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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.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P &amp;lt; .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Abstract Background Previous studies demonstrate that certain asymptomatic MAPT variant carriers (Asymp‐ MAPT ) exhibit altered baseline gray matter volume (GMV) and functional connectivity (FC) profiles. It remains unclear whether these imaging measures may herald risk for earlier conversion to the symptomatic phase. To address this, we stratified Asymp‐ MAPT based on baseline GMV and longitudinal FC changes to assess whether any Asymp‐ MAPT subgroups showed signs of longitudinal neurodegeneration or cognitive decline. Method We studied 25 Asymp‐ MAPT recruited from the UCSF Memory and Aging Center and ALLFTD Consortia. Using a median split, we divided Asymp‐ MAPT into groups with smaller (LowGMV; n = 12) and larger baseline GMV (HighGMV; n = 13) within regions atrophied in symptomatic MAPT carriers ( n = 20). Next, we stratified Asymp‐ MAPT based on longitudinal FC changes using k‐means clustering on rates of change in FC for four intrinsic connectivity networks associated with common MAPT ‐related syndromes: salience (SN), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and default mode (DMN) networks. We compared Asymp‐ MAPT subgroups from each stratification on baseline and longitudinal changes in demographics, plasma neurofilament light (NfL) concentration, GMV within 246 Brainnetome regions, and neuropsychological test scores. Result Stratification of Asymp‐ MAPT based on baseline GMV showed that LowGMV had higher education levels compared to HighGMV, with no other demographic differences. Though LowGMV and HighGMV did not differ in baseline NfL, LowGMV showed greater longitudinal NfL increases. These groups did not differ in baseline or longitudinal GMV changes. LowGMV had lower baseline attention and working memory scores, and greater longitudinal decline in set‐shifting and visuospatial performance. Stratification based on FC changes yielded one group (DecFC; n = 17) exhibiting longitudinal decreases in the SN, PSP, and DMN and another (IncFC; n = 8) showing increases in each network. DecFC and IncFC did not differ in demographics, baseline or longitudinal NfL, or baseline GMV. Longitudinally, DecFC showed greater decline in posterior superior temporal and inferior parietal cortices. DecFC showed lower baseline attention and semantic fluency scores, and greater longitudinal decline in set‐shifting and visuospatial memory performance. Conclusion Lower baseline GMV within regions atrophied during the symptomatic phase and longitudinal FC declines within MAPT ‐relevant networks may signal earlier symptomatic conversion in Asymp‐ MAPT .

Abstract Background A hexanucleotide repeat expansion in C9orf72 is the leading genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. There remains a critical need for biomarkers that track disease progression across clinical stages. Cross‐sectionally, intrinsic connectivity networks (ICNs) derived from task‐free fMRI (tf‐fMRI) detects abnormalities in C9orf72 expansion carriers ( C9orf72+ ), even when brain structural differences are subtle (Lee et al. , 2017). Few studies have examined longitudinal connectivity changes in C9orf72+ , however. Methods We analyzed longitudinal structural and tf‐fMRI data and plasma neurofilament light chain (NfL) concentrations of C9orf72+ recruited from UCSF and the ALLFTD Consortia. Mean time from first to last scan was 2.4±1.3 years. Participants included 36 asymptomatic (aSx‐ C9 ), 17 prodromal (prodromal‐ C9 ), 29 symptomatic (Sx‐ C9 ) carriers, and 107 healthy controls (HC). For structural MRI analyses, smoothed gray matter maps were parcellated into 246 regions‐of‐interest based on the Brainnetome atlas. We conducted voxelwise seed‐based tf‐fMRI analyses to examine ICNs showing alterations C9orf72+ based on previous literature: salience network (SN), sensorimotor network (SMN), default mode network (DMN), and a medial pulvinar thalamus network (pulvinar). General linear models and linear mixed models (LMM) compared C9orf72+ groups to HC in baseline and longitudinal gray matter and functional connectivity, as well as examined associations between longitudinal functional connectivity changes and baseline NfL concentrations. Results Despite a lack of longitudinal gray matter decline, aSx‐ and Sx‐ C9orf72+ showed functional connectivity changes. Compared to HC, aSx‐ C9 had baseline hypoconnectivity in the SN, SMN, and pulvinar network. Longitudinally, this group showed declines in the SN and pulvinar network, alongside DMN increases. Prodromal‐ C9 exhibited baseline SMN hypoconnectivity and hyperconnectivity in the DMN and pulvinar network, but no significant longitudinal changes. Sx‐ C9 showed baseline hypoconnectivity in SN, SMN, and DMN, with additional regions of DMN hyperconnectivity, while longitudinally, SN and SMN connectivity increased. In aSx‐ C9 , higher baseline NfL concentrations correlated with regions of SMN decreases over time and both increases and decreases in the pulvinar network. In prodromal‐ C9 and Sx‐ C9 combined, higher NfL was associated with DMN increases longitudinally. Conclusions Though gray matter declines were undetectable over a span of several years, functional connectivity networks changed dynamically in C9orf72+ .

ABSTRACT Objective Autosomal dominant progranulin ( GRN ) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN ‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Methods Utilizing T1 and task‐free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole‐brain degree, and GRN ‐relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive‐compulsive disorder symptom severity, and gray matter volume. Results Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive‐compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN ‐frontotemporal dementia. Interpretation In asymptomatic carriers, the co‐occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P &amp;lt; .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.