Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4
Olichney JM, Hansen LA, Hofstetter CR, Lee JH, Katzman R, Thal LJ.. Archives of neurology, 2000-06-01
Topic: Amyloid, tau and blood-test diagnosis
Background We have previously reported an association between severe cerebral amyloid angiopathy (CAA) and cerebrovascular lesions in Alzheimer disease (AD), which is particularly strong for microinfarcts, hemorrhages, and multiple lesion types. Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 (APOE4) genotype, which is in turn associated with premature coronary artery disease and atherosclerosis. Objective To test whether severe CAA would be more strongly associated with cerebrovascular lesions than would APOE4 genotype. Methods We reviewed 306 cases of autopsy-confirmed AD (from the University of California, San Diego, brain autopsy series) to assess whether APOE genotype and other clinical risk factors were predictive of vascular lesions (VLs) in AD. Cerebral amyloid angiopathy severity was assessed using a semiquantitative scale in 4 brain regions (ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex) and an average score was computed for each case. Results We found that severe CAA was associated with an increased frequency of VLs (33% of the cases of severe CAA had VLs vs 19% of the cases of mild or absent CAA; P=.02). While the APOE4/4 genotype was associated with an increased severity of CAA, there was no significant relationship between APOE genotype and frequency of VLs. Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects. Within strata of APOE genotype, the presence of severe CAA was associated with increased frequency of VLs (eg, within APOE4/4 homozygotes, VLs were present within 47% of the cases of severe CAA vs 9.5% of the cases of mild or absent CAA; P=.01). Conclusions Severe CAA confers a greater risk of VLs in AD, even within strata of APOE genotype. Therefore, the association between severe CAA and VLs in AD is not a spurious one owing to APOE4. Overall, our cases of AD with APOE4 do not seem to be a more "vasculopathic" subtype of AD. The mechanisms by which CAA produces VLs of various types need to be further elucidated, as these are probably important in producing the common entity of "mixed" AD/vascular dementia. Arch Neurol. 2000.
Key findings
- Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 (APOE4) genotype, which is in turn associated with premature coronary artery disease and atherosclerosis.
- Objective To test whether severe CAA would be more strongly associated with cerebrovascular lesions than would APOE4 genotype.
- Results We found that severe CAA was associated with an increased frequency of VLs (33% of the cases of severe CAA had VLs vs 19% of the cases of mild or absent CAA; P=.02).
- While the APOE4/4 genotype was associated with an increased severity of CAA, there was no significant relationship between APOE genotype and frequency of VLs.
- Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects.
Why it matters
In 306 autopsy-confirmed Alzheimer's cases from the UC San Diego brain series, vascular lesions were found in 33% of brains with severe cerebral amyloid angiopathy versus 19% with mild or no CAA, and the gap persisted within APOE genotype groups (47% vs 9.5% among APOE4/4 carriers). The authors conclude the CAA–lesion link "is not a spurious one owing to APOE4," and they point to it as relevant to "mixed" Alzheimer's/vascular dementia. This is an after-death association study; it does not show cause or test any treatment.
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Study details
- Effect size9.5%
- Evidence strengthLow
How this study scored 49/100
Published in a peer-reviewed journal. Scored zero for study design, sample size and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of neurology) |
| Journal's citation record | 3 / 4 | Archives of Neurology: journal h-index 353 (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 | 2000 — 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 | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 108 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.9 citations a year over 28 year(s) since 2000 |
| Impact for its field and year | 2 / 6 | Cited 2.2× 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 | 1 / 4 | Cited 12 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Leon J. Thal: h-index 90 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California San Diego: institution h-index 1,852 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 10867785) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 49 / 100 | — |
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APA 7th
Olichney, J. M., Hansen, L. A., Hofstetter, C. R., Lee, J. H., Katzman, R., & Thal, L. J. (2000). Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4. Archives of neurology. https://doi.org/10.1001/archneur.57.6.869
Vancouver
Olichney JM, Hansen LA, Hofstetter CR, Lee JH, Katzman R, Thal LJ. Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4. Archives of neurology. 2000. doi:10.1001/archneur.57.6.869. PMID: 10867785.
BibTeX
@article{olichney2000-10867785,
author = {Olichney, J. M. and Hansen, L. A. and Hofstetter, C. R. and Lee, J. H. and Katzman, R. and Thal, L. J.},
title = {{Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4}},
journal = {Archives of neurology},
year = {2000},
doi = {10.1001/archneur.57.6.869},
pmid = {10867785},
url = {https://doi.org/10.1001/archneur.57.6.869}
}
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