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Neuropathological alterations in Alzheimer disease
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT.. Cold Spring Harbor perspectives in medicine, 2011-09-01
Topic: Amyloid, tau and blood-test diagnosis
The neuropathological hallmarks of Alzheimer disease (AD) include "positive" lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and "negative" lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between "normal" aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.
Key findings
- The neuropathological hallmarks of Alzheimer disease (AD) include "positive" lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and "negative" lesions such as neuronal and synaptic loss.
- Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide.
- In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between "normal" aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline.
- Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.
Why it matters
This review of postmortem brain studies describes the hallmark changes of Alzheimer's disease: amyloid plaques, tangles and glial responses, plus loss of neurons and synapses. It reports that amyloid builds up mostly before memory and thinking problems begin, while tangles, neuron loss and "particularly synaptic loss" keep pace with cognitive decline, along a continuum from "normal" aging to dementia; brain imaging in living people has "largely validated" this picture. It summarises the basis for staging and diagnosis and is not a treatment, a test, or proof that amyloid causes the disease.
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Study details
- Study designcross-sectional
- Evidence strengthModerate
How this study scored 57/100
Published in a peer-reviewed journal, and it is a snapshot of people at one point in time. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 54 of the 94 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cold Spring Harbor perspectives in medicine) |
| Journal's citation record | 2 / 4 | Cold Spring Harbor Perspectives in Medicine: journal h-index 197 (OpenAlex, 2026-10-29) |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2011 — 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 | 7 / 7 | Cited 3,350 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 197.1 citations a year over 17 year(s) since 2011 |
| 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 | 4 / 6 | Cited by 94 other studies in this library |
| Still being cited | 4 / 4 | Cited 729 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Bradley T. Hyman: h-index 18 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22229116) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 54 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 54 of the 94 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1101/cshperspect.a006189
- PubMed: 22229116
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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.
APA 7th
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011). Neuropathological alterations in Alzheimer disease. Cold Spring Harbor perspectives in medicine. https://doi.org/10.1101/cshperspect.a006189
Vancouver
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harbor perspectives in medicine. 2011. doi:10.1101/cshperspect.a006189. PMID: 22229116.
BibTeX
@article{serranopozo2011-22229116,
author = {Serrano-Pozo, A. and Frosch, M. P. and Masliah, E. and Hyman, B. T.},
title = {{Neuropathological alterations in Alzheimer disease}},
journal = {Cold Spring Harbor perspectives in medicine},
year = {2011},
doi = {10.1101/cshperspect.a006189},
pmid = {22229116},
url = {https://doi.org/10.1101/cshperspect.a006189}
}
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