Evidence map›Paper›PMID 39608471›Full record

ArticleNeurobiology of disease2024

Charting the shared genetic architecture of Alzheimer's disease, cognition, and educational attainment, and associations with brain development.

Piotr Jaholkowski, Shahram Bahrami, Vera Fominykh, Guy F L Hindley, Markos Tesfaye, Pravesh Parekh, Nadine Parker, Tahir T Filiz, Kaja Nordengen, Espen Hagen and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neurobiology of disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–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

1 citing paper in PubMed.

  1. Article
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

23 authors.

Piotr JaholkowskiCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: p.p.jaholkowski@medisin.uio.no.
Shahram BahramiCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Vera FominykhCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Guy F L HindleyCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.
Markos TesfayeCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
Pravesh ParekhCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Nadine ParkerCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Tahir T FilizCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Kaja NordengenDepartment of Neurology, Oslo University Hospital, Oslo, Norway.
Espen HagenCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Elise KochCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Nora R BakkenCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Evgeniia FreiCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Viktoria BirkenæsCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Zillur RahmanCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Oleksandr FreiCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
Jan HaavikDepartment of Biomedicine, Faculty of Medicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
Srdjan DjurovicDepartment of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Anders M DaleDepartment of Radiology, University of California, San Diego, La Jolla, CA 92093, USA; Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
Olav B SmelandCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Kevin S O'ConnellCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Alexey A ShadrinCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway.
Ole A AndreassenCenter for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo and Oslo University Hospital, Oslo, Norway. Electronic address: ole.andreassen@medisin.uio.no.

Funding

OTA-21-015A Post-Acute Sequelae of SARS-CoV-2 Infection Initiative: NYU Langone Health Clinical Science Core, Data Resource Core, and PASC Biorepository CoreOT2HL161847 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI GROSS, RACHEL SHARON, HORWITZ, LEORA · 2021 to 2025
$651.0M
ABCD-USA Consortium: Data Analysis, Informatics and Resource CenterU24DA041123 · NIDA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ANDERS M DALE · 2015 to 2026
$51.5M
Healthy Brain and Child Development National Consortium Data Coordinating CenterU24DA055330 · NIDA · WASHINGTON UNIVERSITY · PI ANDERS M DALE, Damien A Fair · 2021 to 2026
$34.6M
The VETSA Longitudinal MRI Twin Study of Aging (VETSA MRI 4)R01AG076838 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ANDERS M DALE, Jeremy A Elman · 2022 to 2026
$8.7M
A Trans-Nordic Study of Extreme Major DepressionR01MH123724 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI PATRICK F SULLIVAN, Lu Yi · 2020 to 2026
$4.7M
3/7 Psychiatric Genomics Consortium: Advancing Discovery and ImpactR01MH124839 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI ANDREASSEN, OLE A, HUCKINS, LAURA MARIANNE · 2021 to 2025
$2.0M
NHLBI NIH HHS OT2 HL161847NIA NIH HHS R01 AG076838NIDA NIH HHS U24 DA041123NIDA NIH HHS U24 DA055330NIMH NIH HHS R01 MH123724NIMH NIH HHS R01 MH124839
6 · The paper itself

Abstract

The observation that the risk of developing Alzheimer's disease is reduced in individuals with high premorbid cognitive functioning, higher educational attainment, and occupational status has led to the 'cognitive reserve' hypothesis. This hypothesis suggests that individuals with greater cognitive reserve can tolerate a more significant burden of neuropathological changes before the onset of cognitive decline. The underpinnings of cognitive reserve remain poorly understood, although a shared genetic basis between measures of cognitive reserve and Alzheimer's disease has been suggested. Using the largest samples to date and novel statistical tools, we aimed to investigate shared genetic variants between Alzheimer's disease, and measures of cognitive reserve; cognition and educational attainment to identify molecular and neurobiological foundations. We applied the causal mixture model (MiXeR) to estimate the number of trait-influencing variants shared between Alzheimer's disease, cognition, and educational attainment, and condFDR/conjFDR to identify shared loci. To provide biological insights loci were functionally characterized. Subsequently, we constructed a Structural Equation Model (SEM) to determine if the polygenic foundation of cognition has a direct impact on Alzheimer's disease risk, or if its effect is mediated through established risk factors for the disease, using a case-control sample from the UK Biobank. Univariate MiXeR analysis (after excluding chromosome 19) revealed that Alzheimer's disease was substantially less polygenic (450 trait-influencing variants) compared to cognition (11,100 trait-influencing variants), and educational attainment (12,700 trait-influencing variants). Bivariate MiXeR analysis estimated that Alzheimer's disease shared approximately 70 % of trait-influencing variants with cognition, and approximately 40 % with educational attainment, with mixed effect directions. Using condFDR analysis, we identified 18 loci jointly associated with Alzheimer's disease and cognition and 6 loci jointly associated with Alzheimer's disease and educational attainment. Genes mapped to shared loci were associated with neurodevelopment, expressed in early life, and implicated the dendritic tree and phosphatidylinositol phosphate binding mechanisms. Spatiotemporal gene expression analysis of the identified genes showed that mapped genes were highly expressed during the mid-fetal period, further suggesting early neurodevelopmental stages as critical periods for establishing cognitive reserve which affect the risk of Alzheimer's disease in old age. Furthermore, our SEM analysis showed that genetic variants influencing cognition had a direct effect on the risk of developing Alzheimer's disease, providing evidence in support of the neurodevelopmental hypothesis of the disease.

Indexed as

Alzheimer DiseaseBrainCognitionCognitive ReserveEducational StatusAgedFemaleHumansMaleMultifactorial InheritanceAlzheimer's diseaseBrain developmentCognitionEducational attainmentGenetics/genomicsMiXeRNeurodevelopment

Identifiers

PMID39608471
PMCPMC12576965

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