Evaluating the Efficacy and Risks of Early Lecanemab Treatment in APOE4 Humanized Alzheimer's Disease Mouse Models
Bibliographic record
Abstract
Abstract Background Alzheimer's disease (AD) is the leading cause of dementia. AD disproportionately affects APOE4 carriers, who experience accelerated amyloid β (Aβ) accumulation, including cerebral amyloid angiopathy (CAA). While monoclonal antibodies (mAbs) like lecanemab reduce amyloid plaques, their use is complicated by amyloid‐related imaging abnormalities (ARIA‐likely related to brain bleeds), particularly in APOE4 carriers. Lecanemab, a humanized mAb targeting Aβ protofibrils, but still poses an enhanced risk for APOE4 carriers. This study explores whether early lecanemab treatment can reduce the risk of microbleeds and prevent cognitive deficits as well as brain atrophy in APOE4 humanized AD mouse models. Methods Advanced AD mouse models with humanized APP (hApp), Tau (hMAPT), and APOE3/APOE4 genes were used. The murine version of lecanemab (mAb158) was synthesized and shown to target synthetic Aβ oligomers and pre‐fibrillar amyloid in these models. Starting at 3 months of age, hApp NL‐F ‐hMAPT‐APOE4 and hApp NL‐F ‐hMAPT‐APOE3 mice received mAb158 (20 mg/kg weekly for 26 weeks) or vehicle (PBS). Cognitive performance was assessed at 6, 9, and 12 months using a touchscreen‐based Continuous Performance Test (CPT) to assess attention. At study end, brain tissues were analyzed via light‐sheet microscopy, immunohistochemistry, Prussian Blue staining, and ELISA to evaluate plaques, amyloid deposits, microbleeds, and Aβ levels. Results Immunohistochemistry and light‐sheet microscopy revealed significant amyloid accumulation in the brain and blood vessels of hApp NL‐F ‐hMAPT‐APOE4 mice, from 6 months of age onward, compared to hApp NL‐F ‐hMAPT‐APOE3. In the mAb158 treated mice, insoluble Aβ accumulation was negligible in both genotypes at 9 months of age and significantly reduced at 15 months of age in hApp NL‐F ‐hMAPT‐APOE4 mice compared to vehicle. hApp NL‐F ‐hMAPT‐APOE4 mice showed CPT deficits starting at 6 months under vehicle and mAb158, with no difference in performance between treatment groups. Preliminary analyses suggest mAb158 causes microhemorrhages. Conclusions Early mAb158 treatment reduces key Alzheimer's disease pathology but fails to prevent attention deficits in hApp NL‐F ‐hMAPT‐APOE4 mice and may increase microbleeds in this vulnerable group. By combining new generation mouse models of genetic AD risk with translational cognitive and imaging biomarkers, we propose a preclinical platform to better predict the safety and efficacy of monoclonal antibody treatments.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".