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Deciphering the mechanism underlying late-onset Alzheimer disease
Krstic D, Knuesel I.. Nature reviews. Neurology, 2012-11-27
Topic: Amyloid, tau and blood-test diagnosis
Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD.
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APA 7th
Krstic, D., & Knuesel, I. (2013). Deciphering the mechanism underlying late-onset Alzheimer disease. Nature reviews. Neurology. https://doi.org/10.1038/nrneurol.2012.236
Vancouver
Krstic D, Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nature reviews. Neurology. 2013. doi:10.1038/nrneurol.2012.236. PMID: 23183882.
BibTeX
@article{krstic2013-23183882,
author = {Krstic, D. and Knuesel, I.},
title = {{Deciphering the mechanism underlying late-onset Alzheimer disease}},
journal = {Nature reviews. Neurology},
year = {2013},
doi = {10.1038/nrneurol.2012.236},
pmid = {23183882},
url = {https://doi.org/10.1038/nrneurol.2012.236}
}
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Key findings
- A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD.
- Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD.
- We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport.
- Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death.
Why it matters
This review proposes that the mechanism causing genetically determined Alzheimer's disease may not be the same as the mechanism causing late-onset Alzheimer's disease, and it suggests a role for chronic inflammation. It offers a hypothesis about late-onset disease but does not report a treatment, cure, or prevention.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, 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 (Nature reviews. Neurology) |
| Journal's citation record | 3 / 4 | Nature Reviews Neurology: journal h-index 269 (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 | 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 457 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 30.5 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 3 / 6 | Cited 4.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 11 other studies in this library |
| Still being cited | 2 / 4 | Cited 42 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Irène Knuesel: h-index 37 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Zurich: institution h-index 1,220 (OpenAlex) |
| Multi-centre 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 23183882) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 45 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/nrneurol.2012.236
- PubMed: 23183882
- Original source →
- Free full text: Nature Reviews Neurology →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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