Topic: Brain proteins, microglia and lab models
Context Apolipoprotein E (APOE) genotype is the most influential Alzheimer disease (AD) risk factor after advanced age. The APOE4 alleles decrease and the APOE2 alleles increase age at onset of AD. Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions. This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD. Objective To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown. Design Cross-sectional. Setting Metropolitan university medical center. Participants Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE. Main outcome measures Calculated transverse relaxation rates, an indirect measure of white matter structural integrity, for late-myelinating frontal lobe white matter (Fwm) and early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and the genu (Gwm). Results The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm. Furthermore, APOE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in Swm. In Fwm and Gwm, APOE4+ individuals had a steeper slope of decline in relaxation rates with age than APOE2+ individuals; those with APOE3/3 alleles had an intermediate slope. Conclusions In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD. Combining APOE status with noninvasive measures of myelin breakdown may be useful in assessing treatment strategies for the primary prevention of AD.
Key findings
- Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions.
- This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD.
- Objective To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown.
- Results The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm.
- Conclusions In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD.
Why it matters
In a single MRI scan of 104 healthy people aged 55 to 75, older participants showed lower white-matter integrity (measured indirectly) in late-maturing frontal and corpus callosum regions, and this age-related drop was steepest in APOE4 carriers, intermediate in APOE3/3, and shallowest in APOE2 carriers; an early-maturing region showed no APOE difference. Because people were compared at one point in time rather than followed, this is an association, which the authors say "support[s] the hypothesis" that myelin breakdown "may contribute to age at onset of AD." No memory or dementia outcomes were measured.
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Study details
- Study designcross-sectional
- Participants104
- Evidence strengthLow
How this study scored 53/100
Published in a peer-reviewed journal, and it is a snapshot of people at one point in time. Scored zero for effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of general psychiatry) |
| Journal's citation record | 4 / 4 | Archives of General Psychiatry: journal h-index 543 (OpenAlex, 2026-10-29) |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| 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 | 2006 — older than 20 years, still counted |
| Sample size | 2 / 4 | 104 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 128 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.8 citations a year over 22 year(s) since 2006 |
| Impact for its field and year | 3 / 6 | Cited 5.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Jeffrey L. Cummings: h-index 175 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, Los Angeles: institution h-index 1,923 (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 16389198) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.
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
Bartzokis, G., Lu, P. H., Geschwind, D. H., Edwards, N., Mintz, J., & Cummings, J. L. (2006). Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Archives of general psychiatry. https://doi.org/10.1001/archpsyc.63.1.63
Vancouver
Bartzokis G, Lu PH, Geschwind DH, Edwards N, Mintz J, Cummings JL. Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Archives of general psychiatry. 2006. doi:10.1001/archpsyc.63.1.63. PMID: 16389198.
BibTeX
@article{bartzokis2006-16389198,
author = {Bartzokis, G. and Lu, P. H. and Geschwind, D. H. and Edwards, N. and Mintz, J. and Cummings, J. L.},
title = {{Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia}},
journal = {Archives of general psychiatry},
year = {2006},
doi = {10.1001/archpsyc.63.1.63},
pmid = {16389198},
url = {https://doi.org/10.1001/archpsyc.63.1.63}
}
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