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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 INTRODUCTION White matter lesions on fluid‐attenuated inversion recovery magnetic resonance imaging (FLAIR‐MRI) reflect small vessel disease (SVD) and aid in identifying vascular contributions to impairment and dementia (VCID). Emerging diffusion MRI (dMRI) biomarkers are sensitive to early SVD but the lack of validated approaches for defining dMRI abnormality has limited their clinical utility. METHODS In 3934 participants (8749 observations) from a population‐based sample, we classified 9% as vascular cognitive impairment versus not (VCI+/VCI−) using abnormal FLAIR‐MRI and cognitive testing. We evaluated four distinct dMRI positivity criteria and assessed performance in an independent clinical sample. RESULTS The young referent criterion performed best and yielded an estimated prevalence of dMRI positivity aligned with pathology literature. About 40% of the population were dMRI positive, and these individuals had lower baseline cognition and faster longitudinal decline. Cutpoints were validated in an independent clinical sample. DISCUSSION The proposed dMRI abnormality framework can detect VCID and aid in identification of individuals at risk of VCI.

Rural populations are underrepresented in cognitive impairment research and have limited resources for education about brain and cognitive health, Alzheimer's disease and related dementias, or caregiving. As our Outreach, Recruitment, and Engagement team aimed to expand activities into more rural communities, we also wanted to better understand the characteristics of the communities surrounding our center and gain insight into the social exposome of the areas. The goal of the manuscript is to reflect on our experience and share measures that were useful in this effort, which can be further enriched and adjusted by other outreach teams.

This cross-sectional study evaluates the performance of the US Food and Drug Administration–cleared phosphorylated tau 217 (p-tau217) to β-amyloid 42 ratio cut points used to detect amyloid pathology associated with Alzheimer disease.

Abstract INTRODUCTION We describe the reliability of remote self‐administered digital cognitive measures completed via the Mayo Test Drive (MTD) web‐based platform. METHODS A total of 1846 participants (mean age = 70, SD = 12, range 31–101; 48% male; 96% White; 99% non‐Hispanic; 97% cognitively unimpaired) with two to four complete MTD sessions at ∼7.5‐month intervals were included. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed intraclass correlation coefficients (ICCs) with 95% confidence intervals. ICCs for in‐person‐administered traditional neuropsychological measures were compared to MTD for a subset of 244 participants. Analyses also compared reliability across demographic, residential, and session context subgroups. RESULTS Reliability was good for the MTD Composite (total ICC = 0.79 [0.77, 0.80]), and moderate‐to‐good for the primary outcome variables for each MTD subtest (total ICCs 0.70–0.83 for Stricker Learning Span and Symbols). The reliability of the remote self‐administered MTD was similar to in‐person‐administered cognitive measures. DISCUSSION MTD showed moderate‐to‐good reliability, supporting its use in longitudinal monitoring.

Abstract Introduction The relationship between sleep and brain metabolism remains unclear. This study aimed to examine whether overnight sleep features, using a home sleep apnea system based on peripheral arterial tonometry, are associated with regional FDG-PET changes in older adults. Methods We analyzed cognitively unimpaired adults (≥60 years) from the Mayo Clinic Study of Aging (MCSA) cohort who were not receiving sleep apnea treatment. Participants underwent overnight sleep assessment with the WatchPAT system, followed by FDG-PET imaging the next morning. FDG-PET data were co-registered to 3T MRI and automatically segmented into 122 anatomical regions. PET signal was referenced to the pons (SUVR). We computed voxel-weighted median FDG signal across 47 bilateral cortical and subcortical regions of interest (ROIs), excluding brainstem and cerebellum. Associations between sleep architecture and sleep apnea/hypoxemia burden and regional metabolism were assessed using partial Spearman’s rank correlation, adjusting for age. Results Thirty-seven participants were included (70.3% female; median [IQR] age: 72.0 [68.0–78.0] years). Wake after sleep onset (WASO) showed widespread negative associations with FDG uptake in cortical regions (p< 0.05), particularly the ventromedial/ventrolateral (rs=–0.47 to –0.33) prefrontal cortex, lateral temporal (rs=–0.38 to –0.33), and occipital (rs=–0.47 to –0.37) cortices. Total sleep time (TST) was positively associated with medial structures (p< 0.05), including the posterior cingulate (rs=0.39), retrosplenial cortex (rs=0.48), hippocampus/parahippocampal (rs=0.34 to 0.36), calcarine cortex (ρ=0.38), thalamus (rs=0.37), and caudate (rs=0.43). Hypoxic burden was positively associated with medial occipital regions (rs=0.35 to 0.39) and AHI-4% with cuneus (rs=0.33). Regional gray matter volume did not mediate these associations. WASO correlated with Insomnia Severity Index (rs=0.43, p=0.008) and self-reported refreshing sleep (rs=0.046). Conclusion Overnight sleep macrostructure features (WASO and TST) and hypoxic burden are significantly associated with brain metabolism, potentially underlying symptoms of sleep disturbance and cognitive aging. Support (if any) Mayo Clinic Alzheimer’s Disease Research Center Development Award (P30 AG062677), R01 AG056366, U01 AG006786, R01 AG056366, R01 AG034676, R37 AG011378, R01 AG041851, R01 NS097495, R01 AG068206, P30 AG062677, R01 HL065176. CLARA project work with funding from the European Union’s HORIZON EUROPE research and innovation programme (No 101136607).

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.