Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition
Ge T, Sabuncu MR, Smoller JW, Sperling RA, Mormino EC, Alzheimer's Disease Neuroimaging Initiative.. Neurology, 2018-03-28
Topic: Amyloid, tau and blood-test diagnosis
Objective To investigate the effects of genetic risk of Alzheimer disease (AD) dementia in the context of β-amyloid (Aβ) accumulation. Methods We analyzed data from 702 participants (221 clinically normal, 367 with mild cognitive impairment, and 114 with AD dementia) with genetic data and florbetapir PET available. A subset of 669 participants additionally had longitudinal MRI scans to assess hippocampal volume. Polygenic risk scores (PRSs) were estimated with summary statistics from previous large-scale genome-wide association studies of AD dementia. We examined relationships between APOE ε4 status and PRS with longitudinal Aβ and cognitive and hippocampal volume measurements. Results APOE ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present. APOE ε4 was additionally related to greater memory decline and hippocampal atrophy in Aβ+ participants. When APOE ε4 was controlled for, PRS was related to cognitive decline in Aβ+ participants. Finally, PRSs were associated with hippocampal atrophy in Aβ- participants and weakly associated with baseline hippocampal volume in Aβ+ participants. Conclusions Genetic risk factors of AD dementia demonstrate effects related to Aβ, as well as synergistic interactions with Aβ. The specific effect of faster cognitive decline in Aβ+ individuals with higher genetic risk may explain the large degree of heterogeneity in cognitive trajectories among Aβ+ individuals. Consideration of genetic variants in conjunction with baseline Aβ may improve enrichment strategies for clinical trials targeting Aβ+ individuals most at risk for imminent cognitive decline.
Key findings
- Results APOE ε4 was strongly related to baseline Aβ, whereas only weak associations between PRS and baseline Aβ were present.
- Finally, PRSs were associated with hippocampal atrophy in Aβ- participants and weakly associated with baseline hippocampal volume in Aβ+ participants.
Why it matters
In 702 participants, APOE ε4 was strongly related to baseline amyloid and to memory decline and hippocampal shrinkage in those with amyloid, while a broader polygenic risk score showed only weak links to amyloid. This describes genetic influences on disease markers and does not test any treatment.
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Study details
- Study designlongitudinal study
- Participants702
- Evidence strengthModerate
How this study scored 64/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for effect reported and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 61 of the 96 points we could judge it on, which is 64 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A longitudinal study following the same people over 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 | 2 / 5 | 2018 — within 10 year(s) of the newest study here |
| Sample size | 2 / 4 | 702 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 | 4 / 7 | Cited 90 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 9.0 citations a year over 10 year(s) since 2018 |
| Impact for its field and year | 3 / 6 | Cited 7.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 22 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 29592889) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 61 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 61 of the 96 points we could judge it on is 64 out of 100. |
| Total | 64 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1212/wnl.0000000000005415
- PubMed: 29592889
- 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
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APA 7th
Ge, T., Sabuncu, M. R., Smoller, J. W., Sperling, R. A., Mormino, E. C., & Alzheimer's Disease Neuroimaging Initiative. (2018). Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition. Neurology. https://doi.org/10.1212/wnl.0000000000005415
Vancouver
Ge T, Sabuncu MR, Smoller JW, Sperling RA, Mormino EC, Alzheimer's Disease Neuroimaging Initiative. Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition. Neurology. 2018. doi:10.1212/wnl.0000000000005415. PMID: 29592889.
BibTeX
@article{ge2018-29592889,
author = {Ge, T. and Sabuncu, M. R. and Smoller, J. W. and Sperling, R. A. and Mormino, E. C. and {Alzheimer's Disease Neuroimaging Initiative}},
title = {{Dissociable influences of APOE ε4 and polygenic risk of AD dementia on amyloid and cognition}},
journal = {Neurology},
year = {2018},
doi = {10.1212/wnl.0000000000005415},
pmid = {29592889},
url = {https://doi.org/10.1212/wnl.0000000000005415}
}
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