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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 OpenAlex
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

Why this work is in the frame

A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.

fundA Canadian funder is recorded on the work.
no affNo Canadian affiliation: this work is invisible to an affiliation-only frame.
No Canadian affiliation. An affiliation-only frame, the usual design, would never have seen this work. It is one of the works that make the case for inverting the frame.

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.

Full frame distilled prediction

Teacher imitation

Not calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.

metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: Bench or experimental
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.285
Threshold uncertainty score0.733

Codex and Gemma teacher scores by category

CategoryCodexGemma
Metaresearch0.0000.000
Meta-epidemiology (narrow)0.0000.000
Meta-epidemiology (broad)0.0000.000
Bibliometrics0.0000.000
Science and technology studies0.0000.000
Scholarly communication0.0000.000
Open science0.0000.000
Research integrity0.0000.000
Insufficient payload (model declined to judge)0.0000.000

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