural variants. Moreover, we discovered, replicated, and validated TPCN1 as a novel risk locus for LBD (p‐value = 9.18×10‐6, OR = 1.43, 95% CI = 1.22–1.67). Further, we identified rare exonic variants with known pathogenic or likely pathogenic effects, such as an SNCA gene duplication in LBD and a deletion of exons 1 and 2 in CHCHD10 in FTD/ALS. We additionally observed structural variants in regulatory regions, e.g. a deletion of a key PSEN2 enhancer, which resulted in an approximate 0.70 fold‐change in PSEN2 expression in LBD. Finally, we built an interactive web app where structural variants can be visualized and explored (https://ndru-ndrs-lng-nih.shinyapps.io/non_ad_dementias_sv_app/).ConclusionCommon and rare structural variants play a role in LBD and FTD/ALS. Our structural variant resource is publicly available and can be used to further explore the role of structural variants in LBD and FTD/ALS.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.