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Current advances and unmet needs in Alzheimer's disease trials for individuals with Down syndrome: Navigating new therapeutic frontiers
Isabel Barroeta, Laura Videla, María Carmona‐Iragui, Juan Fortea, Michael S. Rafii. Alzheimer s & Dementia, 2025-06-01
Topic: Amyloid, tau and blood-test diagnosis
Individuals with Down syndrome (DS) have a genetically determined form of Alzheimer's disease (AD) due to the amyloid precursor protein (APP) gene dose effect. Nearly all individuals with DS develop AD pathology by age 40. Although dementia is rare before this age, its incidence rises sharply thereafter. Longitudinal studies estimate a lifetime dementia risk exceeding 90%, with prevalence reaching 88%-100% after age 65-a marked contrast to 10%-15% in the general population. Recent breakthroughs in sporadic AD, including anti-amyloid therapies such as lecanemab and donanemab, have shown efficacy in slowing progression. However, individuals with DS were excluded from these trials, leaving critical gaps in safety and efficacy data. This perspective highlights the current state of AD clinical trials in DS, key challenges-(including ethical considerations, recruitment barriers, and cognitive assessment adaptations), and emerging research efforts. Addressing these gaps is essential to ensure equitable access to disease-modifying therapies for individuals with DS. HIGHLIGHTS: Despite recent progress in Alzheimer's disease (AD) treatments for the general population-particularly monoclonal anti-amyloid therapies such as lecanemab and donanemab-individuals with Down syndrome (DS) were excluded from pivotal trials, leaving significant gaps in knowledge regarding safety and efficacy. A key concern in DS is the heightened risk of amyloid-related imaging abnormalities (ARIAs), a known side effect of anti-amyloid therapies, which may be aggravated by the increased prevalence and severity of cerebral amyloid angiopathy (CAA) in this population. For the first time, growing awareness of the nearly universal AD risk in DS is driving a stronger focus on tailored clinical research. Ongoing and forthcoming studies, including TRC-DS, ABATE, HERO, ALADDIN, and LESS-AD, are beginning to address these gaps. Beyond amyloid-targeting therapies, investigating alternative mechanisms such as tau pathology, neuroinflammation, and synaptic dysfunction is key to advancing treatments for DS-related AD. Collaboration between advocacy groups, researchers, and pharmaceutical companies is essential for overcoming barriers in AD clinical trials for DS, including ethical concerns, recruitment challenges, and the need for adapted cognitive assessments. This perspective also proposes strategies to enhance inclusivity in future studies, ensuring broader access to emerging treatments.
Key findings
- HIGHLIGHTS: Despite recent progress in Alzheimer's disease (AD) treatments for the general population-particularly monoclonal anti-amyloid therapies such as lecanemab and donanemab-individuals with Down syndrome (DS) were excluded from pivotal trials, leaving significant gaps in knowledge regarding safety and efficacy.
Why it matters
This perspective notes that people with Down syndrome, who have a genetically determined form of Alzheimer's disease, were excluded from pivotal trials of anti-amyloid therapies such as lecanemab and donanemab. It highlights gaps in safety and efficacy data for this group rather than reporting a treatment, cure or prevention.
Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 55/100
Published in a peer-reviewed journal, and it is a longitudinal study following the same people over time. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 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 | 3 / 7 | Cited 16 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 8.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 16 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Michael S. Rafii: h-index 50 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Southern California: institution h-index 1,521 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40528298) |
| Free to read | 2 / 2 | Free to read |
| Total | 55 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Barroeta, I., Videla, L., Carmona‐Iragui, M., Fortea, J., & Rafii, M. S. (2025). Current advances and unmet needs in Alzheimer's disease trials for individuals with Down syndrome: Navigating new therapeutic frontiers. Alzheimer s & Dementia. https://doi.org/10.1002/alz.70258
Vancouver
Barroeta I, Videla L, Carmona‐Iragui M, Fortea J, Rafii MS. Current advances and unmet needs in Alzheimer's disease trials for individuals with Down syndrome: Navigating new therapeutic frontiers. Alzheimer s & Dementia. 2025. doi:10.1002/alz.70258. PMID: 40528298.
BibTeX
@article{barroeta2025-40528298,
author = {Barroeta, Isabel and Videla, Laura and Carmona‐Iragui, María and Fortea, Juan and Rafii, Michael S.},
title = {{Current advances and unmet needs in Alzheimer's disease trials for individuals with Down syndrome: Navigating new therapeutic frontiers}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz.70258},
pmid = {40528298},
url = {https://doi.org/10.1002/alz.70258}
}
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