APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer's disease
Hung C, Fertan E, Livesey FJ, Klenerman D, Patani R. Brain, 2024-07-05
Topic: Amyloid, tau and blood-test diagnosis
APP gene dosage is strongly associated with Alzheimer's disease (AD) pathogenesis. Genomic duplication of the APP locus leads to autosomal dominant early-onset AD. Individuals with Down syndrome (trisomy of chromosome 21) harbour three copies of the APP gene and invariably develop progressive AD with highly characteristic neuropathological features. Restoring expression of APP to the equivalent of that of two gene copies, or lower, is a rational therapeutic strategy, as it would restore physiological levels of neuronal APP protein without the potentially deleterious consequences of inadvertently inducing loss of APP function. Here we find that antisense oligonucleotides (ASOs) targeting APP are an effective approach to reduce APP protein levels and rescue endolysosome and autophagy dysfunction in APP duplication and Trisomy 21 human induced pluripotent stem cell (hiPSC)-derived cortical neurons. Importantly, using ultrasensitive single-aggregate imaging techniques, we show that APP targeting ASOs significantly reduce both intracellular and extracellular amyloid-β-containing aggregates. Our results highlight the potential of APP ASOs as a therapeutic approach for forms of AD caused by duplication of the APP gene, including monogenic AD and AD related to Down syndrome.
Key findings
- APP gene dosage is strongly associated with Alzheimer's disease (AD) pathogenesis.
- Importantly, using ultrasensitive single-aggregate imaging techniques, we show that APP targeting ASOs significantly reduce both intracellular and extracellular amyloid-β-containing aggregates.
- Our results highlight the potential of APP ASOs as a therapeutic approach for forms of AD caused by duplication of the APP gene, including monogenic AD and AD related to Down syndrome.
Why it matters
In human stem cell-derived neurons, antisense oligonucleotides targeting APP reduced APP protein levels, rescued endolysosome and autophagy dysfunction, and reduced amyloid-beta aggregates. These are laboratory cell results, and the approach is proposed only for forms of Alzheimer's caused by duplication of the APP gene, including Down syndrome-related Alzheimer's.
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Study details
- Evidence strengthPreliminary
How this study scored 52/100
Published in a leading specialty 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 free to read, so that was left out: it earned 51 of the 98 points we could judge it on, which is 52 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain) |
| Journal's citation record | 4 / 4 | Brain: journal h-index 503 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 2 / 5 | Rated “preliminary” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2024 — 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 | 4 / 7 | Cited 41 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 10.2 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 4 / 6 | Cited 9.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 40 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Rickie Patani: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38527856) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 51 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 51 of the 98 points we could judge it on is 52 out of 100. |
| Total | 52 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Hung, C., Fertan, E., Livesey, F. J., Klenerman, D., & Patani, R. (2024). APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer's disease. Brain. https://doi.org/10.1093/brain/awae092
Vancouver
Hung C, Fertan E, Livesey FJ, Klenerman D, Patani R. APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer's disease. Brain. 2024. doi:10.1093/brain/awae092. PMID: 38527856.
BibTeX
@article{hung2024-38527856,
author = {Hung, C. and Fertan, E. and Livesey, F. J. and Klenerman, D. and Patani, R.},
title = {{APP antisense oligonucleotides reduce amyloid-β aggregation and rescue endolysosomal dysfunction in Alzheimer's disease}},
journal = {Brain},
year = {2024},
doi = {10.1093/brain/awae092},
pmid = {38527856},
url = {https://doi.org/10.1093/brain/awae092}
}
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