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Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span
Jack CR, Wiste HJ, Weigand SD, Knopman DS, Vemuri P, Mielke MM, Lowe V, Senjem ML et al.. JAMA neurology, 2015-05-01
Topic: Amyloid, tau and blood-test diagnosis
Importance Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging. Objective To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old. Design, setting, and participants Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old. Main outcomes and measures Memory, HVa, and amyloid PET. Results Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P Conclusions and relevance Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.
Key findings
- Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.
- Results Overall, memory worsened from age 30 years through the 90s.
- Memory was worse in men than in women overall (P Conclusions and relevance Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not.
- In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not.
- Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.
Why it matters
In 1,246 cognitively normal people aged 30 to 95, all measured at one point in time at a single academic center, those in older age groups had poorer memory and smaller hippocampi, starting decades before the ages at which amyloid on PET scans rose (the median stayed low until about 70). Men had poorer memory and smaller hippocampi than women but no difference in amyloid, while APOE ε4 carriers had more amyloid from age 70 onward but not poorer memory or smaller hippocampi. The authors conclude that something other than amyloid drives memory and brain-structure decline in middle age; this compares age groups rather than following people over time, and it does not test any treatment.
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Study details
- Study designcross-sectional
- Participants1,246
- Evidence strengthLow
How this study scored 63/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (JAMA neurology) |
| Journal's citation record | 2 / 4 | JAMA Neurology: journal h-index 235 (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 | 2015 — within 20 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,246 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 | 6 / 7 | Cited 387 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 29.8 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 5 / 6 | Cited 30.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 35 other studies in this library |
| Still being cited | 3 / 4 | Cited 72 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Ronald Carl Petersen: h-index 209 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (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 25775353) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 63 / 100 | — |
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Read the original
- DOI: 10.1001/jamaneurol.2014.4821
- PubMed: 25775353
- 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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Jack, C. R., Wiste, H. J., Weigand, S. D., Knopman, D. S., Vemuri, P., Mielke, M. M., et al. (2015). Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span. JAMA neurology. https://doi.org/10.1001/jamaneurol.2014.4821
Vancouver
Jack CR, Wiste HJ, Weigand SD, Knopman DS, Vemuri P, Mielke MM, et al. Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span. JAMA neurology. 2015. doi:10.1001/jamaneurol.2014.4821. PMID: 25775353.
BibTeX
@article{jack2015-25775353,
author = {Jack, C. R. and Wiste, H. J. and Weigand, S. D. and Knopman, D. S. and Vemuri, P. and Mielke, M. M. and Lowe, V. and Senjem, M. L. and others},
title = {{Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span}},
journal = {JAMA neurology},
year = {2015},
doi = {10.1001/jamaneurol.2014.4821},
pmid = {25775353},
url = {https://doi.org/10.1001/jamaneurol.2014.4821}
}
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