Age‐dependent effects of the p75 neurotrophin receptor modulator LM11A‐31 on Alzheimer’s disease biomarkers in a 26‐week safety and exploratory endpoint trial
Bibliographic record
Abstract
Abstract Background The p75 neurotrophin receptor (p75NTR) modulates pro‐ and anti‐apoptotic pathways as well as neurite and neuritic spine integrity. This receptor is expressed in cells vulnerable to aging and disease, including basal forebrain cholinergic neurons and hippocampal pyramidal neurons. It is also expressed by glial cells under pathological conditions. Pharmacological modulation of the p75NTR with LM11A‐31 alters both age‐ and disease‐related neuronal dysfunction. For example, LM11A‐31 reverses neuritic pathology in aged mice and reduces amyloid‐induced tau phosphorylation in mouse models of Alzheimer’s disease (AD). In this proof‐of‐concept study, we examined the effects of LM11A‐31 treatment on longitudinal neuroimaging and CSF biomarkers in humans with mild to moderate Alzheimer’s disease. Based on our preclinical work, we hypothesized that age and disease may interact to predict response to LM11A‐31 treatment in humans. Therefore, we additionally conducted subgroup analyses of drug effect in older and younger individuals. Method Participants with mild to moderate AD (MMSE score = 18‐26; age 55‐85 years) were enrolled in a 26‐week placebo‐controlled phase 2a safety and exploratory endpoint trial of LM11A‐31. Exploratory outcome measures included structural MRI, CSF AD core biomarkers, and CSF biomarkers related to pathological processes affected in mouse studies including synaptic integrity and inflammation. For placebo and drug, age subgroups were defined using a median‐split: younger (<72 years) and older (> = 72 years). Result Whole brain structural MRI analyses revealed that 26‐week treatment with LM11A‐31 reduced longitudinal grey matter degeneration in AD‐vulnerable brain regions including the inferior temporal gyrus, insula, frontal operculum and retrosplenial cortex. Furthermore, drug treatment, compared to placebo, prevented longitudinal increases of CSF tau, the presynaptic biomarker SNAP25, and the inflammatory biomarker YKL‐40. Median split analyses demonstrated that drug effects for structural MRI and CSF measures were consistently stronger in younger individuals. Conclusion This investigation highlights that biomarkers may demonstrate age‐dependency in response to therapeutic interventions in the context of mild‐moderate AD. Our results may inform biomarker selection and design of future studies of LM11A‐31 in human AD.
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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 | 0.004 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".