The incidence of Alzheimer's disease (AD) has risen exponentially worldwide over the past decade. A growing body of research indicates that AD is linked to diabetes mellitus (DM) and suggests that impaired insulin signaling acts as a crucial risk factor in determining the progression of this devastating disease. Many studies suggest people with diabetes, especially type 2 diabetes, are at higher risk of eventually developing Alzheimer's dementia or other dementias. Despite nationwide efforts to increase awareness, the prevalence of Diabetes Mellitus (DM) has risen significantly in the Middle East and North African (MENA) region which might be due to rapid urbanization, lifestyle changes, lack of physical activity and rise in obesity. Growing body of evidence indicates that DM and AD are linked because both conditions involve impaired glucose homeostasis and altered brain function. Current theories and hypothesis clearly implicate that defective insulin signaling in the brain contributes to synaptic dysfunction and cognitive deficits in AD. In the periphery, low-grade chronic inflammation leads to insulin resistance followed by tissue deterioration. Thus insulin resistance acts as a bridge between DM and AD. There is pressing need to understand on how DM increases the risk of AD as well as the underlying mechanisms, due to the projected increase in age related disorders. Here we aim to review the incidence of AD and DM in the Middle East and the possible link between insulin signaling and ApoE carrier status on Aβ aggregation, tau hyperphosphorylation, inflammation, oxidative stress and mitochondrial dysfunction in AD. We also critically reviewed mutation studies in Arab population which might influence DM induced AD. In addition, recent clinical trials and animal studies conducted to evaluate the efficiency of anti-diabetic drugs have been reviewed.
Keywords: AAV, Adeno-associated virus; ABCA1, ATP binding cassette subfamily A member 1; AD, Alzheimer’s disease; ADAMTS9, ADAM Metallopeptidase With Thrombospondin Type 1 Motif 9; AGPAT1, 1-acyl-sn-glycerol-3-phosphate acyltransferase alpha; Alzheimer’s disease; Anti-diabetic drugs; ApoE, Apolipoprotein E; Arab population; Aβ, Amyloid-beta; BACE1, Beta-secretase 1; BBB, Blood-Brain Barrier; BMI, Body mass index; CALR, calreticulin gene; CIP2A, Cancerous Inhibitor Of Protein Phosphatase 2A; COX-2, Cyclooxygenase 2; CSF, Cerebrospinal fluid; DM, Diabetes mellitus; DUSP9, Dual Specificity Phosphatase 9; Diabetes mellitus; ECE-1, Endotherin converting enzyme 1; FDG-PET, Fluorodeoxyglucose- positron emission tomography; FRMD4A, FERM Domain Containing 4A; FTO, Fat Mass and Obesity Associated Gene; GLP-1, Glucagon like peptide; GNPDA2, Glucosamine-6-phosphate deaminase 2; GSK-3β, Glycogen synthase kinase 3 beta; IDE, Insulin degrading enzyme; IGF-1, Insulin-like growth factor 1; IR, Insulin receptor; IR, Insulin resistance; Insulin signaling; LPA, Lipophosphatidic acid; MC4R, Melanocortin 4 receptor; MCI, Myocardial infarction; MENA, Middle East North African; MG-H1, Methylglyoxal-hydroimidazolone isomer trifluoroactic acid salt; MRI, Magnetic resonance imaging; NDUFS3, NADH:Ubiquinone Oxidoreductase Core Subunit S3; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFT, Neurofibrillary tangles; NOTCH4, Neurogenic locus notch homolog protein 4; PI3K, Phosphoinositide-3; PP2A, Protein phosphatase 2; PPAR-γ2, Peroxisome proliferator-activated receptor gamma 2; Pit-PET, Pittsburgh compound B- positron emission tomography; RAB1A, Ras-related protein 1A; SORT, Sortilin; STZ, Streptozotocin; T1DM, Type 1 Diabetes Mellitus; T2DM, Type 2 Diabetes Mellitus; TCF7L2, Transcription Factor 7 Like 2; TFAP2B, Transcription Factor AP-2 Beta.
© 2019 Published by Elsevier B.V. on behalf of King Saud University.