This rigorous PRISMA systematic review of 213 studies concluded that insulin resistance is consistently identified as a key pathological driver of Alzheimer's disease, impairing brain glucose uptake, amyloid-beta clearance, and tau phosphorylation. Disruption of insulin signalling pathways — particularly PI3K/Akt and GLUT4 translocation — is directly associated with neuroinflammation, oxidative stress, and cognitive decline. The authors conclude: "Insulin resistance and disrupted glucose metabolism play a central role in the development and progression of AD, supporting the concept of Type 3 Diabetes."

This foundational paper — one of the most cited in this field — demonstrates that Alzheimer's disease involves primary brain insulin resistance and insulin deficiency that are distinct from, but overlapping with, Type 1 and Type 2 diabetes. The authors show that the term "Type 3 Diabetes" accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain. Key evidence includes: insulin receptor expression is reduced in AD brains; insulin/IGF signalling deficits account for the majority of AD's molecular, biochemical, and histopathological lesions; and treatment with insulin sensitiser agents improves cognitive performance in animal models of brain diabetes.

This comprehensive review reports that observational studies demonstrate Type 2 diabetes nearly doubles the risk of Alzheimer's disease and increases overall dementia likelihood (Leibson et al., 1997; Luchsinger et al., 2001; Xu et al., 2009). Critically, over 80% of Alzheimer's patients have Type 2 diabetes or display abnormal blood glucose levels. Insulin resistance drives both primary AD pathological hallmarks: extracellular amyloid-beta plaque deposition and tau-based neurofibrillary tangles. The authors emphasise that even people with mild or moderate insulin resistance — who do not have Type 2 diabetes — show many of the same brain and memory changes as diabetic patients.

In a study of 150 late middle-aged adults (average age 60) at risk for Alzheimer's but showing no memory loss, brain PET scans found that higher levels of insulin resistance were directly associated with significantly lower glucose metabolism in the hippocampus and other brain regions most susceptible to Alzheimer's. This reduced brain glucose use was linked to measurable memory performance decline. Notably, this effect was seen in people with mild-to-moderate insulin resistance who did not have Type 2 diabetes — confirming that the 10–20 year pre-diabetic window is the critical intervention period. The lead researcher stated: "Even people with mild or moderate insulin resistance who don't have Type 2 diabetes might have an increased risk for Alzheimer's disease."

This review highlights critically important timing data: glucose metabolism in the brain decreases more than 10 years before the occurrence of dementia symptoms. This metabolic change — directly related to insulin resistance — is closely linked to the onset of Alzheimer's. The review explains how insulin resistance in the brain impairs APP (amyloid precursor protein) metabolism, elevates tau protein concentration, triggers neuroinflammation, and impairs hippocampal plasticity. Drugs used in clinical practice provide only temporary symptom relief — they do not prevent disease progression — making early detection and reversal of insulin resistance the only currently viable strategy to prevent Alzheimer's development.

This PRISMA systematic review found that AD and T2DM are interlinked through insulin resistance, neuroinflammation, oxidative stress, advanced glycosylation end products (AGEs), mitochondrial dysfunction, and metabolic syndrome. Both beta-amyloid and tau protein can accumulate in both Type 2 diabetes and Alzheimer's brains. The review also highlights that insulin plays a vital role in the brain's neurotransmitters, energy homeostasis, and memory capacity — and that disrupted insulin signalling undermines all three simultaneously.

In this landmark study of over 5.5 million participants followed for over 7 years, dementia was diagnosed in 142,714 people (2.55%). Alzheimer's accounted for 74.3% of cases. Using the TyG index as a validated measure of insulin resistance, those in the highest insulin resistance quartile had significantly higher risk of both Alzheimer's disease and vascular dementia compared to those with low insulin resistance. The study confirms the population-level relationship between metabolic dysfunction and cognitive decline, independent of other risk factors.