# Type 2 Diabetes, Central Insulin Resistance, and Dementia: A Comprehensive Narrative Review of the Bidirectional Relationship and Shared Pathophysiological Mechanisms

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### Background and Context

The convergence of two of the most prevalent chronic diseases of aging — type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) — represents one of the most consequential and mechanistically rich intersections in contemporary biomedical research. Globally, approximately 537 million adults were living with diabetes in 2021, a figure projected to reach 783 million by 2045 (PMC11765393). Nearly 50 million people had dementia in 2018, with AD accounting for 60–80% of these cases, and this number is projected to more than triple in the coming decades (PMC7357086). In the United States, an estimated 7.2 million Americans aged 65 and older are currently living with AD, with prevalence growing continually as the population ages (PMC13032323). The economic burden is staggering: the global cost of diabetic care was estimated at $1.6 trillion in 2018, projected to reach $2.5 trillion annually by 2030, while the total estimated cost of AD care in 2018 was $1 trillion, expected to double to $2 trillion by 2030 (PMC7357086). These parallel epidemics, both driven by population aging and lifestyle factors, are not merely coincidental co-morbidities — a growing body of evidence suggests they are mechanistically intertwined in ways that have profound implications for prevention, diagnosis, and treatment.

The historical recognition of a link between diabetes and dementia dates to the 1990s, when the Rotterdam Study — a landmark large prospective cohort — first provided epidemiological evidence of a nearly doubled risk of dementia and AD in people with T2DM, reporting a relative risk of 1.9 (95% CI: 1.3–2.8) (PMC9739879). This finding catalyzed decades of investigation into the shared biology of metabolic and neurodegenerative disease. The concept that AD might represent a brain-specific form of diabetes — variously termed "type 3 diabetes" or "brain diabetes" — was formally proposed in the early 2000s and has since accumulated substantial molecular, neuropathological, and clinical support (PMC8910482, PMC9569835, PMC8389322). The framing of AD as a neuroendocrine disorder characterized by central insulin deficiency and resistance, overlapping with both type 1 and type 2 diabetes at the molecular level, has reshaped how researchers conceptualize the pathogenesis of late-onset sporadic AD, which accounts for more than 95% of all AD cases (PMC9569835).

The clinical stakes of this relationship are substantial. Approximately 45% of people with T2DM suffer from mild cognitive impairment, and T2DM raises the risk of developing dementia by 1.5–2.5 times (PMC10594452). Insulin-treated T2DM patients face a relative risk as high as 4.3-fold for developing dementia, and a meta-analysis found a 73% increased risk of dementia overall and a 56% increased risk specifically for AD in patients with diabetes (PMC11765393). Conversely, more than 80% of AD patients develop diabetes or glucose intolerance during the course of their illness (PMC8389322). This bidirectionality — wherein T2DM promotes AD pathology and AD pathology in turn exacerbates metabolic dysfunction — is now a central organizing principle of the field, supported by epidemiological, neuropathological, animal model, and multi-omics evidence. The present review synthesizes this evidence comprehensively, examining the molecular mechanisms linking the two conditions, the epidemiological data supporting bidirectionality, the cerebrovascular contributions to vascular dementia (VaD), and the therapeutic implications of these shared pathways.

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### Molecular and Mechanistic Pathways

#### Central Insulin Signaling Impairment and the "Type 3 Diabetes" Hypothesis

Insulin is not merely a peripheral glucoregulatory hormone; it is a critical neuromodulatory and neuroprotective factor in the central nervous system. Insulin receptors (IRs) are abundantly expressed in the brain, with the highest densities in the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, striatum, and cerebellum (PMC9569835). In the brain, insulin binding activates a cascade involving IRS-1 and IRS-2, PI3K, and AKT, with downstream effects on synaptic plasticity, neuronal survival, glucose metabolism, neurotransmitter regulation, and long-term potentiation; insulin also modulates NMDA, AMPA, and GABA receptor expression and promotes PSD-95 expression (PMC9739879, PMC9569835). The brain's insulin supply derives primarily from peripheral pancreatic secretion, with transport across the blood-brain barrier (BBB) mediated by a saturable, receptor-mediated transcytosis mechanism; CSF insulin levels typically represent approximately 25% of plasma levels (PMC9739879).

In T2DM, the sequence of events leading to central insulin resistance begins peripherally. Compensatory hyperinsulinemia — the pancreatic response to peripheral insulin resistance — initially elevates brain insulin levels because BBB transport is driven partly by peripheral concentration gradients. However, chronic hyperinsulinemia leads to compensatory downregulation of insulin transporters at the BBB, progressively reducing the amount of insulin entering the brain, creating a paradox of peripheral hyperinsulinemia coexisting with central insulin deficiency (PMC9029855, PMC12428013). Postmortem analysis of brain from AD patients has detected significantly decreased expression and activation of IR, IGF-1, and IRS-1, with a pattern resembling that observed during age-related changes; the higher plasma insulin and lower CSF insulin found in AD patients compared to healthy adults support the hypothesis that decreased insulin transport into the brain may trigger cognitive decline and neurodegeneration (PMC8389322). Increased IRS-1 inhibitory serine phosphorylation — a molecular hallmark of insulin resistance — has been documented in AD patients and in hippocampal neurons of APP/PS1 transgenic mouse models (PMC9739879).

The downstream consequences of impaired insulin signaling in the brain are multifaceted and directly implicate the canonical neuropathological hallmarks of AD. When the PI3K/AKT pathway is compromised, glycogen synthase kinase-3β (GSK-3β) — normally held in check by AKT-mediated phosphorylation at serine-9 — becomes constitutively active, phosphorylating tau protein at multiple sites and promoting neurofibrillary tangle formation; simultaneously, peripheral hyperinsulinemia in T2DM competitively diverts IDE toward insulin degradation, reducing Aβ clearance and promoting its accumulation (PMC9029855, PMC9739879, PMC8389322). Impaired insulin signaling may also indirectly enhance the cleavage of APP by controlling the γ-secretase complex, increasing the level of Aβ (PMC11765393). The concept of "type 3 diabetes" thus captures a state in which the combined effects of central insulin deficiency and resistance drive both tau hyperphosphorylation and Aβ accumulation — the two defining neuropathological features of AD (PMC8910482, PMC8389322).

#### The Insulin-Degrading Enzyme (IDE) Nexus and Amyloid-β Clearance

The insulin-degrading enzyme occupies a uniquely pivotal position at the intersection of T2DM and AD pathophysiology. IDE is a neutral thiol-dependent metallopeptidase (molecular weight 110 kDa) encoded on chromosome 10q23-q25 in humans, and it is the primary enzyme responsible for the degradation of both insulin and Aβ in the brain (PMC12428013). The dual substrate specificity of IDE creates a direct competitive relationship: when peripheral hyperinsulinemia drives elevated brain insulin levels, IDE is preferentially occupied with insulin degradation, leaving Aβ to accumulate. IDE is more specific to insulin and has more affinity binding sites for its receptors compared to the Aβ protein, meaning that even modest elevations in brain insulin can substantially impair Aβ clearance (PMC12428013).

The functional consequences of IDE deficiency have been directly demonstrated in animal models. Homozygous deletion of the IDE gene (IDE−/−) in mice resulted in a 50% decrease in Aβ clearance in brain homogenates and primary neuronal cultures, accompanied by increased cerebral accumulation of endogenous Aβ, hyperinsulinemia, and glucose intolerance — a phenotype that recapitulates key features of both T2DM and AD (PMC6008657, PMC8910482). mRNA levels, protein levels, and the activity of IDE are decreased in AD brains (PMC9739879). Genetic studies have demonstrated that IDE gene variations share clinical symptoms of both AD and T2DM, and the deficiency of IDE — whether caused by genetic variation or competitive diversion toward insulin — creates extracellular deposits of Aβ neuritic plaques (PMC12428013). Neprilysin (NEP), another Aβ-degrading enzyme, is also involved in insulin degradation and may be intrinsically altered in both AD and DM, further compounding clearance deficits (PMC10594452).

Beyond IDE, insulin modulates Aβ metabolism through multiple additional mechanisms. Under physiological conditions, insulin and IGF-1 inhibit Aβ production by inactivating GSK-3α (which stimulates Aβ production via γ-secretase), inhibiting BACE-1 mRNA translation, and increasing α-secretase expression to favor the non-amyloidogenic APP processing pathway (PMC9739879). Insulin also accelerates the trafficking of APP and Aβ from the trans-Golgi network to the plasma membrane, facilitating extracellular secretion and reducing intracellular accumulation (PMC9739879). Additionally, insulin stimulates the transport of Aβ-binding carrier proteins — including albumin and transthyretin — in the brain, providing additional clearance capacity (PMC9739879). In insulin-resistant states, all of these protective mechanisms are simultaneously impaired, creating a convergent failure of Aβ production control and clearance that dramatically accelerates amyloid burden.

#### GSK-3β, Tau Hyperphosphorylation, and Neurofibrillary Tangle Formation

GSK-3β is arguably the most critical molecular node linking T2DM and AD pathophysiology. This constitutively active serine/threonine kinase is normally held in check by AKT-mediated phosphorylation at serine-9 (inhibitory) and is activated by phosphorylation at tyrosine-216 (PMC8389322, PMC9739879). In the insulin-sensitive state, insulin binding to its receptor activates the PI3K/AKT cascade, which phosphorylates GSK-3β at Ser9, maintaining tau in its physiologically functional, microtubule-associated state. In insulin-resistant states — whether peripheral T2DM or central brain insulin resistance — reduced AKT activation leaves GSK-3β constitutively active, leading to tau hyperphosphorylation at pathological epitopes including AT8, AT100, and PHF1 (PMC6008657).

Normal brain tau contains 2–3 moles of phosphate per mole of protein; in AD brains, tau is hyperphosphorylated at 6–9 moles per mole — a three-fold increase — promoting detachment from microtubules and self-aggregation into paired helical filaments and NFTs (PMC6008657). GSK-3β phosphorylates a large number of neuronal substrates including tau, and immunohistochemical studies have shown the co-localization of GSK-3β in PHF-tau aggregates in AD brains; GSK-3β levels are increased in the brains of AD patients (PMC9739879). Activated AKT also inhibits GSK-3α, an isoform which stimulates the production of Aβ by γ-secretase, and insulin and IGF-1 resistance in the brain activates pro-apoptotic, pro-inflammatory, and pro-APP-Aβ cascades, contributing to neurodegeneration (PMC9739879). In T2DM, GSK-3β is hyperactivated in peripheral insulin-sensitive tissues including skeletal muscle, contributing to peripheral insulin resistance through IRS-1 serine phosphorylation — the same mechanism that drives central insulin resistance in AD (PMC9739879). This dual role of GSK-3β in both peripheral metabolic dysfunction and central neurodegeneration makes it one of the most compelling shared therapeutic targets between the two diseases.

The protein phosphatase PP2A, which plays an important role in the homeostasis of tau phosphorylation, is downregulated in T2DM animal models, and insulin resistance may increase tau phosphorylation through this mechanism (PMC11765393). It should be noted that the evidence for PP2A downregulation derives primarily from T2DM animal models; whether this finding extends equivalently to T1DM models or to human disease remains less clearly established in the reviewed literature. Caspase-3, activated by hyperglycemia and diabetic conditions, cleaves tau at the C-terminus to generate the Asp421 residue, which has a high propensity for aggregation and is found in neurofibrillary pathology in AD brains (PMC6008657, PMC11765393). The DYRK1A kinase — encoded on chromosome 21 and overexpressed in Down syndrome — phosphorylates tau at Thr-212, primes it for subsequent GSK-3β phosphorylation, and also phosphorylates APP at Thr-668 and PSEN1 at Thr-354 to increase amyloidogenic cleavage; DYRK1A additionally suppresses β-cell proliferation, linking it mechanistically to both T2DM and AD (PMC9739879). The convergence of GSK-3β and DYRK1A hyperactivity in insulin-resistant states thus creates a self-reinforcing cycle of tau pathology and Aβ accumulation.

#### Neuroinflammation, Cytokine Signaling, and the JNK/IKK Pathway

Chronic low-grade systemic inflammation — termed "metaflammation" in the context of metabolic disorders — is a defining feature of T2DM, obesity, and insulin resistance, and it constitutes a critical mechanistic bridge to neurodegeneration (PMC8389322). In T2DM, adipose tissue-derived inflammatory mediators including TNF-α, IL-1β, IL-6, and IL-18 are chronically elevated in the circulation (PMC9029855, PMC8389322). These cytokines can cross the BBB — which exhibits increased permeability in diabetic states — and activate brain-resident microglia and astrocytes, initiating a neuroinflammatory cascade that directly impairs insulin signaling and promotes AD pathology (PMC9029855, PMC12428013).

The molecular mechanism by which peripheral inflammation induces central insulin resistance is well-characterized. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-18) activate JNK, the NF-κB/IKK complex, and PKR, which phosphorylate IRS-1 at serine residues, inhibiting intracellular insulin signaling and promoting central insulin resistance (PMC8389322). By impairing the protective activities of insulin in the brain, these effects may increase the progression speed of AD development. Critically, Aβ oligomers themselves activate the TNF-α/JNK pathway in neurons, creating a bidirectional amplification loop wherein peripheral T2DM-driven inflammation promotes central insulin resistance, which promotes Aβ accumulation, which in turn activates neuroinflammatory pathways that further impair insulin signaling (PMC9739879, PMC8389322).

Microglia — the brain's resident immune cells — play a dual role in this process. In their homeostatic state, microglia perform immunosurveillance, phagocytose cellular debris, and clear Aβ via IDE and neprilysin. However, chronic activation by Aβ oligomers, AGEs, and pro-inflammatory cytokines drives microglia toward a pro-inflammatory M1 phenotype, characterized by secretion of TNF-α, IL-1β, IL-6, IL-18, nitric oxide, superoxide, and matrix metalloproteinases (PMC12428013, PMC13032323). This chronic microglial activation impairs Aβ phagocytosis, promotes tau hyperphosphorylation via MAPK pathways, and exacerbates synaptic dysfunction and neuronal death (PMC12428013). Postmortem studies of AD brains from patients with T2DM show higher levels of AGEs and activated microglia compared to AD patients without T2DM (PMC11765393). The NF-κB pathway, activated by hyperglycemia and neuronal damage, drives the production of TNF-α and IL-6 and can induce apoptosis; in streptozotocin-injected rats (a model of diabetic encephalopathy), NF-κB activation increases reactive oxygen species (ROS) in the hippocampus (PMC9029855). Astrocytes, which constitute up to 40% of all glia in the human brain, also respond to insulin and are regulated by it regarding cytokine secretion; in inflammatory states, reactive astrocytes (A1 phenotype) secrete neurotoxic factors and degrade the extracellular matrix and tight junctions of the BBB via MMP and VEGF-A secretion, further amplifying neuroinflammation (PMC12428013).

The "inflammaging" concept — the chronic, low-level inflammatory state characteristic of aging — provides an additional layer of mechanistic integration. In both T2DM and AD, the balance between pro-inflammatory (IL-1β, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines is disrupted, with pro-inflammatory mediators predominating (PMC13032323, PMC8389322). Elevated serum levels of IL-1β and TNF-α have been proposed as potential biomarkers of AD risk based on data from the Framingham study (PMC8389322). The TREM2 receptor on microglia — whose rare missense variants increase late-onset AD risk by 2–3-fold — regulates microglial activation, survival, and phagocytosis, and its dysfunction has been linked to impaired Aβ clearance and exacerbated neuroinflammation (PMC13032323). The discovery of AD risk factor genes linked to immune function (CD33, TREM2, PLCG2) through GWAS has reinforced the centrality of neuroinflammation in AD pathogenesis and its potential intersection with metabolic disease (PMC12428013, PMC13032323).

#### Advanced Glycation End Products, Oxidative Stress, and Mitochondrial Dysfunction

Hyperglycemia drives the non-enzymatic glycation of proteins and lipids, generating advanced glycation end products (AGEs) that accumulate in tissues and interact with their receptors (RAGE) to activate inflammatory signaling, vascular injury, and oxidative stress (PMC9029855, PMC11765393). In the brain, AGEs promote the glycation of Aβ and tau, accelerating their aggregation; proteins from amyloid deposits such as Aβ-peptide, IAPP, tau, prions, and transthyretin can be glycated, indicating a direct relationship between protein glycation and amyloidosis (PMC9569835, PMC7357086). RAGE is expressed on neurons, microglia, astrocytes, and endothelial cells, and its interaction with Aβ plays a crucial role in AD pathophysiology — guiding microglia to Aβ deposits, activating pro-inflammatory cascades, and promoting vascular complications. Increased RAGE expression has been documented in astrocytes and microglia of AD brains, and neuron-specific overexpression of dominant-negative RAGE has been reported to restore cognitive functions and halt the progression of neuropathological changes in AD mice (PMC6008657).

Oxidative stress — the imbalance between ROS production and antioxidant defense — is a central feature of both T2DM and AD. Approximately 5% of cellular oxygen is converted to ROS under physiological conditions, primarily at mitochondrial respiratory complexes I and III (PMC8389322). In T2DM, chronic hyperglycemia drives auto-oxidation of glucose, impairs antioxidant enzyme synthesis, and overloads mitochondrial metabolic processes, generating excess superoxide, hydrogen peroxide, and hydroxyl radicals (PMC11765393, PMC8389322). In AD brains, elevated markers of oxidative damage — including 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) — are detected in vulnerable brain regions and CSF, and oxidative modifications of Aβ and tau promote their aggregation and impair clearance (PMC13032323). Copper and zinc concentrations have been found to be three times higher in AD brains compared to healthy controls, and these metal ions catalyze ROS production when bound to Aβ, further amplifying oxidative damage (PMC13032323).

Mitochondrial dysfunction represents perhaps the most fundamental shared pathophysiological mechanism between T2DM and AD. The brain constitutes only 2% of the total body mass but consumes around 25% of the glucose and 20% of the oxygen used by the whole body, making it exquisitely dependent on mitochondrial function (PMC12428013). In both conditions, mitochondrial structural and functional abnormalities — including reduced mitochondrial mass, altered morphology, impaired electron transport chain (ETC) activity, decreased ATP production, and increased ROS generation — have been consistently documented (PMC8389322). In AD brains, Aβ accumulates within mitochondria, causing mitochondrial swelling, ROS overproduction, impaired respiratory chain function, and altered calcium homeostasis; this mitochondrial Aβ accumulation may precede extracellular plaque deposition and represent an early pathological event (PMC8389322). The "mitochondrial cascade hypothesis" proposes that mitochondrial failure is a primary driver of late-onset AD, compromising ATP production, dysregulating calcium buffering, opening the mitochondrial permeability transition pore (mPTP), and triggering cytochrome C release and apoptotic cascades (PMC8389322). In T2DM, mitochondrial dysfunction in pancreatic β-cells impairs insulin secretion (which is entirely ATP-dependent), while in peripheral tissues, reduced mitochondrial mass and fatty acid oxidation capacity contribute to insulin resistance (PMC8389322). The sirtuins SIRT1 and SIRT3 — NAD+-dependent deacetylases that regulate mitochondrial biogenesis via PGC-1α — are linked to neuroprotection in AD and have been proposed as shared therapeutic targets; SIRT1 deacetylates and activates PGC-1α, and impaired SIRT1 activity may disrupt autophagy/mitophagy quality control, resulting in mitochondrial dysfunction and accumulation of Aβ plaques and tau tangles (PMC8389322).

#### Amyloid Cross-Seeding: IAPP, Aβ, and the Pancreas-Brain Axis

One of the most structurally and mechanistically compelling links between T2DM and AD is the shared amyloidogenic nature of both diseases. In T2DM, islet amyloid polypeptide (IAPP, also known as amylin) — a 37-amino acid peptide co-secreted with insulin by pancreatic β-cells at a molar ratio of approximately 1:100 — aggregates in the pancreatic islets of Langerhans, contributing to β-cell dysfunction and loss (PMC7357086). In AD, Aβ peptides aggregate in the brain to form senile plaques. Structurally, IAPP and Aβ share approximately 25% identical amino acid sequences, have high binding affinity for each other, and exert similar cytotoxic mechanisms when aggregated, including mitochondrial dysfunction, ROS generation, and calcium homeostasis disruption (PMC7357086, PMC9739879).

Autopsy studies found amyloid deposits in 59% of diabetic versus 12% of non-diabetic cases in one series, and 39.6% versus 3% in a multicenter autopsy study; diabetics treated with insulin had the highest prevalence (89%) and most severe degree of pancreatic islet amyloidosis (PMC7357086). Brain samples from AD patients contained 1.4 times higher concentrations of IAPP than non-AD samples by Western blot analysis, and immunohistochemical examination of the gray matter of the temporal lobe from diabetic patients with dementia revealed many amylin plaques (PMC7357086). Pancreatic amylin accumulates in the brain as independent plaques or co-primes with Aβ to form complex amyloid-β/amylin plaques, contributing to neurodegeneration in patients with T2DM (PMC7357086).

The phenomenon of cross-seeding — wherein aggregated IAPP can seed Aβ fibrillation and vice versa — has been demonstrated in multiple experimental systems. Intravenous injection of preformed IAPP fibrils into human IAPP transgenic mice increased the number of mice with islet amyloid from 2.7% (saline control) to 24.1%, while injection of Aβ fibrils increased islet amyloid to 15.2%, demonstrating heterologous cross-seeding between the two peptides (PMC7357086). In double transgenic mice co-expressing human APP and human IAPP, both plaque density and Aβ burden in the brain were exacerbated compared to single transgenic AD animals; intracerebral injection of aggregated IAPP homogenates into APP mice led to more intense AD pathology and severe memory deficits (PMC7357086). Non-human primates that spontaneously develop both AD and diabetes showed accelerated Aβ pathology compared to non-diabetic monkeys, providing translational support for the cross-seeding hypothesis (PMC7357086). These findings suggest that the coexistence of Aβ and IAPP in the same patient — common in elderly individuals with both T2DM and AD — may create a self-amplifying amyloidogenic cycle that accelerates both diseases.

#### Autophagy Dysfunction and Proteostasis Failure

Autophagy — the lysosome-dependent degradative process by which cells eliminate defective proteins and organelles — is critically impaired in both T2DM and AD, providing another mechanistic convergence point. In AD, macroautophagy is severely disrupted: autophagic vacuoles accumulate in dystrophic neurites, beclin-1 deficiency in neuronal cultures of transgenic mice leads to increased Aβ production and amyloid plaques, and absence of ATG7 in the forebrain of knockout mice leads to increased concentrations of phospho-tau (PMC9029855). In T2DM, insulin resistance generates oxidative stress that impairs the endoplasmic reticulum and mitochondria, resulting in increased aggregation of misfolded proteins; in OLEF rats (a model of T2DM), increased concentrations of tau and phospho-tau were combined with reduction of p62 protein, which is crucial for autophagic degradation of tau (PMC9029855). In the brains of AD and T2DM mouse models, decreased levels of ATG7 and LC3-II have been observed, implicating shared autophagic pathway dysfunction (PMC9029855).

The mTOR pathway — a master regulator of autophagy — provides a direct mechanistic link. The mTOR pathway inhibits autophagy and impairs the clearance of Aβ and tau aggregates; rapamycin (an mTOR inhibitor that upregulates autophagy) reduces both Aβ pathology in AD mouse models and improves cognition (PMC6008657). The AMPK pathway — which promotes autophagy by inhibiting mTOR — is downregulated in both AD and T2DM: AMPK subunits PRKAA1, PRKAA2, PRKAB2, and PRKAG3 are downregulated in AD, while PRKAG1 and PRKAG2 are downregulated in T2DM, and STK11 (which activates AMPK) is under-expressed in both conditions (PMC5611890). Heat shock proteins (HSPs), particularly HSP70 and HSP90, which normally prevent Aβ and tau aggregation and facilitate their degradation through chaperone-assisted selective autophagy, are dysregulated in AD, further compromising proteostasis (PMC13032323).

#### Blood-Brain Barrier Dysfunction and Cerebrovascular Mechanisms

The BBB — a highly specialized multicellular structure comprising brain microvascular endothelial cells (BMVECs), pericytes, astrocyte end-feet, and the extracellular matrix — is a critical interface between peripheral metabolic dysfunction and central neurodegeneration. In T2DM, chronic hyperglycemia and oxidative stress damage the vascular endothelium, promote atherosclerosis, and lead to remodeling of cerebral microvascularization, evidenced by thickening of the cerebral capillary basement membrane in both diabetic animal models and diabetic patients (PMC9739879). This thickening alters the integrity of vascular smooth muscle cells, increases microvascular resistance, and impairs the vascular-mediated Aβ clearance system — including LRP1-mediated Aβ efflux across the BBB and the glymphatic/perivascular clearance pathways (PMC9739879). In late-onset AD, the Aβ clearance rate is 30% slower than in controls (5.3%/hour vs. 7.6%/hour, p = 0.03), and impaired vascular clearance is a major contributor to this deficit (PMC9739879).

The APOE ε4 allele confers up to 4-fold increased AD risk in heterozygotes and up to 15-fold in homozygotes; APOE4 activates cyclophilin A (CypA) in pericytes, which stimulates MMP-9, leading to degradation of BBB tight junction and basement membrane proteins (PMC12428013). APOE3 and APOE2, by contrast, act via LRP1 on pericytes to inhibit this pro-inflammatory CypA-MMP-9 pathway. The CSF/serum albumin quotient (Qalb) is elevated in AD patients, with pathological values (>9) reported in 16–22% of patients with mild-to-moderate AD dementia; Qalb values correlate positively with both CypA (r = 0.37, p < 0.01) and active MMP-9 (r = 0.45, p < 0.01) in CSF (PMC12428013). Cognitively intact APOE4 carriers show leaky BBB initially in the hippocampus and para-hippocampal gyrus, with remarkable atrophy in these regions leading to memory and cognitive impairment (PMC12428013).

In T2DM, insulin resistance negatively affects cerebral blood pressure regulation, increases BBB permeability, and increases intracerebral Aβ accumulation (PMC12428013). Prediabetes and T2DM promote increased accumulation of Aβ in the form of amyloid angiopathy (AAC) around blood vessels, which is associated with an increased risk of vascular rupture (PMC10594452). In murine models of AD combined with T1DM or T2DM, serum Aβ levels were reduced while intracerebral soluble Aβ levels were elevated, consistent with impaired BBB-mediated clearance — the inability to expel Aβ peptides from the CNS across the BBB (PMC10594452). Chronic cerebral hypoperfusion (CCH) — provoked experimentally by bilateral carotid artery stenosis — represents another major exacerbating factor in sporadic AD, interacting with amyloid toxicity and brain insulin resistance (PMC9029855). The two-hit vascular hypothesis of AD proposes that cerebrovascular damage (BBB dysfunction) leads to Aβ accumulation, which itself is sufficient to initiate neuronal loss and neurodegeneration (PMC12428013).

#### Shared Genetic and Epigenetic Architecture

Multi-omics causal inference analyses have provided compelling evidence that T2DM and AD share not only phenotypic and mechanistic features but also a substantial portion of their genetic and epigenetic architecture. A genome-wide causation study applied to the ROSMAP dataset (n = 432 individuals) identified 13 shared causal genes directly or indirectly connected to both AD and T2DM, 16 shared causal pathways directly connected to both diseases, 754 gene expression nodes and 101 gene methylation nodes connected to both diseases in the multi-omics causal network, and a total of 759 genes connected to both AD and T2DM through direct or indirect paths; the inferred multilevel causal network comprised 2,814 nodes and 22,184 edges (arxiv:1901.05537). Key shared causal pathways between AD and T2DM identified in the ROSMAP multi-omics causal network included MAPK, PI3K-AKT, FoxO, morphine addiction, neuroactive ligand receptor interaction, fatty acid biosynthesis, primary bile acid biosynthesis, dopaminergic synapse, and AMPK signaling (arxiv:1901.05537). Specific shared causal gene chains were traced, including CREBBP→CBL→MAP2K4→MAPK8→MAPK1→PIK3CA and TTC3→NLK→PLK2→MAPK8→MAPK1→PIK3CA (arxiv:1901.05537). Six phenotypes — age, cholesterol, HDL ratio, LDL, semantic memory, and working memory — were directly connected to both diseases in the causal network.

A knowledge-driven BEL (Biological Expression Language) modeling approach, applied to 448 AD articles and 106 T2DM articles, identified approximately 31 commonly impaired biological processes shared between the two diseases — including insulin resistance, insulin signaling, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis — as well as 9 common comorbid pathologies such as cardiovascular disorders, obesity, and amyloidosis (PMC5611890). AKT1 was found to be consistently downregulated in both diseases, and AMPK subunits were downregulated in both conditions (PMC5611890). The DUSP8 gene — encoding a dual-specificity phosphatase involved in MAPK signaling and predominantly expressed in the brain — was implicated by GWAS as a T2DM risk gene and has been shown to have sex-specific effects on hypothalamic insulin resistance, hippocampal size, and cognitive, emotional, and hedonic behaviors (PMC9569835).

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### Dose-Response and Pharmacokinetics of Central Insulin Signaling

The relationship between insulin concentration and brain function follows a non-linear, dose-dependent pattern that is critical for understanding both the pathophysiology of central insulin resistance and the therapeutic potential of insulin-based interventions. Under physiological conditions, moderate insulin concentrations at the brain level have neurotrophic properties, while elevated concentrations are associated with reduced amyloid clearance (PMC7357086). In older men, those with the highest insulin levels made 25% more errors on the Mini-Mental State Examination compared to those with very low insulin levels, illustrating the inverted-U relationship between insulin and cognitive function (PMC7357086). The ACCORD-MIND study demonstrated that HbA1c levels — a proxy for chronic glycemic exposure — had a negative impact on cognitive tests, with higher HbA1c associated with worse cognitive performance (PMC7357086).

The distinction between peripheral and central insulin pharmacokinetics is clinically important. Peripheral hyperinsulinemia — the compensatory response to insulin resistance — paradoxically reduces central insulin availability by downregulating BBB insulin transporters. The CSF/plasma insulin ratio is reduced in AD patients compared to healthy controls, and this ratio decreases further with disease progression (PMC9739879). Intranasal insulin delivery bypasses this BBB transport limitation by delivering insulin directly to the olfactory epithelium and thence to the brain via olfactory and trigeminal nerve pathways, achieving therapeutically relevant central concentrations without causing peripheral hypoglycemia (PMC8389322). Intranasal insulin administration has been shown to enhance verbal memory in patients with mild cognitive impairment and late-onset AD, with a concomitant improved cerebral glucose metabolism in those brain regions affected by AD changes (PMC8389322). However, the therapeutic window appears to be narrow and APOE4-dependent: the variable therapeutic results of acute insulin administration on CNS may depend on APOE genotype, a strong genetic predictor for AD, and the intranasal administration of insulin has been beneficial in improving memory in AD patients who do not have the ApoE4 allele (PMC8389322, PMC9739879).

The timing of insulin exposure relative to disease stage also appears critical. Early hyperinsulinemia — even in the prediabetic state, before clinical T2DM is established — is sufficient to worsen AD pathology in animal models, promoting vascular damage and increasing inflammatory processes at the central level (PMC10594452). In prediabetic-AD and T2D-AD mice, greater involvement was observed in regions close to senile plaques than in areas away from them, and diabetes promoted more toxic soluble forms of Aβ (PMC10594452). Conversely, late-stage insulin deficiency (as in T1DM or advanced T2DM with β-cell exhaustion) also promotes tau hyperphosphorylation and Aβ accumulation through different mechanisms — primarily through reduced IDE activity and impaired PI3K/AKT/GSK-3β signaling (PMC10594452, PMC11765393). This biphasic relationship — wherein both excess and deficiency of insulin are harmful to the brain — underscores the importance of maintaining physiological insulin signaling throughout the lifespan.

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### Clinical Evidence and Implications

#### Epidemiological Evidence for T2DM as a Risk Factor for AD and Dementia

The epidemiological evidence linking T2DM to AD and dementia is now extensive and consistent across multiple study designs, populations, and geographic regions. The landmark Rotterdam Study (1999) first reported a relative risk of 1.9 (95% CI: 1.3–2.8) for dementia/AD in T2DM patients (PMC9739879). Subsequent large-scale studies have consistently confirmed and extended this finding. A meta-analysis of diabetes mellitus cases and dementia risk found a 73% increased risk of dementia overall and a 56% increased risk specifically for AD in patients with diabetes (PMC11765393). The risk of AD is increased by 50–60% in patients with T2DM in some analyses, while other epidemiological studies report at least a 2-fold increased risk (PMC11765393). Insulin-treated T2DM patients face a relative risk as high as 4.3-fold for developing dementia (PMC11765393). Investigations performed on Japanese-Americans in Hawaii revealed that diabetic patients had a 1.8-fold higher risk of vascular dementia (PMC11765393).

A formal meta-analysis following PRISMA guidelines, including 18 longitudinal human studies, found that for hazard ratios (9 studies, total n = 4,229,828), the association between abnormal glucose metabolism and AD risk was highly significant (p = 0.0007) with very high heterogeneity (I² = 97%); for odds ratios (4 studies, total n = 120,645), the pooled OR was significantly elevated (p = 0.03) with high heterogeneity (PMC9029855). Subgroup analyses showed that both clinical T2DM diagnosis and other definitions of abnormal glucose metabolism (glucose intolerance, fasting glucose levels) were significantly associated with AD risk, though heterogeneity remained moderate to high across all subgroups.

The Cache County Study — a cross-sectional study with retrospective examination of vascular conditions in relation to probable or possible AD with neuropsychiatric symptoms — contributed to the RR meta-analysis and, when removed, the remaining four studies showed significantly increased risk ratios for AD in patients with diabetes (p = 0.008) with no heterogeneity, suggesting that the Cache County Study's design contributed disproportionately to heterogeneity (PMC9029855). A cohort study from Manhattan (1992–1994, followed 1999–2001) demonstrated that T2DM is associated strongly with late-onset AD (LOAD) after adjustment for sex and age, and suggested that the link between T2DM and LOAD is partly mediated by cerebrovascular pathology (PMC6008657). Longitudinal studies by Leibson et al. and Huang et al. found that patients with adult-onset diabetes exhibited a significantly higher risk of developing AD than age-matched subjects without T2DM (PMC6008657). Observations of an elderly Chinese population with mild cognitive impairment showed that T2DM stimulates the progression of AD, while no association was observed in age-matched controls (PMC11765393).

The relationship between T2DM duration and dementia risk has also been examined. One study found a statistical significance for T2DM duration over five years in relation to AD risk (PMC9029855). A meta-analysis of population-based cohort studies showed a 38% increased risk of developing Parkinson's disease in diabetic patients (RR = 1.38, 95% CI: 1.18–1.62, p < 0.0001), with a higher risk in women (RR = 1.50, 95% CI: 1.07–2.11) than men (RR = 1.40, 95% CI: 1.17–1.67) (PMC11765393). Evidence from longitudinal studies also indicates that older patients with T2DM and a history of severe hypoglycemic episodes show a greater risk of dementia, highlighting the contribution of glycemic variability and hypoglycemic events to dementia risk (PMC8910482).

#### Neuroimaging Evidence for Shared Brain Vulnerability

Neuroimaging studies using PET and MRI have provided in vivo evidence of overlapping patterns of brain vulnerability in T2DM and AD. FDG-PET studies demonstrate reduced glucose uptake in the frontal, parietotemporal, and cingulate cortices in early-stage AD patients; the brain's ability to use glucose is reduced by up to 25% in AD patients, particularly in the hippocampus; autopsy studies showed reduced levels of GLUT1 and GLUT3 in the hippocampus, frontal cortex, parietal lobe, and temporal lobe in AD patients (PMC9739879, PMC8910482). Insulin-resistant elderly people, T2DM patients with mild cognitive impairment, and even prediabetic patients with normal cognitive function all show brain hypometabolism quantified by decreased [18F]-FDG uptake on PET imaging (PMC9739879).

MRI studies of T2DM patients show structural alterations resembling those in AD. A study of 350 T2DM patients and 363 controls found that T2DM was associated with more cerebral infarcts and reduced volumes of gray matter, white matter, and hippocampus, with gray matter loss most prominent in medial temporal, anterior cingulate, and medial frontal lobes — regions maximally vulnerable to AD (PMC6008657). A study of 1,437 elderly individuals without dementia found that midlife T2DM was associated with reduced hippocampal and whole brain volumes, strongly indicating cognitive decline later in life (PMC6008657). A study of 233 cognitively normal individuals found that higher blood glucose was associated with reduced average cortical thickness in AD-vulnerable regions (PMC6008657). Using brain imaging, subjects with diabetes show hippocampal and amygdala atrophy compared to non-diabetic subjects — the same regions atrophied in AD (PMC7357086). Diffusion tensor imaging (DTI) has detected early remodeling of brain structural networks in T2DM patients with MCI, providing a potential early biomarker for identifying patients at risk of severe cognitive decline (PMC9029855).

#### Vascular Dementia: T2DM as a Cerebrovascular Risk Factor

Vascular dementia (VaD) — the second most common cause of dementia after AD, accounting for 20–30% of cases and affecting 1 in 20 people over 65 years of age — has a particularly direct mechanistic relationship with T2DM (PMC10594452). VaD occurs due to reduced blood flow to the brain, causing damage to different brain structures through hypoxia and ischemia. T2DM is associated with an increased risk of ischemic stroke and acute cerebral infarcts, and chronic hyperglycemia leads to remodeling of cerebral microvascularization, including thickening of the cerebral capillary basement membrane (PMC9739879, PMC10594452). The geographic distribution of VaD is heterogeneous: in North America and Europe it accounts for 15–20% of all dementias, while in Asia and developing countries it accounts for 30% (PMC10594452). The probability of developing dementia doubles every 5.3 years with age, and T2DM synergizes with other vascular risk factors — hypertension, hyperlipidemia, hypercholesterolemia, and smoking — to increase dementia risk (PMC10594452).

The pathological process resulting from vascular damage in T2DM involves alterations in functional markers including increased oxidative stress, elevated pro-inflammatory cytokines, and increased activity of matrix metalloproteinases in vessel walls, all of which have been linked to neuronal death responsible for dementia (PMC10594452). Prediabetes and T2DM promote increased accumulation of Aβ in the form of amyloid angiopathy around blood vessels, which is associated with an increased risk of vascular rupture (PMC10594452). In murine models of AD combined with T2DM (APP × ob/ob and APP × NSY double transgenics), increased levels of amyloid deposition around brain microvessels and enhanced cerebrovascular inflammation were observed even before the manifestation of cerebral amyloid angiopathy, with elevated RAGE in blood vessels and elevated TNF-α and IL-6 in brain microvasculature (PMC6008657). VaD and AD frequently coexist, and vascular pathology may contribute to cognitive decline by promoting AD development — BBB dysfunction affects the Aβ brain-periphery balance and contributes to parenchymal and vascular Aβ deposition (PMC10594452).

#### Therapeutic Implications: Antidiabetic Drugs in Dementia

The mechanistic overlap between T2DM and AD has generated substantial interest in repurposing antidiabetic drugs for dementia prevention and treatment. Multiple drug classes have been investigated, with variable results.

**GLP-1 Receptor Agonists:** GLP-1 receptor agonists (GLP-1 RAs) have emerged as among the most promising candidates, given their ability to enhance insulin signaling, reduce neuroinflammation, and cross the BBB. GLP-1 receptors are present in cultured neurons and in rodent and human brains, including the frontal cortex, hypothalamus, thalamus, hippocampus, cerebellum, and substantia nigra (PMC8389322). In AD mouse models, liraglutide prevents chronic inflammation, reduces neuronal tau hyperphosphorylation, enhances synaptic plasticity, decreases β-amyloid deposits, and improves memory impairment via PI3K/AKT signaling (PMC8389322). Exenatide-4 decreases AD-associated tau hyperphosphorylation in the hippocampus of T2DM rats and improves dysfunctional insulin pathways in the brain (PMC8389322). In murine models of AD, chronic anti-diabetic therapy has been reported to reduce tau deposits and β-amyloid plaque counts by 40–50% and rescue spatial memory and recognition impairments (PMC7357086). Liraglutide has been investigated in randomized controlled trials with promising results, showing increases in brain insulin signaling and possible effects on mental scale scores of patients with mild cognitive impairment (PMC9029855). The GLP-1 analogue semaglutide may also protect from Aβ toxicity, and a clinical trial (EVOKE) has been launched to test its effect on early-onset AD (PMC9029855). The ELAD study (ClinicalTrials.gov NCT01843075) is testing liraglutide in AD patients (PMC8389322).

**Intranasal Insulin:** Intranasal insulin administration has been shown to enhance verbal memory in patients with mild cognitive impairment and late-onset AD, with a concomitant improved cerebral glucose metabolism in brain regions affected by AD changes (PMC8389322). However, the intranasal administration of insulin has been beneficial in improving memory primarily in AD patients who do not have the ApoE4 allele, and recent long-term studies in humans have shown limited overall efficacy of intranasal insulin as a treatment for AD (PMC9739879, PMC10594452, PMC8389322). The variable therapeutic results may depend on APOE genotype, disease stage, and the specific insulin formulation used.

**Thiazolidinediones (TZDs):** TZDs target PPARγ and display neuroprotective effects in AD mainly through inhibition of inflammatory gene expression and decreased Aβ generation and deposition. In initial studies, AD patients treated for 4–6 months with rosiglitazone showed improvement in memory performance and selective attention; however, rosiglitazone was subsequently withdrawn from the market due to increased cardiovascular risk, and subsequent larger trials achieved poor results (PMC8389322). Pioglitazone, the only TZD currently available, has shown controversial results in diabetic patients with mild AD: a network meta-analysis of several clinical trials showed improvement in verbal memory, general cognition, and regional cerebral blood flow compared to placebo, while other clinical studies failed to demonstrate efficacy (PMC8389322). The TOMORROW clinical trial (NCT01931566) tested low-dose pioglitazone to delay the onset of MCI in normal individuals at high risk of AD.

**Metformin:** Metformin has demonstrated neuroprotective, anti-inflammatory, and antioxidant effects in animal models, including inhibition of MAPT phosphorylation through increased PP2A activity, inhibition of the JNK cascade, protection against synaptophysin degradation, and AMPK activation (PMC5611890, PMC10594452). However, metformin also has putative harmful effects in the context of AD: it upregulates BACE1 transcription, promotes Aβ deposition via NF-κB1/PSEN1/APP activation, increases oxidative stress and mitochondrial damage, and promotes insoluble tau aggregation in animal models and gene expression studies (PMC5611890). Gene expression analyses in mice and humans support upregulation of BACE1, PSEN1, and APP with metformin treatment (PMC5611890). Limited studies in humans have shown a more discrete positive relationship with metformin as a treatment for AD, and the current evidence does not support repurposing metformin for dementia prevention or treatment without further investigation (PMC10594452).

**GSK-3β Inhibitors:** Given the central role of GSK-3β in both T2DM and AD, multiple inhibitors have been developed and tested. Tideglusib — an irreversible non-ATP-competitive GSK-3β inhibitor — promotes reduction of tau phosphorylation levels and brain Aβ deposition in transgenic mice and prevents hippocampal neuronal cell death and memory loss; in a randomized trial it slowed atrophy progression in the whole brain, but Phase II trials did not demonstrate significant clinical efficacy in patients with mild-to-moderate AD (PMC8389322). TDZD-8 (another non-ATP competitive thiazolidinedione inhibitor of GSK-3β) administered intrahippocampally in diabetic db/db mice counteracted tau hyperphosphorylation and normalized hippocampus-dependent memory (PMC8389322).

**DPP-4 Inhibitors and Other Agents:** DPP-4 inhibitors, which increase endogenous GLP-1 levels, have been investigated for potential neuroprotective effects. Sitagliptin has been reported to increase MAPT phosphorylation, potentially leading to NFTs — a concerning finding that warrants further investigation (PMC5611890). The overall evidence for DPP-4 inhibitors in dementia prevention remains insufficient to draw firm conclusions.

#### The Bidirectionality Question: Does AD Cause Metabolic Dysfunction?

The relationship between T2DM and AD is not unidirectional. Substantial evidence supports the reverse pathway — wherein AD pathology itself promotes metabolic dysfunction and insulin resistance. In double transgenic APPswe/PS1dE9 × db/+ mice (partially deficient in leptin signaling), the novel mouse model showed non-fasting hyperglycemia, hypercholesterolemia, and hyperinsulinemia, with glucose intolerance, insulin resistance, and altered insulin signaling — providing experimental evidence that abnormal Aβ production can be a mechanistic link underlying insulin resistance and diabetes in AD (PMC7357086). In APP × ob/ob double transgenic mice, the onset of diabetes caused exacerbation of Alzheimer-like cognitive impairment without an increase in Aβ load in the brain, supporting the notion that Alzheimer pathology could promote diabetes (PMC7357086). Aβ oligomers directly impair insulin signaling in hippocampal neurons by competitively binding to insulin receptors, reducing receptor autophosphorylation, and causing the loss of insulin receptors from the neuronal surface (PMC8389322, PMC6008657). Soluble Aβ oligomers increase AKT phosphorylation at Ser473, resulting in insulin resistance, and inhibit insulin signaling by phosphorylating IRS-1 at inhibitory serine residues via the JNK/TNF-α pathway (PMC6008657). Aβ and tau proteins have been detected in pancreatic islets in diabetes, and the prevalence of diabetes was higher in patients with AD versus controls (34.6% vs. 18.1%) in one pathological study (PMC7357086). Mendelian randomization analyses have not found a significant causal genetic relationship between AD and T1DM in either direction (OR = 1.010, 95% CI: 0.911–1.116, p = 0.881 for AD → T1DM), suggesting that the bidirectionality observed clinically may be mediated by shared environmental and lifestyle factors rather than direct genetic causation (PMC10790511).

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### Safety Profile and Adverse Events

The safety considerations relevant to this review pertain primarily to the therapeutic interventions being investigated for the T2DM-AD intersection, as the diseases themselves carry well-characterized adverse outcome profiles.

**Intranasal Insulin:** Intranasal insulin administration has shown a favorable safety profile in clinical studies, with only minor side effects such as mild rhinitis reported (PMC8389322). Unlike intravenous insulin, intranasal delivery does not cause systemic hypoglycemia, as the doses delivered centrally are insufficient to produce meaningful peripheral glucose lowering. However, the therapeutic window appears narrow, and APOE4 carriers may not benefit and could potentially experience adverse effects — a critical safety consideration for patient selection (PMC8389322). Long-term safety data from large-scale trials are lacking.

**GLP-1 Receptor Agonists:** GLP-1 RAs are generally well-tolerated in T2DM, with the most common adverse effects being gastrointestinal (nausea, vomiting, diarrhea), which are typically transient and dose-dependent. In the context of AD, the CNS penetration of GLP-1 RAs raises theoretical concerns about potential effects on appetite regulation and body weight in already-frail elderly patients with dementia. No specific safety signals unique to the AD population have been reported in the available literature, though the clinical trial data in AD patients remain limited (PMC8389322, PMC9029855).

**Thiazolidinediones:** Rosiglitazone was withdrawn from the market due to increased cardiovascular risk — a particularly concerning adverse effect in the elderly AD population, who already carry elevated cardiovascular risk (PMC8389322). Pioglitazone is associated with fluid retention, heart failure exacerbation, bladder cancer risk with long-term use, and bone fracture risk in women — all relevant considerations in elderly patients with dementia (PMC8389322). The TOMORROW trial used low-dose pioglitazone specifically to minimize these risks.

**Metformin:** The dual role of metformin — with both putative beneficial and harmful effects in the context of AD — represents a significant safety concern. Metformin's upregulation of BACE1 and promotion of Aβ deposition and insoluble tau aggregation in animal models and gene expression studies suggests that long-term metformin use in T2DM patients may inadvertently accelerate AD pathology in susceptible individuals (PMC5611890). Metformin also reduces vitamin B12 absorption, leading to reduced epidermal growth factor and increased TNF-α, the latter associated with apoptosis and neuroinflammation (PMC5611890). These findings underscore the need for prospective clinical studies comparing metformin-treated T2DM patients with those on alternative therapies with respect to cognitive outcomes.

**GSK-3β Inhibitors:** Tideglusib demonstrated acceptable safety in Phase II trials, but its clinical efficacy was insufficient to support regulatory approval (PMC8389322). The challenge of selectively inhibiting GSK-3β without disrupting its essential physiological functions in glycogen metabolism, cell survival, and neuronal development remains a significant obstacle to therapeutic development.

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### Unresolved Controversies and Disagreements

#### The Causal Directionality Problem

Perhaps the most fundamental unresolved controversy in this field is the question of causal directionality: does T2DM cause AD, does AD cause T2DM, or do both diseases share common upstream causes that drive them in parallel? The epidemiological evidence strongly supports T2DM as a risk factor for AD, but the reverse pathway — AD pathology promoting metabolic dysfunction — is also supported by experimental evidence (PMC7357086, PMC9029855). Mendelian randomization studies, which use genetic variants as instrumental variables to estimate causal effects, have provided some clarity: a bidirectional two-sample MR study found no significant causal genetic relationship between T1DM and AD in either direction (IVW OR = 0.984, 95% CI: 0.958–1.011, p = 0.247 for T1DM → AD; OR = 1.010, 95% CI: 0.911–1.116, p = 0.881 for AD → T1DM) (PMC10790511). However, sensitivity analyses using MR-Egger (OR = 0.957, p = 0.039), weighted median (OR = 0.955, p = 0.001), and weighted mode (OR = 0.959, p = 0.006) suggested a modest protective signal for T1DM against AD, creating disagreement between the primary and sensitivity analyses (PMC10790511). The ROSMAP-based causal inference study found 759 genes connected to both AD and T2DM through direct or indirect causal paths, supporting a shared causal architecture, but the directionality of individual gene-disease relationships remains incompletely resolved (arxiv:1901.05537).

#### Brain Insulin Synthesis: Peripheral vs. Central Origin

A persistent controversy concerns whether the brain synthesizes its own insulin de novo, or whether all brain insulin derives from peripheral pancreatic secretion. Several studies on laboratory animals and humans have suggested that insulin is synthesized de novo in certain brain regions and is important for maintaining the basal function of local circuits; insulin mRNA transcripts have been detected in the hippocampus, hypothalamus, thalamus, and striatum, and reduced levels of insulin mRNA transcripts in the hippocampus and hypothalamus have been shown in the brains of AD patients in post-mortem studies (PMC9569835). The physiological relevance of any locally synthesized insulin remains debated, and the majority of brain insulin is believed to derive from peripheral pancreatic secretion transported across the BBB (PMC8910482, PMC6008657). The contribution of locally synthesized insulin — particularly in the context of AD, where peripheral insulin transport is impaired — remains an open question with therapeutic implications.

#### The Role of Amyloid Pathology in T2DM: Cause or Consequence?

The role of islet amyloid in T2DM pathogenesis — whether causative or consequential — remains debated. Studies have shown that the formation of amyloid deposits in β-cells is a diabetogenic factor, but it is not certain whether diabetic hyperglycemia and insulin resistance induce amyloid deposition in the islets and brain, or whether amyloid deposition is a downstream consequence of metabolic dysfunction (PMC7357086). Similarly, in the brain, it remains unclear whether Aβ accumulation is a primary driver of insulin resistance or a downstream consequence of impaired insulin signaling. The bidirectional amplification loop — wherein insulin resistance promotes Aβ accumulation and Aβ accumulation exacerbates insulin resistance — makes it difficult to identify the initiating event in any individual patient (PMC9739879, PMC8389322).

#### Metformin: Neuroprotective or Neurotoxic?

The dual role of metformin in the context of AD represents one of the most clinically consequential controversies in the field. On one hand, metformin inhibits MAPT phosphorylation through PP2A, inhibits the JNK cascade, reduces AGE formation, and activates AMPK — all potentially neuroprotective mechanisms (PMC5611890). On the other hand, metformin upregulates BACE1 transcription, promotes Aβ deposition via NF-κB1/PSEN1/APP activation, increases oxidative stress and mitochondrial damage, and promotes insoluble tau aggregation in animal models and gene expression studies (PMC5611890). Epidemiological studies have yielded conflicting results: some observational studies suggest metformin use is associated with reduced dementia risk, while others find no benefit or potential harm. The BEL modeling analysis concluded that metformin's effects on AD pathology are complex and potentially bidirectional, with the net outcome depending on individual genetic makeup, epigenetic modifications, and disease stage (PMC5611890). A prospective clinical study directly comparing metformin-treated T2DM patients with those on alternative therapies with respect to cognitive outcomes and AD biomarkers is urgently needed to resolve this controversy.

#### APOE4 Interaction with Diabetes and Dementia Risk

The interaction between APOE4 genotype and T2DM in determining AD risk is controversial. A longitudinal study in Japanese-American men demonstrated that APOE4 increases the risk of LOAD in individuals with T2DM (PMC6008657). In contrast, population-based studies by Marseglia et al. showed an association between T2DM and risk of dementia only in APOE4 non-carriers (PMC6008657). This discrepancy may reflect genuine biological heterogeneity — APOE4 carriers may already have maximally impaired Aβ clearance and BBB function, leaving less room for T2DM to add additional risk — or may reflect differences in study populations, follow-up duration, and covariate adjustment. The interaction between APOE4 and intranasal insulin therapy further complicates the picture: beneficial effects appear limited to non-APOE4 carriers, while APOE4 carriers may not benefit (PMC8389322). This pharmacogenomic interaction has major implications for clinical trial design and patient selection.

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### Limitations of the Evidence Base

The evidence base linking T2DM, central insulin resistance, and dementia is substantial but carries important methodological limitations that constrain causal inference and clinical translation.

**Heterogeneity in Exposure and Outcome Definitions:** Across the 18 longitudinal studies included in the most comprehensive meta-analysis, definitions of abnormal glucose metabolism varied widely — from clinical T2DM diagnosis to HbA1c levels, fasting plasma glucose, and oral glucose tolerance testing — making pooled estimates difficult to interpret (PMC9029855). Similarly, AD diagnosis criteria varied across studies, with some using NINCDS-ADRDA criteria and others relying on clinical or registry-based diagnoses. This definitional heterogeneity contributed to the very high I² values (up to 97%) observed in the hazard ratio meta-analysis (PMC9029855).

**Predominance of Observational Study Designs:** The vast majority of epidemiological evidence derives from observational cohort studies, which are susceptible to confounding by shared risk factors (age, obesity, hypertension, hyperlipidemia, physical inactivity) that independently increase both T2DM and dementia risk. Residual confounding cannot be excluded even in well-adjusted analyses. Randomized controlled trials of antidiabetic interventions for dementia prevention are few, small, and short in duration, limiting the ability to draw firm causal conclusions about therapeutic efficacy.

**Animal Model Limitations:** Much of the mechanistic evidence derives from transgenic rodent models that overexpress mutant human proteins (APP, PSEN1, tau) under artificial promoters, creating pathological conditions that may not fully recapitulate the complexity of sporadic, late-onset human AD. As noted in the reviewed literature, most transgenic AD mouse models lack progressive neuronal loss in the hippocampus and specific neocortical regions characteristic of human AD, and streptozotocin-induced models do not reproduce neurofibrillary tangles (PMC9569835). Separately, rodents cannot aggregate human IAPP, which limits the translational relevance of studies examining IAPP-Aβ cross-seeding in these species (PMC7357086). Species-specific differences in physiology, anatomy, and pharmacokinetics between rodents and humans further limit direct translation.

**Population Selectivity in Genetic Studies:** The Mendelian randomization studies examining causal relationships between T1DM and AD drew exclusively from GWAS data of European-ancestry individuals, limiting generalizability to non-European populations (PMC10790511). The ROSMAP dataset used for multi-omics causal inference comprised 432 individuals drawn from two longitudinal cohort studies — one enrolling Catholic nuns, priests, and brothers from communities across the United States, and another enrolling participants from continuous care retirement communities and individual homes in the Chicago metropolitan area — populations that may not fully represent the broader diversity of individuals with T2DM and dementia risk (arxiv:1901.05537).

**Insufficient Follow-Up Duration:** Many clinical studies of antidiabetic interventions in cognitive outcomes have follow-up durations of months to a few years, which may be insufficient to detect effects on AD pathology that develops over decades. The preclinical phase of AD — during which Aβ accumulates silently before cognitive symptoms emerge — may last 15–20 years, meaning that interventions initiated after cognitive symptoms appear may be too late to meaningfully alter disease trajectory.

**Publication Bias and Selective Reporting:** Egger's test for the hazard ratio meta-analysis showed only marginally significant publication bias (p = 0.053), suggesting that positive studies may be overrepresented in the published literature (PMC9029855). The BEL modeling approach acknowledged publication bias as a concern, partially mitigated by gene expression validation (PMC5611890). Negative trials of antidiabetic drugs in AD (e.g., rosiglitazone, pioglitazone) may be underreported relative to positive findings.

**Lack of Biomarker-Stratified Analyses:** Most epidemiological and clinical studies have not stratified participants by AD biomarker status (Aβ PET, tau PET, CSF Aβ42/tau ratios), making it impossible to determine whether T2DM accelerates the preclinical, prodromal, or dementia stages of AD differentially. Similarly, most studies have not stratified by APOE4 genotype, despite strong evidence that this genetic factor modifies the T2DM-AD relationship.

---

### Conclusions and Future Directions

The evidence reviewed here supports a robust, bidirectional, and mechanistically multifaceted relationship between T2DM, central insulin resistance, and the development of both Alzheimer's disease and vascular dementia. The epidemiological evidence is consistent and quantitatively substantial: T2DM increases the risk of AD by 50–90% in most analyses, with some studies reporting up to 4.3-fold increased risk in insulin-treated patients, and meta-analyses confirming a 56–73% increased risk of AD and dementia overall (PMC9029855, PMC11765393). The mechanistic evidence is equally compelling: impaired central insulin signaling drives GSK-3β hyperactivation, tau hyperphosphorylation, Aβ accumulation via IDE competition and BACE-1 upregulation, neuroinflammation via JNK/IKK/NF-κB pathways, mitochondrial dysfunction, oxidative stress, and BBB disruption — all converging on the neuropathological hallmarks of AD (PMC9029855, PMC8389322, PMC9739879). The reverse pathway — wherein Aβ oligomers impair neuronal insulin signaling and tau pathology accumulates in pancreatic islets — supports genuine bidirectionality rather than a simple unidirectional causal relationship (PMC7357086, PMC6008657). The concept of AD as "type 3 diabetes" captures the essence of this relationship: a state of combined central insulin deficiency and resistance that drives neurodegeneration through mechanisms overlapping with both T1DM and T2DM (PMC8910482, PMC8389322).

What the evidence does NOT support is equally important to state clearly. The evidence does not support a simple, linear causal model in which T2DM mechanistically causes AD through a single pathway. The relationship is multifactorial, with shared genetic architecture, overlapping environmental risk factors, and multiple interacting molecular mechanisms. The evidence does not support the repurposing of any specific antidiabetic drug class for dementia prevention or treatment based on current clinical trial data — existing results are inconsistent, trials are small and short, and some agents (metformin, rosiglitazone) carry potential for harm in the AD context (PMC10594452, PMC5611890). The evidence does not support the conclusion that T1DM carries the same dementia risk as T2DM: Mendelian randomization analyses found no significant causal genetic relationship between T1DM and AD (PMC10790511), and the mechanisms linking T1DM to neurodegeneration appear distinct from those linking T2DM to AD. The evidence does not support the use of intranasal insulin as a standard-of-care intervention for AD, given the limited and APOE4-dependent efficacy observed in clinical studies (PMC8389322, PMC10594452).

**Future Research Priorities:**

1. **Biomarker-stratified longitudinal cohort studies** are urgently needed to determine whether T2DM accelerates the preclinical, prodromal, or dementia stages of AD differentially, using established AD biomarkers (Aβ PET, tau PET, CSF Aβ42/p-tau ratios) as primary endpoints rather than clinical diagnosis alone.

2. **Large-scale, adequately powered randomized controlled trials** of GLP-1 receptor agonists (particularly semaglutide, given the ongoing EVOKE trial) in individuals with early AD or MCI and concurrent T2DM or prediabetes, with pre-specified APOE4 stratification and biomarker endpoints, are needed to determine whether these agents can meaningfully alter AD trajectory.

3. **Prospective comparative effectiveness studies** of metformin versus alternative antidiabetic therapies (GLP-1 RAs, SGLT2 inhibitors, DPP-4 inhibitors) with cognitive outcomes and AD biomarkers as endpoints are needed to resolve the metformin controversy and guide clinical prescribing in T2DM patients at risk for dementia.

4. **Multi-omics studies integrating genomics, epigenomics, transcriptomics, proteomics, and metabolomics** in large, diverse cohorts with both T2DM and AD biomarker data are needed to fully characterize the shared causal architecture of the two diseases and identify novel therapeutic targets beyond the insulin signaling pathway.

5. **Development and validation of IAPP-Aβ cross-seeding inhibitors** — including macrocyclic peptides and other amyloid aggregation inhibitors — represents a novel therapeutic avenue that could simultaneously target both pancreatic and cerebral amyloidogenesis, warranting dedicated preclinical and early clinical investigation (PMC7357086).

6. **Investigation of the prediabetic window** as a critical intervention period is warranted, given evidence that even compensatory hyperinsulinemia — before clinical T2DM is established — is sufficient to worsen AD pathology in animal models (PMC10594452). Clinical studies examining whether intensive lifestyle intervention or pharmacotherapy during prediabetes can reduce subsequent dementia risk are needed.

7. **Sex-stratified analyses** are needed to address the observation that women account for approximately two-thirds of all AD cases and that the interaction between sex hormones, insulin resistance, and AD risk may be particularly important in postmenopausal women (PMC13032323). The role of estrogen in modulating insulin sensitivity and Aβ metabolism warrants dedicated investigation.

8. **Mitochondria-targeted therapeutic strategies** — including compounds that restore mitochondrial bioenergetics (MitoQ, J147, nicotinamide, rapamycin), enhance mitophagy, and activate SIRT1/SIRT3 pathways — represent a mechanistically grounded approach to simultaneously addressing the shared mitochondrial dysfunction of T2DM and AD, and deserve prioritized clinical development (PMC8389322).

9. **Standardization of diagnostic criteria and biomarker definitions** across epidemiological studies of T2DM and dementia is essential to reduce the heterogeneity (I² up to 97%) that currently limits the interpretability of meta-analytic findings (PMC9029855). Adoption of the NIA-AA biological definition of AD (based on Aβ, tau, and neurodegeneration biomarkers) in future epidemiological studies would substantially improve comparability.

10. **Inclusion of diverse, non-European populations** in both epidemiological and mechanistic studies is critical, given that the majority of existing evidence derives from European-ancestry cohorts and that the prevalence of both T2DM and dementia is rising most rapidly in Asia, Africa, and Latin America (PMC7357086, PMC10790511).

In summary, the convergence of T2DM and AD represents one of the most important and tractable intersections in the biology of aging. The shared molecular mechanisms — central insulin resistance, GSK-3β hyperactivation, IDE competition, neuroinflammation, mitochondrial dysfunction, and BBB disruption — provide multiple potential therapeutic targets. The bidirectional nature of the relationship means that effective management of T2DM may reduce dementia risk, while effective treatment of AD may improve metabolic outcomes. Realizing this therapeutic potential will require the integration of mechanistic insights with rigorously designed clinical trials, biomarker-stratified patient selection, and a commitment to studying diverse populations across the full spectrum of metabolic and cognitive disease.

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