Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases
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.
Authors
- Kazi Asraful Alam (ORCID: https://orcid.org/0000-0001-5498-6977)
- Aurora Martı́nez (ORCID: https://orcid.org/0000-0003-1643-6506)
- Jeffrey Colm Glennon (ORCID: https://orcid.org/0000-0002-2371-0422)
- I. Hyun Ruisch (ORCID: https://orcid.org/0000-0002-4069-8509)
- Jan K. Buitelaar (ORCID: https://orcid.org/0000-0001-8288-7757)
- Stephanie J. B. Vos (ORCID: https://orcid.org/0000-0002-2045-9818)
- Nina Roth Mota (ORCID: https://orcid.org/0000-0003-3504-759X)
- Giuseppe Fanelli (ORCID: https://orcid.org/0000-0001-7930-563X)
- Joanna Widomska
- Simone Berkel (ORCID: https://orcid.org/0000-0002-5134-2217)
- Barbara Franke (ORCID: https://orcid.org/0000-0001-9254-7510)
- Aet O’Leary (ORCID: https://orcid.org/0000-0001-6783-4729)
- Jan Haavik (ORCID: https://orcid.org/0000-0001-7865-2808)
- Csaba Barta (ORCID: https://orcid.org/0000-0002-4350-8838)
- David A. Slattery (ORCID: https://orcid.org/0000-0001-8753-5005)
- Mairéad Sullivan (ORCID: https://orcid.org/0009-0003-3492-2898)
- Ábel Fóthi (ORCID: https://orcid.org/0000-0001-7398-9700)
- Willemijn J. Jansen (ORCID: https://orcid.org/0000-0001-9081-1496)
- Veerle van Gils (ORCID: https://orcid.org/0000-0001-8240-5367)
- Janita Bralten (ORCID: https://orcid.org/0000-0003-1440-8675)
- Geert Poelmans (ORCID: https://orcid.org/0000-0001-7039-6985)
- Ward De Witte (ORCID: https://orcid.org/0000-0001-6085-0400)
Institutions
- University College Dublin (IE)
- Semmelweis University (HU)
- Goethe University Frankfurt (DE)
- Radboud University Nijmegen (NL)
- Heidelberg University (DE)
- Haukeland University Hospital (NO)
- Radboud University Medical Center (NL)
- Maastricht University (NL)
- Institute of Biochemistry (HU)
- Radboud Institute for Molecular Life Sciences (NL)
- University Hospital Frankfurt (DE)
- University of Bergen (NO)
- University of Bologna (IT)
Publication Details
- Journal
- Alzheimer s Research & Therapy
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1186/s13195-024-01609-2
- Citations
- 7
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- Norges Forskningsråd
- National Institute on Aging