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APOE -ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy
Sato K, Niimi Y, Ihara R, Suzuki K, Iwata A, Iwatsubo T.. Frontiers in dementia, 2024-01-15
Topic: Genetics and APOE
APOE -ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, APOE -ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the APOE -ε4 allele's risk for non-ARIA AEs during AD clinical trials. We used data from the Critical Path for Alzheimer's Disease (CPAD) from the placebo arm of randomized controlled trials (RCT) for AD treatment. We determined whether AEs were reported more frequently in APOE -ε4 carriers, quantifying with reporting odds ratio (ROR) using a mixed effect model. We also evaluated the association between ROR levels and the prior probability that an AE is symptomatic ARIA. We analyzed 6,313 patients with AD or mild cognitive impairment in 28 trials. Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: "delusion" (ROR = 4.133), "confusional state" (ROR = 1.419), "muscle spasms" (ROR = 9.849), "irritability" (ROR = 12.62), "sleep disorder" (ROR = 2.944), or "convulsion" (ROR = 13.00). However, none remained significant after adjusting for Mini-Mental State Examination scores. There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE -ε4 carriers. The influence of APOE -ε4 allele[s] on the clinicians' assessment of the likelihood of ARIA during safety monitoring in anti-amyloid beta monoclonal antibody treatment might be unchanged, thus maintaining the current level of awareness of clinicians of AEs.
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APA 7th
Sato, K., Niimi, Y., Ihara, R., Suzuki, K., Iwata, A., & Iwatsubo, T. (2023). APOE -ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy. Frontiers in dementia. https://doi.org/10.3389/frdem.2023.1320329
Vancouver
Sato K, Niimi Y, Ihara R, Suzuki K, Iwata A, Iwatsubo T. APOE -ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy. Frontiers in dementia. 2023. doi:10.3389/frdem.2023.1320329. PMID: 39081988.
BibTeX
@article{sato2023-39081988,
author = {Sato, K. and Niimi, Y. and Ihara, R. and Suzuki, K. and Iwata, A. and Iwatsubo, T.},
title = {{APOE -ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy}},
journal = {Frontiers in dementia},
year = {2023},
doi = {10.3389/frdem.2023.1320329},
pmid = {39081988},
url = {https://doi.org/10.3389/frdem.2023.1320329}
}
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Key findings
- APOE -ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis.
- Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: "delusion" (ROR = 4.133), "confusional state" (ROR = 1.419), "muscle spasms" (ROR = 9.849), "irritability" (ROR = 12.62), "sleep disorder" (ROR = 2.944), or "convulsion" (ROR = 13.00).
- However, none remained significant after adjusting for Mini-Mental State Examination scores.
- There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE -ε4 carriers.
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Study details
- Participants6,313
- Effect sizeOR = 4.133; OR = 1.419; OR = 9.849
- Evidence strengthHigh
How this study scored 66/100
Published in a peer-reviewed journal. Scored zero for study design and randomized / 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 multicenter collaboration, so those were left out: it earned 38 of the 58 points we could judge it on, which is 66 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Frontiers in dementia) |
| 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 | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2023 — within 6 year(s) of the newest study here |
| Sample size | 3 / 4 | 6,313 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39081988) |
| Free to read | 2 / 2 | Free to read |
| Points | 38 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 38 of the 58 points we could judge it on is 66 out of 100. |
| Total | 66 / 100 | — |
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