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The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy
McGeer PL, McGeer EG.. Acta neuropathologica, 2013-09-20
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
The amyloid cascade hypothesis is widely accepted as the centerpiece of Alzheimer disease (AD) pathogenesis. It proposes that abnormal production of beta amyloid protein (Abeta) is the cause of AD and that the neurotoxicity is due to Abeta itself or its oligomeric forms. We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concentrations of these Abeta forms, while their levels in brain are a million times lower in the picomolar range. AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. Disease-modifying therapeutic attempts to date have failed and may continue to do so as long as the central role of inflammation is not taken into account. Multiple epidemiological and animal model studies show that NSAIDs, the most widely used antiinflammatory agents, have a substantial sparing effect on AD. These studies provide a proof of concept regarding the anti-inflammatory approach to disease modification. Biomarker studies have indicated that early intervention may be necessary. They have established that disease onset occurs more than a decade before it becomes clinically evident. By combining biomarker and pathological data, it is possible to define six phases of disease development, each separated by about 5 years. Phase one can be identified by decreases in Abeta in the CSF, phase 2 by increases of tau in the CSF plus clear evidence of Abeta brain deposits by PET scanning, phase 3 by slight decreases in brain metabolic rate by PET-FDG scanning, phase 4 by slight decreases in brain volume by MRI scanning plus minimal cognitive impairment, phase 5 by increased scanning abnormalities plus clinical diagnosis of AD, and phase 6 by advanced AD requiring institutional care. Utilization of antiinflammatory agents early in the disease process remains an overlooked therapeutic opportunity. Such agents, while not preventative, have the advantage of being able to inhibit the consequences of both Abeta and tau aggregation. Since there is more than a decade between disease onset and cognitive decline, a window of opportunity exists to introduce truly effective disease-modifying regimens. Taking advantage of this opportunity is the challenge for the future.
What this study adds
Evidence grade: Low
This is a trial. They also note biomarker evidence that the disease starts "more than a decade before it becomes clinically evident," so treatment may need to begin early.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
McGeer, P. L., & McGeer, E. G. (2013). The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta neuropathologica. https://doi.org/10.1007/s00401-013-1177-7
Vancouver
McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta neuropathologica. 2013. doi:10.1007/s00401-013-1177-7. PMID: 24052108.
BibTeX
@article{mcgeer2013-24052108,
author = {McGeer, P. L. and McGeer, E. G.},
title = {{The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy}},
journal = {Acta neuropathologica},
year = {2013},
doi = {10.1007/s00401-013-1177-7},
pmid = {24052108},
url = {https://doi.org/10.1007/s00401-013-1177-7}
}
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.
Key findings
- We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concentrations of these Abeta forms, while their levels in brain are a million times lower in the picomolar range.
- AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau.
- Biomarker studies have indicated that early intervention may be necessary.
Why it matters
This 2013 review argues that amyloid alone can't explain Alzheimer's: lab studies show amyloid is toxic only at "micromolar concentrations," while levels in the brain are "a million times lower." The authors propose instead that the brain's inflammatory response to amyloid deposits, later amplified by tau, "probably" drives the disease, and they cite population and animal studies linking anti-inflammatory NSAIDs to a "sparing effect" as proof of concept, which is not evidence from clinical trials. They also note biomarker evidence that the disease starts "more than a decade before it becomes clinically evident," so treatment may need to begin early.
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Study details
- Study designclinical trial
- Evidence strengthLow
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 randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | 3 / 4 | Acta Neuropathologica: journal h-index 287 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | Design recorded as “clinical trial”, which our rubric does not rank (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 | 1 / 5 | 2013 — within 20 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 467 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 31.1 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 5 / 6 | Cited 20.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 16 other studies in this library |
| Still being cited | 3 / 4 | Cited 78 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Edith G. McGeer: h-index 103 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of British Columbia: institution h-index 1,424 (OpenAlex) |
| Multicenter collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 24052108) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 52 / 100 | — |
What each of these 20 components measures, and what this score is not →
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