Citations

ABSTRACT Colony stimulating factor‐1 receptor–related disorder (CSF1R‐RD) is a rare, autosomal dominant neurodegenerative disease caused by loss‐of‐function variants in the CSF1R gene, leading to microglial dysfunction and progressive white matter degeneration. Therapeutic strategies targeting microglial pathways, including activation of triggering receptor expressed on myeloid cells 2 (TREM2), have been proposed to compensate for impaired CSF1R signaling. Iluzanebart (VGL101), a monoclonal antibody TREM2 agonist, has shown promise in preclinical models. We report a longitudinal clinical course, neuroimaging findings, genetic analysis, and postmortem neuropathological examination of a 52‐year‐old patient with genetically confirmed CSF1R‐RD (c.2507G>A, p.Ser836Asn). The patient received iluzanebart as part of a Phase 2 clinical trial. Clinical progression, MRI changes, and histopathological features at autopsy were systematically analyzed. Despite treatment, the patient experienced progressive cognitive decline, neuropsychiatric symptoms, motor impairment, and seizures, culminating in death. Serial neuroimaging demonstrated worsening white matter degeneration and brain atrophy without evidence of therapeutic response. Neuropathological examination revealed characteristic features of CSF1R‐RD, including severe myelin loss, axonal spheroids, infiltration of Iba1‐positive cells with macrophage‐like morphology, and cortical neuronal abnormalities. There was no histological evidence of treatment‐related benefit or harm. This case represents the first clinicopathological assessment of iluzanebart in CSF1R‐RD and demonstrates no observable clinical, radiological, or neuropathological improvement. These findings highlight the challenges of targeting microglial dysfunction in advanced disease and suggest that TREM2 activation alone may be insufficient to alter disease progression.

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.