Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition
Vijay K. Ramanan, Michael G. Heckman, Ekaterina I. Hofrenning, Scott A. Przybelski, Jonathan Graff‐Radford, Val J. Lowe, Mary M. Machulda, Melissa Erin Murray et al.. Neurology Genetics, 2025-07-21
Topic: Amyloid, tau and blood-test diagnosis
The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Ramanan, V. K., Heckman, M. G., Hofrenning, E. I., Przybelski, S. A., Graff‐Radford, J., Lowe, V. J., et al. (2025). Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition. Neurology Genetics. https://doi.org/10.1212/nxg.0000000000200266
Vancouver
Ramanan VK, Heckman MG, Hofrenning EI, Przybelski SA, Graff‐Radford J, Lowe VJ, et al. Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition. Neurology Genetics. 2025. doi:10.1212/nxg.0000000000200266. PMID: 40703204.
BibTeX
@article{ramanan2025-40703204,
author = {Ramanan, Vijay K. and Heckman, Michael G. and Hofrenning, Ekaterina I. and Przybelski, Scott A. and Graff‐Radford, Jonathan and Lowe, Val J. and Machulda, Mary M. and Murray, Melissa Erin and others},
title = {{Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition}},
journal = {Neurology Genetics},
year = {2025},
doi = {10.1212/nxg.0000000000200266},
pmid = {40703204},
url = {https://doi.org/10.1212/nxg.0000000000200266}
}
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Key findings
- The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology.
- However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis.
- Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association).
- We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults.
Why it matters
This study proposes that studying people who carry only the APOE ε3 form of the gene may reveal new genetic predictors of brain amyloid buildup. It has not yet reported any new predictors; it describes the rationale for a planned analysis.
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Study details
- Evidence strengthLow
How this study scored 33/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people 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 32 of the 96 points we could judge it on, which is 33 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurology Genetics) |
| Journal's citation record | 0 / 4 | Neurology Genetics: journal h-index 53 (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 | 4 / 5 | 2025 — within 3 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 | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 2 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 | 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 40703204) |
| Free to read | 2 / 2 | Free to read |
| Points | 32 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 32 of the 96 points we could judge it on is 33 out of 100. |
| Total | 33 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1212/nxg.0000000000200266
- PubMed: 40703204
- Original source →
- Free full text: Neurology Genetics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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