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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 < .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 TMEM106B encodes a lysosomal protein and is a genetic susceptibility factor for frontotemporal lobar degeneration (FTLD). Aptamer‐based proteomics quantifies TMEM106B protein levels in CSF. The associations of CSF TMEM106B with measures of disease severity have not been previously evaluated, and the value of CSF TMEM106B as a clinical biomarker is unknown. Method CSF TMEM106B and NfL protein levels were quantified with aptamer‐based proteomics in participants from two independent cohorts: sporadic FTLD with neuropathology‐confirmed FTLD‐tau and FTLD‐TDP, clinically diagnosed PSP‐Richardson Syndrome, and controls (UCSF MAC, n = 95; mean age = 69 ± 6 yrs; 48% female) and familial FTLD comprised of presymptomatic and symptomatic FTLD mutation carriers with family non‐carrier controls (ALLFTD, n = 179; mean age = 49 ± 13 yrs; 53% female). The association between biomarkers and diverse measures of disease severity, including the CDR®+NACC‐FTLD and CDR®+NACC‐FTLD sum of boxes, were determined with linear regressions or mixed linear models. Associations with brain volumes were determined within the framework of voxel‐based morphometry. Result In both cohorts, at baseline, CSF TMEM106B did not differ by sex, age, FTLD phenotype, or CSF NfL. CSF TMEM106B was lower in cases with worse disease severity (Figure 1) and in participants with the protective TMEM106B rs1990622 G/G genotype, regardless of pathological diagnosis or FTLD‐causing mutation. Low CSF TMEM106B was associated with more severe longitudinal worsening in FTLD disease severity (Figure 2), basic and instrumental function, global cognition, executive function, and depression scores. These associations were weaker than those of NfL. Low CSF TMEM106B was associated with low brain volumes in frontal, parietal, and temporal regions (FWE‐corrected p < 0.05) (Figure 3A). CSF NfL negatively correlated (FWE‐corrected p < 0.05) with brain volumes in frontotemporal regions (Figure 3B). Conclusion CSF TMEM106B concentrations are influenced by the TMEM106B rs1990622 genotype, and correlate with disease severity and brain volume in both genetic and sporadic FTLD. Lower levels of CSF TMEM106B correlate with more severe disease and brain atrophy. Disease severity is more strongly associated with CSF NfL, while brain volumes are more strongly associated with CSF TMEM106B. CSF TMEM106B may have value as a biomarker of neurodegeneration in FTLD.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

Abstract The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

AbstractBackgroundTMEM106B, a lysosomal trafficking protein, is an important genetic susceptibility risk factor for frontotemporal lobar degeneration (FTLD). In GRN mutation carriers, minor allele homozygosity in the TMEM106B rs1990622 SNP modulates the risk of FTLD. TMEM106B is often the main component of amyloid fibrils in FTLD with TDP43 aggregates. TMEM106B has been quantified in human brain specimens, but its role as a fluid biomarker is unknown. Here, we investigate the clinical value of CSF TMEM106B in FTLD.MethodsCSF TMEM106B was quantified with SOMAmer proteomics (v3.0, SomaLogic®) in an original cohort of C9orf72, GRN and MAPT symptomatic and asymptomatic mutation carriers and family non‐carrier controls, recruited through ALLFTD (n = 182), and a validation cohort of sporadic neuropathology‐confirmed FTLD‐tau and FTLD‐TDP43, clinically‐diagnosed progressive supranuclear palsy – Richardson syndrome (PSP‐RS) and age‐matched controls (n = 96). CSF TMEM106B was correlated with disease severity, measured by the Frontotemporal Lobar Degeneration module global scores (CDR+NACC/FTLD); brain volume, measured with Bayesian linear mixed‐effect modeling, using age, sex and total‐intracranial volume‐corrected permutations with threshold‐free cluster enhancement; and CSF neurofilament light chain (NfL) measured with Simoa. TMEM106B SOMAmer specificity was validated in cell culture overexpression systems and human brain specimens with high TMEM106B burden.ResultsIn both cohorts, there were no differences in CSF TMEM106B by sex, phenotype or neuropathological diagnosis, except for lower levels in PSP‐RS compared to controls (‐0.31 Log2‐fold change, p < 0.001). CSF TMEM106B did not correlate with age. Regardless of disease‐causing mutation, lower CSF TMEM106B was associated with worse disease severity (Figure 1 and 2). CSF TMEM106B was lower in homozygous TMEM106B rs1990622 protective allelein C9orf2 and MAPT, but not in GRN mutation carriers (Figures 3). CSF TMEM106B showed a trend for inverse correlation with NfL in the whole sample (r = ‐0.135, p = 0.052), and correlated positively with left frontal volume in symptomatic FTLD mutation gene carriers (p < 0.05).ConclusionCSF TMEM106B is quantifiable in CSF in vivo. CSF TMEM106B levels are affected by an interaction of disease severity and FTLD and TMEM106B genotypes. Further work is needed to determine its value as a clinical biomarker.

AbstractBackgroundThe pathophysiological mechanisms driving frontotemporal lobar degeneration (FTLD) disease progression and corresponding biomarkers that capture these changes are not fully understood. We leveraged high‐throughput proteomics to identify networks of co‐expressed CSF proteins and candidate biomarkers for prediction of disease progression in adults with autosomal dominant FTLD mutations.Method113 adults carrying autosomal dominant FTLD mutations (C9orf72/GRN/MAPT) and 38 noncarrier controls from the ALLFTD consortium completed baseline lumbar puncture and longitudinal neuropsychological testing. CSF was assayed for SOMAmer proteomics on SOMAscan® v3.0 (4,140 proteins). Network analysis identified weighted protein co‐expression modules, which were annotated via gene ontology and cell‐type enrichment analysis. Disease age estimates that capture proximity to symptom onset were derived from a Bayesian disease progression model incorporating genotype‐specific clinical (cognition, CDR®+NACC FTLD) and biomarker (brain volume, plasma NfL) information. At baseline, local‐weighted regression examined module z‐scores (based on mean/SD of module levels [first principal component] in noncarriers) in relation to disease age. Longitudinal linear mixed‐effects models examined global cognitive trajectories in relation to baseline module z‐scores, as well as individual proteins within prognostic modules.ResultNetwork analysis identified 32 CSF protein co‐expression modules (37 to 223 proteins/module). 16 modules showed mutation‐related deviations from noncarriers. Deviations in ion transport, neurodevelopmental, metabolic, and transcriptional modules occurred several decades before estimated symptom onset (disease age: ‐30 to ‐20 years) and persisted across disease age. Deviations in neuroinflammatory and ubiquitination/autophagy modules occurred ∼10 years before estimated symptom onset. Sharp deviations in RNA binding, protein phosphorylation, neurogenesis, synaptic function, and lysosomal modules occurred near symptom onset (disease age: ‐1 to 4 years). Baseline synaptic and neurogenesis modules were the strongest prognosticators of cognitive decline (module x time: bs>.10, ps<.05). Within these modules, individual proteins with stronger intramodular connectivity exhibited stronger associations with cognitive decline (e.g., synaptic/transmembrane module: r = .40, p = 2.85e‐6; e.g., EPHA5, LRRTM2).ConclusionLarge‐scale analysis of the CSF proteome reveals a biologically‐diverse landscape of protein networks associated with presymptomatic and symptomatic stages of autosomal dominant FTLD. Synaptic and neuron‐enriched protein networks exhibited prodromal deviations that forecasted incipient cognitive decline. ‘Hub’ proteins derived from these affected networks warrant further validation as candidate biomarkers for early FTLD disease progression.

Background The prognostic significance of obstructive sleep apnea ( OSA ) in patients with acute coronary syndrome ( ACS ) in the contemporary era is unclear. We performed a large, prospective cohort study and did a landmark analysis to delineate the association of OSA with subsequent cardiovascular events after ACS onset. Methods and Results Between June 2015 and May 2017, consecutive eligible patients admitted for ACS underwent cardiorespiratory polygraphy during hospitalization. OSA was defined as an apnea‐hypopnea index ≥15 events·h −1 . The primary end point was major adverse cardiovascular and cerebrovascular event ( MACCE ), including cardiovascular death, myocardial infarction, stroke, ischemia‐driven revascularization, or hospitalization for unstable angina or heart failure. OSA was present in 403 of 804 (50.1%) patients. During median follow‐up of 1 year, cumulative incidence of MACCE was significantly higher in the OSA group than in the non‐ OSA group (log‐rank, P =0.041). Multivariate analysis showed that OSA was nominally associated with incidence of MACCE (adjusted hazard ratio, 1.55; 95% CI, 0.94–2.57; P =0.085). In the landmark analysis, patients with OSA had 3.9 times the risk of incurring a MACCE after 1 year (adjusted hazard ratio, 3.87; 95% CI, 1.20–12.46; P =0.023), but no increased risk was found within 1‐year follow‐up (adjusted hazard ratio, 1.18; 95% CI, 0.67–2.09; P =0.575). No significant differences were found in the incidence of cardiovascular death, myocardial infarction, and ischemia‐driven revascularization, except for a higher rate of hospitalization for unstable angina in the OSA group than in the non‐ OSA group (adjusted hazard ratio, 2.10; 95% CI, 1.09–4.05; P =0.027). Conclusions There was no independent correlation between OSA and 1‐year MACCE after ACS . The increased risk associated with OSA was only observed after 1‐year follow‐up. Efficacy of OSA treatment as secondary prevention after ACS requires further investigation.