Evidence map›Paper›PMID 36447297›Full record

ArticleActa neuropathologica communications2022

Methylation differences in Alzheimer's disease neuropathologic change in the aged human brain.

Anna-Lena Lang, Tiffany Eulalio, Eddie Fox, Koya Yakabi, Syed A Bukhari, Claudia H Kawas, Maria M Corrada, Stephen B Montgomery, Frank L Heppner, David Capper and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed, 2 pooled it
–field-weighted citation impact
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

17 citing papers in PubMed, 2 syntheses or guidelines pooled it.

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  12. bioRxiv : the preprint server for biology · 2024
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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

12 authors.

Anna-Lena LangDepartment of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany. annalena.lang.26@gmail.com.ORCID 0000-0002-4089-2678
Tiffany EulalioDepartment of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA.
Eddie FoxDepartment of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.
Koya YakabiDepartment of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.
Syed A BukhariDepartment of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.
Claudia H KawasDepartment of Neurology, University of California Irvine, Orange, CA, 92868-4280, USA.
Maria M CorradaDepartment of Neurology, University of California Irvine, Orange, CA, 92868-4280, USA.
Stephen B MontgomeryDepartment of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.
Frank L HeppnerDepartment of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
David CapperDepartment of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Daniel Nachun *Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
Thomas J Montine *Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA, 94305, USA.

Funding

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
Diversity Supplement to R01AG021055; Clinical, Imaging, and Pathological Studies in the Oldest Old: The 90+ StudyR01AG021055 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI CORRADA, MARIA, KAWAS, CLAUDIA H. · 2002 to 2024
$36.9M
The Alzheimer's Disease Research Center at the University of California, IrvineP30AG066519 · NIA · UNIVERSITY OF CALIFORNIA-IRVINE · PI Crystal M. Glover · 2020 to 2026
$27.9M
POSTDOCTORAL TRAINING IN MEDICAL INFORMATION SCIENCEST15LM007033 · NLM · STANFORD UNIVERSITY · PI SYLVIA KATINA PLEVRITIS · 1985 to 2026
$25.5M
Neuropathologic substrates for motor and cognitive impairment in three existing cohort studies of Alzheimer's disease and related dementiasUF1AG057707 · NIA · STANFORD UNIVERSITY · PI MONTINE, THOMAS J, WHITE, LON RAY · 2017 to 2017
$3.9M
Mapping Molecular and Phenotypic Interactions in Alzheimers DiseaseR01AG066490 · NIA · STANFORD UNIVERSITY · PI MONTGOMERY, STEPHEN · 2020 to 2024
$3.6M
Identifying causal genetic variants and molecular mechanisms impacting mental healthR01MH125244 · NIMH · STANFORD UNIVERSITY · PI KUNDAJE, ANSHUL, MONTGOMERY, STEPHEN · 2021 to 2025
$3.0M
NIA NIH HHS P30 AG066519NIA NIH HHS R01 AG021055NIA NIH HHS R01 AG066490NIA NIH HHS U24 AG021886NIA NIH HHS UF1 AG057707NIMH NIH HHS R01 MH125244NLM NIH HHS T15 LM007033
6 · The paper itself

Abstract

Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aβ) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aβ plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aβ peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases.

Indexed as

Alzheimer DiseaseAgedAged, 80 and overAmyloid beta-PeptidesBrainDNA MethylationHumansMiddle AgedNeuropathologyPlaque, AmyloidAmyloid beta-Peptides90 plusADAlzheimer’s diseaseBrainDeconvolutionGamma secretaseMethylationOld agePEN-2

Identifiers

PMID36447297
PMCPMC9710143

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Registered trials

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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.