Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases
Abstract Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic...
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| Format: | Article |
| Language: | English |
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BMC
2024-10-01
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| Series: | Alzheimer’s Research & Therapy |
| Online Access: | https://doi.org/10.1186/s13195-024-01609-2 |
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| author | I. Hyun Ruisch Joanna Widomska Ward De Witte Nina R. Mota Giuseppe Fanelli Veerle Van Gils Willemijn J. Jansen Stephanie J. B. Vos Abel Fóthi Csaba Barta Simone Berkel Kazi A. Alam Aurora Martinez Jan Haavik Aet O’Leary David Slattery Mairéad Sullivan Jeffrey Glennon Jan K. Buitelaar Janita Bralten Barbara Franke Geert Poelmans |
| author_facet | I. Hyun Ruisch Joanna Widomska Ward De Witte Nina R. Mota Giuseppe Fanelli Veerle Van Gils Willemijn J. Jansen Stephanie J. B. Vos Abel Fóthi Csaba Barta Simone Berkel Kazi A. Alam Aurora Martinez Jan Haavik Aet O’Leary David Slattery Mairéad Sullivan Jeffrey Glennon Jan K. Buitelaar Janita Bralten Barbara Franke Geert Poelmans |
| author_sort | I. Hyun Ruisch |
| collection | DOAJ |
| description | Abstract Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments. |
| format | Article |
| id | doaj-art-ec15a71192f24d8aaffafb95a2cae7a1 |
| institution | OA Journals |
| issn | 1758-9193 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-ec15a71192f24d8aaffafb95a2cae7a12025-08-20T02:18:20ZengBMCAlzheimer’s Research & Therapy1758-91932024-10-0116111610.1186/s13195-024-01609-2Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseasesI. Hyun Ruisch0Joanna Widomska1Ward De Witte2Nina R. Mota3Giuseppe Fanelli4Veerle Van Gils5Willemijn J. Jansen6Stephanie J. B. Vos7Abel Fóthi8Csaba Barta9Simone Berkel10Kazi A. Alam11Aurora Martinez12Jan Haavik13Aet O’Leary14David Slattery15Mairéad Sullivan16Jeffrey Glennon17Jan K. Buitelaar18Janita Bralten19Barbara Franke20Geert Poelmans21Department of Cognitive Neuroscience, Radboud University Medical CenterDepartment of Cognitive Neuroscience, Radboud University Medical CenterDepartment of Cognitive Neuroscience, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht UniversityDepartment of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht UniversityDepartment of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht UniversityDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis UniversityDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis UniversityInstitute of Human Genetics, Heidelberg UniversityDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Psychiatry, University HospitalDepartment of Psychiatry, Psychosomatics and Psychotherapy, Goethe-UniversitätConway Institute of Biomedical and Biomolecular Research, School of Medicine, University College DublinConway Institute of Biomedical and Biomolecular Research, School of Medicine, University College DublinDepartment of Cognitive Neuroscience, Radboud University Medical CenterDepartment of Human Genetics, Radboud University Medical CenterDepartment of Cognitive Neuroscience, Radboud University Medical CenterDepartment of Cognitive Neuroscience, Radboud University Medical CenterAbstract Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.https://doi.org/10.1186/s13195-024-01609-2 |
| spellingShingle | I. Hyun Ruisch Joanna Widomska Ward De Witte Nina R. Mota Giuseppe Fanelli Veerle Van Gils Willemijn J. Jansen Stephanie J. B. Vos Abel Fóthi Csaba Barta Simone Berkel Kazi A. Alam Aurora Martinez Jan Haavik Aet O’Leary David Slattery Mairéad Sullivan Jeffrey Glennon Jan K. Buitelaar Janita Bralten Barbara Franke Geert Poelmans Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases Alzheimer’s Research & Therapy |
| title | Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases |
| title_full | Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases |
| title_fullStr | Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases |
| title_full_unstemmed | Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases |
| title_short | Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases |
| title_sort | molecular landscape of the overlap between alzheimer s disease and somatic insulin related diseases |
| url | https://doi.org/10.1186/s13195-024-01609-2 |
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