Sporadic Alzheimer's Disease Research Articles

EMBER multidimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains

In neurodegenerative diseases, proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations insitu. Here, we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid-binding dyes to identify six distinct different conformational strains invitro, as well as amyloid-β (Aβ) deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in Aβ and tau deposits from Down syndrome, sporadic and familial Alzheimer's disease human brain slices. EMBER has insitu identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick's disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.

Of dolphins, humans, other long-lived animals and Alzheimer's disease (Commentary on Vacher et al.).

Of dolphins, humans, other long-lived animals and Alzheimer's disease (Commentary on Vacher et al.).

Neutrophils as a potential therapeutic target in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in the United States. Sporadic or late-onset AD remains incompletely understood, with age as the current greatest risk factor. Inflammation in general and neutrophils, a potent mediator of inflammation, have been shown to exacerbate AD associated dementia. This review explores the latest research on neutrophils in AD mouse models and in human cohort studies and discusses current gaps in research and needs for future studies. AD mouse models have shown neutrophil chemotactic migration towards amyloid beta plaques in the brain. Capillary blood flow stalling decreases blood perfusion to associated brain regions and mouse studies have demonstrated that anti-Ly6G antibodies lead to a decrease in capillary blood flow stalling and memory improvement. Several recent transcriptomic studies of blood and brain tissue from persons with AD have shown an upregulation in neutrophil-related genes, and studies have demonstrated neutrophil involvement in brain capillary adhesion, blood brain barrier breaching, myeloperoxidase release, and the propensity for neutrophil extracellular trap release in AD. Neutrophil-derived inflammation and regulation are a potential potent novel therapeutic target for AD progression. Future studies should further investigate neutrophil functionality in AD. In addition, other aspects of AD that may impact neutrophils including the microbiome and the APOE4 allele should be studied.

Induced human pluripotent stem cells (HEBHMUi013-A) derived from a patient of sporadic Alzheimer's disease

Sporadic Alzheimer’s disease (sAD) is the most common neurodegenerative disease worldwide, which is characterized by the progressive cognitive dysfunction and behavioral impairment. Here, we generated a human induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) isolated from a 78-year-old male patient clinically diagnosed with sAD. The iPSC line expressed pluripotency markers, showed normal karyotype, and had the ability to differentiate into three germ layers in vitro. This iPSC line may provide a powerful tool for modeling AD in vitro and studying the pathogenesis of sAD.

BMP4-SMAD1/5/9-RUNX2 pathway activation inhibits neurogenesis and oligodendrogenesis in Alzheimer's patients' iPSCs in senescence-related conditions.

In addition to increasing β-amyloid plaque deposition and tau tangle formation, inhibition of neurogenesis has recently been observed in Alzheimer's disease (AD). This study generated a cellular model that recapitulated neurogenesis defects observed in patients with AD, using induced pluripotent stem cell lines derived from sporadic and familial AD (AD iPSCs). AD iPSCs exhibited impaired neuron and oligodendrocyte generation when expression of several senescence markers was induced. Compound screening using these cellular models identified three drugs able to restore neurogenesis, and extensive morphological quantification revealed cell-line- and drug-type-dependent neuronal generation. We also found involvement of elevated Sma- and Mad-related protein 1/5/9 (SMAD1/5/9) phosphorylation and greater Runt-related transcription factor 2 (RUNX2) expression in neurogenesis defects in AD. Moreover, BMP4 was elevated in AD iPSC medium during neural differentiation and cerebrospinal fluid of patients with AD, suggesting a BMP4-SMAD1/5/9-RUNX2 signaling pathway contribution to neurogenesis defects in AD under senescence-related conditions.

Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer’s Disease: A CSF/18F-FDG-PET Study

Glial and microglial cells contribute to brain glucose consumption and could actively participate in shaping patterns of brain hypometabolism. Here, we aimed to investigate the association between 18F-fluorodeoxyglucose (18F-FDG) uptake and markers of microglial and astrocytic activity in a cohort of patients with Alzheimer's Disease (AD). We dosed cerebrospinal fluid (CSF) levels of soluble Triggering Receptor Expressed on Myeloid cells (sTREM2), Glial Fibrillary Acidic Protein (GFAP), a marker of reactive astrogliosis, and β-S100, a calcium-binding protein associated with a neurotoxic astrocytic profile. No associations were found between sTREM-2 and 18F-FDG uptake. Instead, 18F-FDG uptake was associated negatively with CSF β-S100 in the left supramarginal gyrus, inferior parietal lobe and middle temporal gyrus (Brodmann Areas (BA) 21 and 40). Increased β-S100 levels could negatively regulate neuronal activity in the temporo-parietal cortex to prevent damage associated with AD hyperactivity, or rather they could reflect neurotoxic astrocytic activation contributing to AD progression in key strategic areas. We also identified a trend of positive association of 18F-FDG uptake with CSF GFAP in the right fronto-medial and precentral gyri (BA 6, 9 and 11), which has been reported in early AD and could either be persisting as an epiphenomenon tied to disease progression or be specifically aimed at preserving functions in the frontal cortex. Overall, CSF markers of astrogliosis seem to correlate with cortical glucose uptake in symptomatic sporadic AD, highlighting the role of astrocytes in shaping regional hypometabolism and possibly clinical presentation.

A multidimensional ODE-based model of Alzheimer’s disease progression

Data-driven Alzheimer’s disease (AD) progression models are useful for clinical prediction, disease mechanism understanding, and clinical trial design. Most dynamic models were inspired by the amyloid cascade hypothesis and described AD progression as a linear chain of pathological events. However, the heterogeneity observed in healthy and sporadic AD populations challenged the amyloid hypothesis, and there is a need for more flexible dynamical models that accompany this conceptual shift. We present a statistical model of the temporal evolution of biomarkers and cognitive tests that allows diverse biomarker paths throughout the disease. The model consists of two elements: a multivariate dynamic model of the joint evolution of biomarkers and cognitive tests; and a clinical prediction model. The dynamic model uses a system of ordinary differential equations to jointly model the rate of change of an individual’s biomarkers and cognitive tests. The clinical prediction model is an ordinal logistic model of the diagnostic label. Prognosis and time-to-onset predictions are obtained by computing the clinical label probabilities throughout the forecasted biomarker trajectories. The proposed dynamical model is interpretable, free of one-dimensional progression hypotheses or disease staging paradigms, and can account for the heterogeneous dynamics observed in sporadic AD. We developed the model using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative. We illustrate the patterns of biomarker rates of change and the model performance to predict the time to conversion from MCI to dementia.

Intrahippocampal Inoculation of Aβ1-42 Peptide in Rat as a Model of Alzheimer's Disease Identified MicroRNA-146a-5p as Blood Marker with Anti-Inflammatory Function in Astrocyte Cells.

Circulating microRNAs (miRNAs) have aroused a lot of interest as reliable blood diagnostic biomarkers of Alzheimer's disease (AD). Here, we investigated the panel of expressed blood miRNAs in response to aggregated Aβ1-42 peptides infused in the hippocampus of adult rats to mimic events of the early onset of non-familial AD disorder. Aβ1-42 peptides in the hippocampus led to cognitive impairments associated with an astrogliosis and downregulation of circulating miRNA-146a-5p, -29a-3p, -29c-3p, -125b-5p, and-191-5p. We established the kinetics of expression of selected miRNAs and found differences with those detected in the APPswe/PS1dE9 transgenic mouse model. Of note, miRNA-146a-5p was exclusively dysregulated in the Aβ-induced AD model. The treatment of primary astrocytes with Aβ1-42 peptides led to miRNA-146a-5p upregulation though the activation of the NF-κB signaling pathway, which in turn downregulated IRAK-1 but not TRAF-6 expression. As a consequence, no induction of IL-1β, IL-6, or TNF-α was detected. Astrocytes treated with a miRNA-146-5p inhibitor rescued IRAK-1 and changed TRAF-6 steady-state levels that correlated with the induction of IL-6, IL-1β, and CXCL1 production, indicating that miRNA-146a-5p operates anti-inflammatory functions through a NF-κB pathway negative feedback loop. Overall, we report a panel of circulating miRNAs that correlated with Aβ1-42 peptides' presence in the hippocampus and provide mechanistic insights into miRNA-146a-5p biological function in the development of the early stage of sporadic AD.

From attention-deficit hyperactivity disorder to sporadic Alzheimer's disease-Wnt/mTOR pathways hypothesis.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the strongest genetic risk for sAD. Currently, the only clinically approved disease-modifying drugs for AD are aducanumab (Aduhelm) and lecanemab (Leqembi). All other AD treatment options are purely symptomatic with modest benefits. Similarly, attention-deficit hyperactivity disorder (ADHD), is one of the most common neurodevelopmental mental disorders in children and adolescents, acknowledged to persist in adulthood in over 60% of the patients. Moreover, for ADHD whose etiopathogenesis is not completely understood, a large proportion of patients respond well to treatment (first-line psychostimulants, e.g., methylphenidate/MPH), however, no disease-modifying therapy exists. Interestingly, cognitive impairments, executive, and memory deficits seem to be common in ADHD, but also in early stages of mild cognitive impairment (MCI), and dementia, including sAD. Therefore, one of many hypotheses is that ADHD and sAD might have similar origins or that they intercalate with one another, as shown recently that ADHD may be considered a risk factor for sAD. Intriguingly, several overlaps have been shown between the two disorders, e.g., inflammatory activation, oxidative stress, glucose and insulin pathways, wingless-INT/mammalian target of rapamycin (Wnt/mTOR) signaling, and altered lipid metabolism. Indeed, Wnt/mTOR activities were found to be modified by MPH in several ADHD studies. Wnt/mTOR was also found to play a role in sAD and in animal models of the disorder. Moreover, MPH treatment in the MCI phase was shown to be successful for apathy including some improvement in cognition, according to a recent meta-analysis. In several AD animal models, ADHD-like behavioral phenotypes have been observed indicating a possible interconnection between ADHD and AD. In this concept paper, we will discuss the various evidence in human and animal models supporting the hypothesis in which ADHD might increase the risk for sAD, with common involvement of the Wnt/mTOR-pathway leading to lifespan alteration at the neuronal levels.

Simulating the multicausality of Alzheimer's disease with system dynamics.

In Alzheimer's disease (AD), cognitive decline is driven by various interlinking causal factors. Systems thinking could help elucidate this multicausality and identify opportune intervention targets. We developed a system dynamics model (SDM) of sporadic AD with 33 factors and 148 causal links calibrated with empirical data from two studies. We tested the SDM's validity by ranking intervention outcomes on 15 modifiable risk factors to two sets of 44 and 9 validation statements based on meta-analyses of observational data and randomized controlled trials, respectively. The SDM answered 77% and 78% of the validation statements correctly. Sleep quality and depressive symptoms yielded the largest effects on cognitive decline with which they were connected through strong reinforcing feedback loops, including via phosphorylated tau burden. SDMs can be constructed and validated to simulate interventions and gain insight into the relative contribution of mechanistic pathways.

Alterations of ATG4A and LC3B in neurons derived from Alzheimer's disease patients.

We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimer's disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid β peptide (Aβ). This upregulation was reversed by inhibiting Aβ production, suggesting that the intracellular Aβ may be responsible for the upregulation of ATG4A. The LC3B-II/LC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.

Alzheimer's Disease: An Updated Overview of Its Genetics.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1-5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aβ) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the new genetic findings that are closely related to the pathophysiology of AD. Likewise, it analyzes the multiple mutations identified to date through GWAS that are associated with a high or low risk of developing this neurodegeneration. Understanding genetic variability will allow for the identification of early biomarkers and opportune therapeutic targets for AD.

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling.

Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. Methods: We analyzed genes differentially expressed in induced pluripotent stem cell-derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

Type-2 Diabetes, Pancreatic Amylin, and Neuronal Metabolic Remodeling in Alzheimer's Disease.

Type-2 diabetes raises the risk for Alzheimer's disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic β-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid β (Aβ) pathology, in both sporadic and familial Alzheimer's disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. This review summarizes recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggests nutritional and medical effects of food constituents that might prevent and/or ameliorate amylin-mediated neuronal metabolic remodeling.

Chinese herbal compound Jinsiwei improves synaptic plasticity in mice with sporadic Alzheimer's disease induced by streptozotocin.

To investigate the efficacy of Jinsiwei (a patented Chinese herbal compound) on learning and memory impairment, the number of synapses and synaptic plasticity-related structural and functional protein expression in mice with sporadic Alzheimer's disease (SAD) induced by streptozotocin. Seventy-five C57/BL6J male mice were intracerebroventricularly injected with streptozotocin to establish the animal model of SAD. Mice were randomly divided into the model group (MG), donepezil group (DG), and the Jinsiwei high, medium, and low-dose groups (JH, JM, JL). Another fifteen C57/BL6J male mice were injected with artificial cerebrospinal fluid as the control group (CG). The intervention groups were intragastrically administrated with corresponding medicine, while the CG and MG were given 0.5% carboxymethyl cellulose by gavage. After 3 months, the Morris Water Maze test and step-down passive avoidance test were used to assess the learning and memory ability of mice. Synapses in hippocampal CA1 were observed by transmission electron microscope. Immunohistochemistry and western blotting were used to assess the distribution and expression levels of synaptic plasticity-related structural and functional proteins involving drebrin, cofilin, synapsin (syn), and N-methyl D-aspartate receptor subtype 2B (NR2B). The Morris Water Maze results showed that the escape latency in the Jinsiwei intervention groups was significantly shorter than that of the MG. Results of the step-down passive-avoidance test showed that the error times in the Jinsiwei intervention groups were significantly reduced compared with the MG. Transmission electron microscope results showed that the number of synapses in hippocampal CA1 was obviously increased in the Jinsiwei intervention groups compared with the MG. Immunohistochemical and western blotting results revealed that the positive cells and expression levels of drebrin, syn, and NR2B were significantly decreased in the MG and meanwhile cofilin significantly increased, while these changes were reversed after the Jinsiwei treatment. Jinsiwei can alleviate learning and memory impairments in a mouse model of SAD, increase the number of synapses and enhance synaptic plasticity rescuing the expression of drebrin, syn, and NR2B and inhibiting cofilin expression.

The microglial immunoreceptor tyrosine-based motif-Syk signaling pathway is a promising target of immunotherapy for Alzheimer's disease.

The microglial immunoreceptor tyrosine-based motif-Syk signaling pathway is a promising target of immunotherapy for Alzheimer's disease.

The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment.

The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the β-amyloid (Aβ) peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aβ are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase in App gene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. The GCaMP8f Ca2+ reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown of App block the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aβ, either fibrillar or oligomeric, has no effect. In culture, APPSwe (a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and βIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model, both females and males, neurons have elevated levels of APP protein that invade the AIS. In vivo as in vitro, this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD.SIGNIFICANCE STATEMENT While the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity. In vivo and in vitro, modest amounts of excess APP alter the properties of the axon initial segment. The β-amyloid peptide derived from APP is without effect. Consistent with the observed changes in the axon initial segment which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the axon initial segment, suggesting a relationship with AD dementia.

Ether Lipid-Mediated Antioxidant Defense in Alzheimer's Disease.

One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This oxidative stress is a determinant in brain aging, as well as in the onset and progression of sporadic (late-onset) Alzheimer's disease (sAD). Glycerophospholipids are the main lipid category widely distributed in neural cell membranes, with a very significant presence for the ether lipid subclass. Ether lipids have played a key role in the evolution of the human brain compositional specificity and functionality. Ether lipids determine the neural membrane structural and functional properties, membrane trafficking, cell signaling and antioxidant defense mechanisms. Here, we explore the idea that ether lipids actively participate in the pathogenesis of sAD. Firstly, we evaluate the quantitative relevance of ether lipids in the human brain composition, as well as their role in the human brain evolution. Then, we analyze the implications of ether lipids in neural cell physiology, highlighting their inherent antioxidant properties. Finally, we discuss changes in ether lipid content associated with sAD and their physiopathological implications, and propose a mechanism that, as a vicious cycle, explains the potential significance of ether lipids in sAD.

The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer’s Disease

Modeling Alzheimer's disease (AD) using human-induced pluripotent stem cells (iPSCs) is a field now spanning 15 years. Developments in the field have shown a shift in using simple 2D cortical neuron models to more advanced tri-cultures and 3D cerebral organoids that recapitulate more features of the disease. This is largely due to development and optimization of new cell protocols. In this review, we highlight recent major breakthroughs in the AD field and the implications this has in modeling AD using iPSCs (AD-iPSCs). To date, AD-iPSCs have been largely used to recapitulate and study impaired amyloid precursor protein (APP) processing and tau phosphorylation in both familial and sporadic AD. AD-iPSCs have also been studied for varying neuronal and glial dysfunctions. Moreover, they have been useful for discovering new molecular mechanisms, such as identifying proteins that bridge APP processing with tau phosphorylation and for identifying molecular pathways that bridge APP processing dysfunction with impaired cholesterol biosynthesis. Perhaps the greatest use of AD-iPSCs has been in discovering compounds via drug screening, that reduce amyloid beta (Aβ) in neurons, such as the anti-inflammatory compound, cromolyn, and antiparasitic drugs, avermectins. In addition, high content screening using AD-iPSCs has led to the identification of statins that can reduce levels of phosphorylated tau (p-Tau) in neurons. Some of these compounds have made it through to testing in human clinical trials. Improvements in omic technologies including single cell RNA sequencing and proteomics as well as advances in production of iPSC-cerebral organoids and tri-cultures is likely to result in the further discovery of new drugs and treatments for AD. Some caveats remain in the field, including, long experimental conditions to create mature neurons, high costs of media that limit research capabilities, and a lack of reproducibility using current iPSC-cerebral organoid protocols. Despite these current limitations, AD-iPSCs remain an excellent cellular model for studying AD mechanisms and for drug discovery.

Is Alzhezimer’s disease a New Type Diabetes? Crosstalk between two serious disorders: review

Introduction and purpose: More and more reports suggest that diabetes plays an important role in the pathogenesis of Alzheimer's disease (AD). Understanding this link may provide a new approach to modulating the onset and progression of sporadic AD cases. The aim of the study is to present the current state of knowledge on the basic mechanisms and factors influencing the development of AD in patients with type 2 diabetes in the context of clinical practice.&#x0D; State of knowledge: It is estimated that up to 80% of Alzheimer's patients have glucose intolerance or diabetes. Impaired insulin signaling can lead to abnormal processing and accumulation of beta-amyloid protein, which can result in memory deficits and cognitive decline. Insulin deficiency can also cause over-activity of the GSK3 enzyme, leading to tau hyperphosphorylation and senile plaque accumulation. Diabetes can also cause fibrotic changes in cerebral vessels, disrupting brain metabolism and potentially leading to hippocampus atrophy. The release of cytokines during the metabolic syndrome can also cause oxidative stress and neuroinflammation, which may contribute to neuronal atrophy. It has been reported that healthy diet, physical exercises and prevention of metabolic diseases may reduce the incidence of AD.&#x0D; Conclusions: Epidemiological data and pathophysiological studies indicate a significant relationship between these diseases that AD is sometimes called Type 3 diabetes. Early detection of hyperglycemia and its proper management, may be crucial in the context of the clinical prevention of dementia diseases. It is essential to pay attention to the cognitive abilities of patients with metabolic diseases.