Oxidative damage is the earliest event in Alzheimer disease
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H et al.. Journal of neuropathology and experimental neurology, 2001-08-01
Topic: Amyloid, tau and blood-test diagnosis
Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.
Key findings
- Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD).
- Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression.
- Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage.
- These relationships are more significant in ApoE epsilon4 carriers.
- Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT.
Why it matters
In brain neurons from people with Alzheimer's disease, two markers of oxidative damage were highest early in the disease and lower with longer illness and more plaques and tangles; neurons with tangles had 40%–56% lower relative levels of oxidised RNA (8OHG) than tangle-free neurons. Unexpectedly, more amyloid deposition was associated with less oxidative damage, especially in ApoE ε4 carriers, which the authors suggest may reflect compensatory changes. These are associations from a single measurement per person, so they do not show that oxidative damage causes Alzheimer's or that antioxidants would prevent or treat it.
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Study details
- Evidence strengthLow
How this study scored 52/100
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 (Journal of neuropathology and experimental neurology) |
| Journal's citation record | 2 / 4 | Journal of Neuropathology & Experimental Neurology: journal h-index 239 (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 | 2001 — older than 20 years, still counted |
| 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 / 7 | Cited 1,886 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 69.9 citations a year over 27 year(s) since 2001 |
| Impact for its field and year | 5 / 6 | Cited 30.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 49 other studies in this library |
| Still being cited | 3 / 4 | Cited 126 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Mark A. Smith: h-index 38 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Case Western Reserve University: institution h-index 1,159 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 11487050) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 52 / 100 | — |
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Read the original
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APA 7th
Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., et al. (2001). Oxidative damage is the earliest event in Alzheimer disease. Journal of neuropathology and experimental neurology. https://doi.org/10.1093/jnen/60.8.759
Vancouver
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. Journal of neuropathology and experimental neurology. 2001. doi:10.1093/jnen/60.8.759. PMID: 11487050.
BibTeX
@article{nunomura2001-11487050,
author = {Nunomura, A. and Perry, G. and Aliev, G. and Hirai, K. and Takeda, A. and Balraj, E. K. and Jones, P. K. and Ghanbari, H. and others},
title = {{Oxidative damage is the earliest event in Alzheimer disease}},
journal = {Journal of neuropathology and experimental neurology},
year = {2001},
doi = {10.1093/jnen/60.8.759},
pmid = {11487050},
url = {https://doi.org/10.1093/jnen/60.8.759}
}
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