APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations
Shinohara M, Kanekiyo T, Yang L, Linthicum D, Shinohara M, Fu Y, Price L, Frisch-Daiello JL et al.. Annals of neurology, 2016-03-29
Topic: Amyloid, tau and blood-test diagnosis
Objective Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified. Methods We reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology. Results Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease-related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3-TR or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms. Interpretation APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758-774.
Key findings
- Objective Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease.
- Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified.
- Results Clinically, the APOE2 allele was associated with less cognitive decline during aging.
- Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3-TR or apoE4-TR mice.
- These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms.
Why it matters
In a review of National Alzheimer's Coordinating Center records, the APOE2 gene variant was associated with less cognitive decline during aging, including in people with little amyloid and after adjusting for other Alzheimer's-related brain changes. In mice carrying human APOE genes, APOE2 animals kept better memory with age even though they showed similar or greater synaptic loss, inflammation and oxidative stress. Memory instead tracked how much apoE protein the animals had (highest with APOE2) and how much cholesterol was in the brain (lowest with APOE2), but these are associations, and the study does not show that changing either one protects memory.
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Study details
- Evidence strengthLow
How this study scored 48/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (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 | 2016 — 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 | 5 / 7 | Cited 110 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 9.2 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 3 / 6 | Cited 7.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 9 other studies in this library |
| Still being cited | 2 / 4 | Cited 28 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Guojun Bu: h-index 120 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26933942) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 48 / 100 | — |
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APA 7th
Shinohara, M., Kanekiyo, T., Yang, L., Linthicum, D., Fu, Y., Price, L., et al. (2016). APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Annals of neurology. https://doi.org/10.1002/ana.24628
Vancouver
Shinohara M, Kanekiyo T, Yang L, Linthicum D, Fu Y, Price L, et al. APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations. Annals of neurology. 2016. doi:10.1002/ana.24628. PMID: 26933942.
BibTeX
@article{shinohara2016-26933942,
author = {Shinohara, M. and Kanekiyo, T. and Yang, L. and Linthicum, D. and Fu, Y. and Price, L. and Frisch-Daiello, J. L. and others},
title = {{APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations}},
journal = {Annals of neurology},
year = {2016},
doi = {10.1002/ana.24628},
pmid = {26933942},
url = {https://doi.org/10.1002/ana.24628}
}
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