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Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease
Sharma A, Singh TG.. Brain research, 2025-11-13
Topic: Amyloid, tau and blood-test diagnosis
Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation via anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies-especially dual Aβ/tau targeting-demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood-brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.
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APA 7th
Sharma, A., & Singh, T. G. (2026). Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease. Brain research. https://doi.org/10.1016/j.brainres.2025.150047
Vancouver
Sharma A, Singh TG. Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease. Brain research. 2026. doi:10.1016/j.brainres.2025.150047. PMID: 41241266.
BibTeX
@article{sharma2026-41241266,
author = {Sharma, A. and Singh, T. G.},
title = {{Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease}},
journal = {Brain research},
year = {2026},
doi = {10.1016/j.brainres.2025.150047},
pmid = {41241266},
url = {https://doi.org/10.1016/j.brainres.2025.150047}
}
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Key findings
- Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations.
- Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Brain research) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41241266) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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