Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis

Erwin Lemche; Richard Killick; Jackie Mitchell; Paul W Caton; Pratik Choudhary; Jane K Howard

doi:10.1016/j.nbd.2024.106485

Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis

Neurobiol Dis. 2024 Apr 21:196:106485. doi: 10.1016/j.nbd.2024.106485. Online ahead of print.

Authors

Erwin Lemche¹, Richard Killick², Jackie Mitchell³, Paul W Caton⁴, Pratik Choudhary⁵, Jane K Howard⁶

Affiliations

¹ Section of Cognitive Neuropsychiatry and Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom. Electronic address: erwin.lemche@kcl.ac.uk.
² Section of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom.
³ Department of Basic and Clinical Neurosciences, Maurice Wohl CIinical Neurosciences Institute, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom.
⁴ Diabetes Research Group, School of Life Course Sciences, King's College London, Hodgkin Building, Guy's Campus, London SE1 1UL, United Kingdom.
⁵ Diabetes Research Group, Weston Education Centre, King's College London, 10 Cutcombe Road, London SE5 9RJ, United Kingdom.
⁶ School of Cardiovascular and Metabolic Medicine & Sciences, Hodgkin Building, Guy's Campus, King's College London, Great Maze Pond, London SE1 1UL, United Kingdom.

PMID: 38643861
DOI: 10.1016/j.nbd.2024.106485

Abstract

Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.

Keywords: Alzheimer's disease; Amylin; Biomarkers; Diabetes; Epidemiology; Glucagon; Glycosylation; Inflammasome; Insulin signalling; Neuroimmunology; β-Amyloid.

Publication types

Review