Evidence map›Paper›PMID 36191742›Full record

ArticleNeurobiology of disease2022

Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities.

Yuriko Katsumata, Lincoln M Shade, Timothy J Hohman, Julie A Schneider, David A Bennett, Jose M Farfel, Alzheimer’s Disease Genetics Consortium, Walter A Kukull, David W Fardo, Peter T Nelson

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
33citing papers in PubMed, 2 pooled it
4.7field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

33 citing papers in PubMed, 2 syntheses or guidelines pooled it, 41 citations in OpenAlex.

  1. Pooled it
  2. Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Pooled it
  3. Review
  4. TMEM106B is a selective modulator of TDP-43 pathology in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
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  12. Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  13. Article
  14. Review
  15. Article
  16. Article
  17. Article
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  19. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 4 institutions in 1 country.

Yuriko KatsumataDepartment of Biostatistics, University of Kentucky, Lexington, KY, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Lincoln M ShadeDepartment of Biostatistics, University of Kentucky, Lexington, KY, USA.
Timothy J HohmanVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Julie A SchneiderDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Department of Pathology, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
David A BennettDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Department of Pathology, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Jose M FarfelDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Department of Pathology, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Alzheimer’s Disease Genetics Consortium
Walter A KukullDepartment of Epidemiology, University of Washington, Seattle, WA, USA.
David W FardoDepartment of Biostatistics, University of Kentucky, Lexington, KY, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Peter T NelsonSanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Pathology, University of Kentucky, Lexington, KY 40536, USA. Electronic address: peter.nelson@uky.edu.
University of Kentucky · USRush University Medical Center · USUniversity of Washington · USVanderbilt University Medical Center · US

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
Large Scale Genome SequencingU54HG003079 · NHGRI · WASHINGTON UNIVERSITY · PI DUTCHER, SUSAN K · 2004 to 2016
$445.7M
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3M
Project 1U19AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · PI MICHAEL W WEINER · 2016 to 2026
$226.7M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
TRIAL OF VALPROATE TO ATTENUATE THE PROGRESSION OF ADU01AG010483 · NIA · UNIVERSITY OF ROCHESTER · PI AISEN, PAUL S. · 1991 to 2012
$116.2M
VCID and Stroke in a Bi-racial National CohortU01NS041588 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI CUSHMAN, MARY, HOWARD, GEORGE · 2002 to 2022
$96.0M
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
ARIC Neurocognitive Study (ARIC-NCS) Renewal 2023-2028U01HL096812 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI JOSEF CORESH, THOMAS H MOSLEY · 2010 to 2026
$65.7M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
Medical Research CouncilNCATS NIH HHS TL1 TR001997NCI NIH HHS R01 CA129769NCRR NIH HHS UL1 RR029893NHGRI NIH HHS RC2 HG005605NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NHGRI NIH HHS U01 HG008657NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG003079NHGRI NIH HHS U54 HG003273NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201100005CNHLBI NIH HHS HHSN268201100005GNHLBI NIH HHS HHSN268201100005INHLBI NIH HHS HHSN268201100006CNHLBI NIH HHS HHSN268201100007CNHLBI NIH HHS HHSN268201100007INHLBI NIH HHS HHSN268201100008CNHLBI NIH HHS HHSN268201100008INHLBI NIH HHS HHSN268201100009CNHLBI NIH HHS HHSN268201100009INHLBI NIH HHS HHSN268201100010CNHLBI NIH HHS HHSN268201100011CNHLBI NIH HHS HHSN268201100011INHLBI NIH HHS HHSN268201100012CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI 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AG041718NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG048927NIA NIH HHS R01 AG049607NIA NIH HHS R01 AG054060NIA NIH HHS R01 AG054076NIA NIH HHS R01 AG057187NIA NIH HHS R01 AG061111NIA NIH HHS R01 AG067482NIA NIH HHS R01 AG079280NIA NIH HHS R21 AG061551NIA NIH HHS R37 AG015473NIA NIH HHS R56 AG051876NIA NIH HHS R56 AG057191NIA NIH HHS RC2 AG036502NIA NIH HHS RC2 AG036528NIA NIH HHS RC4 AG039085NIA NIH HHS RF1 AG015473NIA NIH HHS RF1 AG051504NIA NIH HHS RF1 AG054023NIA NIH HHS RF1 AG054052NIA NIH HHS RF1 AG054074NIA NIH HHS RF1 AG057519NIA NIH HHS RF1 AG058066NIA NIH HHS RF1 AG058267NIA NIH HHS T32 AG057461NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG010483NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG049505NIA NIH HHS U01 AG049506NIA NIH HHS U01 AG049507NIA NIH HHS U01 AG049508NIA NIH HHS U01 AG052409NIA NIH HHS U01 AG052410NIA NIH HHS U01 AG052411NIA NIH HHS U01 AG057659NIA NIH HHS U01 AG058589NIA NIH HHS U01 AG058635NIA NIH 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6 · The paper itself

Abstract

The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with "AD-type" (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans-e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies.

Indexed as

Alzheimer DiseaseGenome-Wide Association StudyHumansLDL-Receptor Related ProteinsMembrane ProteinsMembrane Transport ProteinsNerve Tissue ProteinsNeurofibrillary TanglesPlaque, AmyloidLDL-Receptor Related ProteinsMembrane ProteinsMembrane Transport ProteinsNerve Tissue ProteinsSORL1 protein, humanTMEM106B protein, humanABCA7APH1BHippocampal sclerosisNACCPLCG2PleiotropySNPTDP-43

Identifiers

PMID36191742
PMCPMC9641973
OpenAlexW4298127824

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.