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Record W4412532565 · doi:10.1212/nxg.0000000000200266

Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition

2025· article· en· W4412532565 on OpenAlexfundno aff
Vijay K. Ramanan, Michael G. Heckman, Ekaterina I. Hofrenning, Scott A. Przybelski, Jonathan Graff‐Radford, Val J. Lowe, Mary M. Machulda, Melissa E. Murray, Alicia Algeciras‐Schimnich, Daniel J. Figdore, David A. Bennett, David S. Knopman, Clifford R. Jack, Ronald C. Petersen, Owen A. Ross, Prashanthi Vemuri

Bibliographic record

VenueNeurology Genetics · 2025
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicBioinformatics and Genomic Networks
Canadian institutionsnot available
FundersNational Institutes of HealthGenentechIXICOH. Lundbeck A/SServierEisaiCanadian Institutes of Health ResearchGHR FoundationNorthern California Institute for Research and EducationPfizerNovartis Pharmaceuticals CorporationMayo Foundation for Medical Education and ResearchUniversity of Southern CaliforniaMayo ClinicBiogenEli Lilly and CompanyBristol-Myers SquibbBioClinicaMeso Scale DiagnosticsNational Institute on AgingAlzheimer's Association
KeywordsDeposition (geology)Genetic heterogeneityBiologyAmyloid (mycology)Amyloid βGeneticsNeuroscienceMedicineInternal medicinePathologyPhenotypeDiseaseGenePaleontology

Abstract

fetched live from OpenAlex

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.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.

How this classification was reachedexpand

Full frame machine prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.

metaresearch head score (Codex)0.004
metaresearch head score (Gemma)0.013
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Simulation or modeling · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.006
Threshold uncertainty score0.023

Distilled classifier scores by category (both heads)

CategoryCodexGemma
Metaresearch0.0040.013
Meta-epidemiology (narrow)0.0010.000
Meta-epidemiology (broad)0.0010.001
Bibliometrics0.0020.002
Science and technology studies0.0010.001
Scholarly communication0.0010.001
Open science0.0010.001
Research integrity0.0010.001
Insufficient payload (model declined to judge)0.0020.000

Machine scores (provisional)

The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.

Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.

Opus teacher head0.009
GPT teacher head0.252
Teacher spread0.243 · how far apart the two teachers sit on this one work
Validation statusscore_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it

Classification

machine, unvalidated

Machine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.

The models applied no category: nothing in the taxonomy fit this work.
Study designSimulation or modeling
Domainnot available
GenreEmpirical

How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".

Quick stats

Citations2
Published2025
Admission routes1
Has abstractyes

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