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Genetic evidence for a causal relationship between 179 lipid species and cognitive function and alzheimer's disease: a bidirectional Mendelian randomization study.

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Τίτλος: Genetic evidence for a causal relationship between 179 lipid species and cognitive function and alzheimer's disease: a bidirectional Mendelian randomization study.
Συγγραφείς: Sun Y; Shandong University of Traditional Chinese Medicine, Jinan, China., Meng D; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China., Yu H; Weifang Hospital of Traditional Chinese Medicine, Weifang, China., Yin G; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China., Zhang X; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China., Yu W; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China., Liu H; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China., Jiang W; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China., Zhang F; Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 250011, Jinan, People's Republic of China. fxzhang0987@163.com.
Πηγή: European archives of psychiatry and clinical neuroscience [Eur Arch Psychiatry Clin Neurosci] 2026 Aug; Vol. 276 (5), pp. 2279-2288. Date of Electronic Publication: 2025 Nov 08.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer International Country of Publication: Germany NLM ID: 9103030 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1433-8491 (Electronic) Linking ISSN: 09401334 NLM ISO Abbreviation: Eur Arch Psychiatry Clin Neurosci Subsets: MEDLINE
Imprint Name(s): Original Publication: Berlin ; New York : Springer International, c1990-
Ιατρικοί όροι (MeSH): Alzheimer Disease*/genetics , Alzheimer Disease*/metabolism , Cognitive Dysfunction*/genetics , Lipids*/genetics , Mendelian Randomization Analysis*, Humans ; Genome-Wide Association Study
Περίληψη: The public health burden of cognitive decline escalates with population aging. While lipid species alterations are associated with cognitive function and Alzheimer's disease (AD), causal evidence remains limited. We applied two-sample Mendelian randomization (TSMR) and Bayesian-weighted MR (BWMR) to investigate the causal effects of lipid species on cognitive function and to assess the bidirectional causal relationships between lipid species and AD. We analyzed genome-wide association study (GWAS) data from large-scale cohorts: AD (East African Development Bank [EADB], N = 487,511); cognitive function (UK Biobank, N = 20,346); and lipid species (THL Biobank, N = 7,174). Analyses were conducted using multiple MR methods, including inverse variance weighting (IVW), BWMR, MR-Egger regression, and false discovery rate (FDR) correction. Sensitivity analyses-MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), Cochran's Q test, and leave-one-out analysis-were conducted to evaluate horizontal pleiotropy and heterogeneity. TSMR results identified 51 lipid species with causal associations for cognitive function and AD, among which 27 showed protective effects. Conversely, AD was found to influence 17 lipid species, with 14 exhibiting negative effects. These genetically supported findings highlight potential lipid-related targets for preventive and therapeutic interventions aimed at combating cognitive decline.
(© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)
Competing Interests: Declarations. Conflict of interest: The authors declare that the research was conducted independently, without any affiliations or financial relationships that could be perceived as potential conflicts of interest. This declaration underscores the integrity of the research process, ensuring that the findings and conclusions are based solely on the data collected and analyzed, free from external commercial influences. Such transparency is essential in academic research, as it maintains the credibility and objectivity of the study, enabling readers to trust the validity of the results presented. Ethical approval and consent to participate: All participants in the study provided informed consent in accordance with protocols approved by the Sardinian Regional Ethics Committee (protocol no. 2171/CE). Additionally, each included study was sanctioned by local ethics committees, ensuring adherence to ethical standards throughout the research. Participants were required to provide written informed consent, and consent was also obtained from their legally authorized representatives (LARs). This rigorous adherence to ethical considerations was fundamental to maintaining the integrity of the study. Furthermore, the research was conducted in compliance with relevant guidelines and regulations, which were meticulously followed throughout the process. It is important to note that this analysis is based on published genome-wide association study (GWAS) data. For further details, such as clinical trial numbers associated with these GWAS findings, this information can be accessed by reviewing the original research publications or by directly contacting the original investigators involved in the studies. Consent to publish: The authors agree to publication. This manuscript has not been published in any journals.
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Protein Cell. 2018 Feb;9(2):196-206. (PMID: 28523433)
PLoS One. 2016 Apr 25;11(4):e0154222. (PMID: 27110937)
PLoS Genet. 2021 Nov 18;17(11):e1009922. (PMID: 34793444)
JAMA. 2021 Oct 26;326(16):1614-1621. (PMID: 34698778)
Front Cell Neurosci. 2018 Oct 25;12:380. (PMID: 30410436)
Front Cell Dev Biol. 2020 Nov 24;8:580599. (PMID: 33330456)
Nature. 1984 Nov 22-28;312(5992):315-21. (PMID: 6095092)
Prog Lipid Res. 2012 Jan;51(1):23-35. (PMID: 22142854)
Front Physiol. 2013 Jul 16;4:168. (PMID: 23882219)
Prog Lipid Res. 2016 Apr;62:75-92. (PMID: 26875545)
Brain Res Rev. 2006 Sep;52(2):201-43. (PMID: 16647138)
Biochem Biophys Res Commun. 2019 May 21;513(1):201-206. (PMID: 30952426)
CNS Drug Rev. 2004 Summer;10(2):127-46. (PMID: 15179443)
Biophys J. 2014 Feb 4;106(3):631-8. (PMID: 24507603)
Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: 26050253)
J Lipid Res. 2020 May;61(5):636-654. (PMID: 31871065)
Int J Mol Sci. 2025 Jul 25;26(15):. (PMID: 40806341)
Nat Commun. 2023 Oct 31;14(1):6934. (PMID: 37907536)
Plant Physiol. 2017 Jul;174(3):1517-1530. (PMID: 28572457)
Stat Med. 2016 Feb 20;35(4):485-95. (PMID: 26303773)
JAMA. 2017 Nov 21;318(19):1925-1926. (PMID: 29164242)
Biomolecules. 2024 Oct 26;14(11):. (PMID: 39595539)
Grant Information: No.81573945 National Natural Science Foundation of China; No.ZR2021MH054 Natural Science Foundation of Shandong Province
Contributed Indexing: Keywords: Alzheimer's disease; Bayesian weighted mendelian randomization; Causal relationship; Cognitive function; Lipid species; Two-sample mendelian randomization
Substance Nomenclature: 0 (Lipids)
Entry Date(s): Date Created: 20251108 Date Completed: 20260818 Latest Revision: 20261008
Update Code: 20261008
DOI: 10.1007/s00406-025-02152-3
PMID: 41205072
Βάση Δεδομένων: MEDLINE
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  Data: Genetic evidence for a causal relationship between 179 lipid species and cognitive function and alzheimer's disease: a bidirectional Mendelian randomization study.
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  Data: <searchLink fieldCode="AU" term="%22Sun+Y%22">Sun Y</searchLink>; Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Meng+D%22">Meng D</searchLink>; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Yu+H%22">Yu H</searchLink>; Weifang Hospital of Traditional Chinese Medicine, Weifang, China.<br /><searchLink fieldCode="AU" term="%22Yin+G%22">Yin G</searchLink>; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Zhang+X%22">Zhang X</searchLink>; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Yu+W%22">Yu W</searchLink>; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Liu+H%22">Liu H</searchLink>; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Jiang+W%22">Jiang W</searchLink>; First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.<br /><searchLink fieldCode="AU" term="%22Zhang+F%22">Zhang F</searchLink>; Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 250011, Jinan, People's Republic of China. fxzhang0987@163.com.
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  Data: The public health burden of cognitive decline escalates with population aging. While lipid species alterations are associated with cognitive function and Alzheimer's disease (AD), causal evidence remains limited. We applied two-sample Mendelian randomization (TSMR) and Bayesian-weighted MR (BWMR) to investigate the causal effects of lipid species on cognitive function and to assess the bidirectional causal relationships between lipid species and AD. We analyzed genome-wide association study (GWAS) data from large-scale cohorts: AD (East African Development Bank [EADB], N = 487,511); cognitive function (UK Biobank, N = 20,346); and lipid species (THL Biobank, N = 7,174). Analyses were conducted using multiple MR methods, including inverse variance weighting (IVW), BWMR, MR-Egger regression, and false discovery rate (FDR) correction. Sensitivity analyses-MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), Cochran's Q test, and leave-one-out analysis-were conducted to evaluate horizontal pleiotropy and heterogeneity. TSMR results identified 51 lipid species with causal associations for cognitive function and AD, among which 27 showed protective effects. Conversely, AD was found to influence 17 lipid species, with 14 exhibiting negative effects. These genetically supported findings highlight potential lipid-related targets for preventive and therapeutic interventions aimed at combating cognitive decline.<br /> (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)
– Name: Abstract
  Label: Competing Interests
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  Data: Declarations. Conflict of interest: The authors declare that the research was conducted independently, without any affiliations or financial relationships that could be perceived as potential conflicts of interest. This declaration underscores the integrity of the research process, ensuring that the findings and conclusions are based solely on the data collected and analyzed, free from external commercial influences. Such transparency is essential in academic research, as it maintains the credibility and objectivity of the study, enabling readers to trust the validity of the results presented. Ethical approval and consent to participate: All participants in the study provided informed consent in accordance with protocols approved by the Sardinian Regional Ethics Committee (protocol no. 2171/CE). Additionally, each included study was sanctioned by local ethics committees, ensuring adherence to ethical standards throughout the research. Participants were required to provide written informed consent, and consent was also obtained from their legally authorized representatives (LARs). This rigorous adherence to ethical considerations was fundamental to maintaining the integrity of the study. Furthermore, the research was conducted in compliance with relevant guidelines and regulations, which were meticulously followed throughout the process. It is important to note that this analysis is based on published genome-wide association study (GWAS) data. For further details, such as clinical trial numbers associated with these GWAS findings, this information can be accessed by reviewing the original research publications or by directly contacting the original investigators involved in the studies. Consent to publish: The authors agree to publication. This manuscript has not been published in any journals.
– Name: Ref
  Label: References
  Group: RefInfo
  Data: Stat Med. 2017 May 20;36(11):1783-1802. (PMID: <searchLink fieldCode="PM" term="%2228114746%22">28114746)</searchLink><br />Protein Cell. 2018 Feb;9(2):196-206. (PMID: <searchLink fieldCode="PM" term="%2228523433%22">28523433)</searchLink><br />PLoS One. 2016 Apr 25;11(4):e0154222. (PMID: <searchLink fieldCode="PM" term="%2227110937%22">27110937)</searchLink><br />PLoS Genet. 2021 Nov 18;17(11):e1009922. (PMID: <searchLink fieldCode="PM" term="%2234793444%22">34793444)</searchLink><br />JAMA. 2021 Oct 26;326(16):1614-1621. (PMID: <searchLink fieldCode="PM" term="%2234698778%22">34698778)</searchLink><br />Front Cell Neurosci. 2018 Oct 25;12:380. (PMID: <searchLink fieldCode="PM" term="%2230410436%22">30410436)</searchLink><br />Front Cell Dev Biol. 2020 Nov 24;8:580599. (PMID: <searchLink fieldCode="PM" term="%2233330456%22">33330456)</searchLink><br />Nature. 1984 Nov 22-28;312(5992):315-21. (PMID: <searchLink fieldCode="PM" term="%226095092%22">6095092)</searchLink><br />Prog Lipid Res. 2012 Jan;51(1):23-35. (PMID: <searchLink fieldCode="PM" term="%2222142854%22">22142854)</searchLink><br />Front Physiol. 2013 Jul 16;4:168. (PMID: <searchLink fieldCode="PM" term="%2223882219%22">23882219)</searchLink><br />Prog Lipid Res. 2016 Apr;62:75-92. (PMID: <searchLink fieldCode="PM" term="%2226875545%22">26875545)</searchLink><br />Brain Res Rev. 2006 Sep;52(2):201-43. (PMID: <searchLink fieldCode="PM" term="%2216647138%22">16647138)</searchLink><br />Biochem Biophys Res Commun. 2019 May 21;513(1):201-206. (PMID: <searchLink fieldCode="PM" term="%2230952426%22">30952426)</searchLink><br />CNS Drug Rev. 2004 Summer;10(2):127-46. (PMID: <searchLink fieldCode="PM" term="%2215179443%22">15179443)</searchLink><br />Biophys J. 2014 Feb 4;106(3):631-8. (PMID: <searchLink fieldCode="PM" term="%2224507603%22">24507603)</searchLink><br />Int J Epidemiol. 2015 Apr;44(2):512-25. (PMID: <searchLink fieldCode="PM" term="%2226050253%22">26050253)</searchLink><br />J Lipid Res. 2020 May;61(5):636-654. (PMID: <searchLink fieldCode="PM" term="%2231871065%22">31871065)</searchLink><br />Int J Mol Sci. 2025 Jul 25;26(15):. (PMID: <searchLink fieldCode="PM" term="%2240806341%22">40806341)</searchLink><br />Nat Commun. 2023 Oct 31;14(1):6934. (PMID: <searchLink fieldCode="PM" term="%2237907536%22">37907536)</searchLink><br />Plant Physiol. 2017 Jul;174(3):1517-1530. (PMID: <searchLink fieldCode="PM" term="%2228572457%22">28572457)</searchLink><br />Stat Med. 2016 Feb 20;35(4):485-95. (PMID: <searchLink fieldCode="PM" term="%2226303773%22">26303773)</searchLink><br />JAMA. 2017 Nov 21;318(19):1925-1926. (PMID: <searchLink fieldCode="PM" term="%2229164242%22">29164242)</searchLink><br />Biomolecules. 2024 Oct 26;14(11):. (PMID: <searchLink fieldCode="PM" term="%2239595539%22">39595539)</searchLink>
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