TMEM106B modulates disease severity in genetic frontotemporal dementia phenoconverters
Bibliographic record
Abstract
Abstract Background A common variant within TMEM106B is associated with risk for Frontotemporal Lobar Degeneration‐Tar DNA binding Protein‐43 (FTLD‐TDP). A recent study has shown that the minor allele G of TMEM106B‐rs1990622 confers protection against FTLD‐TDP in symptomatic mutation carriers through reductions in NfL serum levels, brain atrophy, and cognitive decline. It is unknown whether this protective effect is present in phenoconverters of the disease. Method We included 518 participants from the GENetic Frontotemporal dementia Initiative (GENFI), which recruits genetic FTD cases and their family members, both carriers and non‐carriers of FTD mutations. Of these, 21 were phenoconverters, 209 were non‐carrier controls, 70 were presymptomatic and 45 symptomatic C9orf72 carriers, 92 presymptomatic and 29 symptomatic GRN carriers, and 39 presymptomatic and 13 symptomatic MAPT carriers. Effects of interaction between TMEM106B‐rs1990622 and phenoconverter status were examined using mixed effects models, with a random effects structure featuring subjects nested within families and fixed effects for age at baseline and sex. Serum neurofilament light chain (NfL) was measured using the Simoa platform. Cognitive assessment included the Mini‐Mental State Examination (MMSE), tests of attention, processing speed, executive function, and language, as well as the Cambridge Behavioural Inventory (CBI), with mixed effects also including years of education as a covariate. Brain volumetry was assessed using T1‐weighted MRI and these mixed effect models also included additional covariates of total intracranial volume and scanner site. Result In phenoconverters, each copy of the protective allele G was associated with a significant reduction in the rate of serum NfL accumulation (‐5.33 pg/mL/year; p = 7.79 × 10 −9 ). Structural imaging analyses revealed decreased rates of atrophy in fronto‐orbital regions and the insular cortex among protective allele carriers. Cognitive trajectories showed significantly slower decline across multiple domains including general cognition (MMSE; p = 0.003), attention and processing speed ( p = 2.2 × 10 −4 ), executive function ( p = 2.6 × 10 −7 ), language ( p = 2.9 × 10 −3 ), and behavioural symptoms as measured by CBI ( p = 9.5 × 10 −3 ). Conclusion The TMEM106B‐rs1990622 protective variant significantly modulates disease progression in genetic FTD phenoconverters across multiple markers, suggesting its potential as a therapeutic target.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".