{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:59:45Z","timestamp":1790009985543,"version":"4.0.1"},"reference-count":199,"publisher":"SAGE Publications","issue":"s1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2024,10,18]]},"abstract":"<jats:p>Functional impairments in the brain\u2019s insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer\u2019s disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-\u03b2 and hyperphosphorylated tau lesions in AD, insulin\/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin\/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson\u2019s disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.<\/jats:p>","DOI":"10.3233\/jad-240069","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T10:52:36Z","timestamp":1729248756000},"page":"S317-S343","source":"Crossref","is-referenced-by-count":22,"title":["Conquering Insulin Network Dysfunctions in Alzheimer\u2019s Disease: Where Are We Today?"],"prefix":"10.1177","volume":"101","author":[{"given":"Suzanne M.","family":"de la Monte","sequence":"first","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine, Medicine, Neurology and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-240069_ref1","volume-title":"Alzheimer\u2019s Disease","author":"de la Monte","year":"2019"},{"key":"10.3233\/JAD-240069_ref2","first-page":"45","volume-title":"Advances in Experimental Medicine and Biology.","author":"de la Monte","year":"2019"},{"key":"10.3233\/JAD-240069_ref3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.3233\/JAD-2005-7106","article-title":"Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer\u2019s disease","volume":"7","author":"de la Monte","year":"2005","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-240069_ref4","first-page":"950","article-title":"Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: A preliminary study","volume":"13","author":"Watson","year":"2005","journal-title":"Am J Geriatr Psychiatry"},{"key":"10.3233\/JAD-240069_ref5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3233\/JAD-2006-10113","article-title":"Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: Relevance to Alzheimer\u2019s disease","volume":"10","author":"de la Monte","year":"2006","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-240069_ref6","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1177\/193229680800200619","article-title":"Alzheimer\u2019s disease is type 3 diabetes-evidence reviewed","volume":"2","author":"de la Monte","year":"2008","journal-title":"J Diabetes Sci Technol"},{"key":"10.3233\/JAD-240069_ref7","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3233\/JAD-2009-1070","article-title":"Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer\u2019s disease, diabetes mellitus, and non-alcoholic steatohepatitis","volume":"17","author":"de la Monte","year":"2009","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-240069_ref8","first-page":"5","article-title":"[Alzheimer\u2019s disease and diabetes \u2013 the common pathogenesis]","volume":"18","author":"Halmos","year":"2016","journal-title":"Neuropsychopharmacol Hung"},{"key":"10.3233\/JAD-240069_ref9","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1021\/acschemneuro.9b00645","article-title":"Inhibitory activity of insulin on Abeta aggregation is restricted due to binding selectivity and specificity to polymorphic Abeta states","volume":"11","author":"Baram","year":"2020","journal-title":"ACS Chem Neurosci"},{"key":"10.3233\/JAD-240069_ref10","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3233\/JAD-180906","article-title":"Early-stage Alzheimer\u2019s disease is associated with simultaneous systemic and central nervous system dysregulation of insulin-linked metabolic pathways","volume":"68","author":"de la Monte","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"10.3233\/JAD-240069_ref11","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s007020200082","article-title":"The aging brain. 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