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Targeting immunometabolic pathways for combination therapy in Alzheimer's disease
Erichsen J, Craft S.. Alzheimer's & dementia (New York, N. Y.), 2023-09-30
Topic: Gut, metabolism and diet
The recent success of disease-modifying anti-amyloid monoclonal antibodies in slowing Alzheimer's disease (AD) symptoms has been an exciting step forward for the field. Despite successfully clearing amyloid from the brain, however, only modest symptomatic improvement has been demonstrated, and treatment-related side effects such as amyloid-related imaging abnormalities (ARIA) limit use for some. These limitations suggest that fully efficacious AD treatment may require combination therapy regimens, as are used in other complex disorders such as cancer and HIV. One reasonable strategy may be to use agents that address the biological changes that predict future amyloid accumulation, or accompany amyloid accumulation in preclinical disease states. Immunometabolic pathways, including the insulin signaling pathway, are dysregulated at the earliest stages of AD, concomitant with amyloid accumulation. It is plausible that agents that target these pathways may work synergistically with anti-amyloid therapies to halt AD progression. Insulin signaling is integrally involved in innate and adaptive immune systems, with pleiotropic effects that moderate pro- and anti-inflammatory responses. Metabolic modulators that enhance insulin sensitivity and function, such as GLP-1 receptor agonists, SGLT2 inhibitors, and insulin itself have been shown to improve immune function and reduce chronic inflammation. Additional effects of insulin and metabolic modulators demonstrated in preclinical and clinical studies of AD include increased clearance of amyloid-β, slowed tau progression, improved vascular function and lipid metabolism, reduced synaptotoxicity, and improved cognitive and functional outcomes. A large number of compounds that treat metabolic disorders have been extensively characterized with respect to mechanism of action and safety, and thus are readily available to be repurposed for combination therapy protocols. Determining the most successful combination regimens of these agents together with disease-modifying therapies, and the appropriate timing of treatment, are promising next steps in the quest to treat and prevent AD.
Key findings
- Despite successfully clearing amyloid from the brain, however, only modest symptomatic improvement has been demonstrated, and treatment-related side effects such as amyloid-related imaging abnormalities (ARIA) limit use for some.
- These limitations suggest that fully efficacious AD treatment may require combination therapy regimens, as are used in other complex disorders such as cancer and HIV.
- Additional effects of insulin and metabolic modulators demonstrated in preclinical and clinical studies of AD include increased clearance of amyloid-β, slowed tau progression, improved vascular function and lipid metabolism, reduced synaptotoxicity, and improved cognitive and functional outcomes.
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Study details
- Evidence strengthLow
How this study scored 47/100
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 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 27 of the 58 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia (New York, N. Y.)) |
| 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 | 3 / 5 | 2023 — within 6 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 37786483) |
| Free to read | 2 / 2 | Free to read |
| Points | 27 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 27 of the 58 points we could judge it on is 47 out of 100. |
| Total | 47 / 100 | — |
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APA 7th
Erichsen, J., & Craft, S. (2023). Targeting immunometabolic pathways for combination therapy in Alzheimer's disease. Alzheimer's & dementia (New York, N. Y.). https://doi.org/10.1002/trc2.12423
Vancouver
Erichsen J, Craft S. Targeting immunometabolic pathways for combination therapy in Alzheimer's disease. Alzheimer's & dementia (New York, N. Y.). 2023. doi:10.1002/trc2.12423. PMID: 37786483.
BibTeX
@article{erichsen2023-37786483,
author = {Erichsen, J. and Craft, S.},
title = {{Targeting immunometabolic pathways for combination therapy in Alzheimer's disease}},
journal = {Alzheimer's \& dementia (New York, N. Y.)},
year = {2023},
doi = {10.1002/trc2.12423},
pmid = {37786483},
url = {https://doi.org/10.1002/trc2.12423}
}