Hyperinsulinemia,Insulin Resistance and Cognitive Decline in Older Cohort

Objective decline of resistance whether H Type 2 diabetes has been recently recognized as an important risk factor for cognitive patients with Alzheimer＇s disease （AD）. But the roles of hyperinsulinemia （HI） and insulin （IR） in the development of AD are still controversial. This study was designed to evaluate or IR influenced the cognitive functions of older cohort. Methods The cognitive functions of 328 consecutive elderly patients were evaluated with a battery of cognitive rating scales. Their fasting blood glucose （FBG） and fasting insulin （FINS） were analyzed and IR was calculated with modified-Homa. The cognitive scores in different groups and the correlation of cognitive functions with HI or IR were analyzed. Results In our study, there were 180 participants with HI and 148 without HI, and 192 with iR and 136 without IR. The participants with HI showed worse cognitive functions than those without HI in MMSE, MOCA, CDR, orientation, delayed memory, and attention/calculation domains. Similarly, the elderly with IR had lower cognitive scores than those without IR in MMSE, MOCA, CDR, GDS, orientation, delayed memory, and attention/calculation domains. The insulin levels and Homa IR had negative correlation with the scores of MMSE and delayed memory, not only in the model I adjusted for FBG and diabetes history, but also in the model 2 adjusted for all nine demographic characteristics. Conclusion HI and IR are important risk factors for cognitive decline of the elderly, especially for the dysfunctions in delayed memory domains.

Hyperinsulinemia,cancer and maqui berry:The promise of nutritional supplementation

Nutritional supplementation has long been studied as a possible treatment alternative or as an adjunct to the standard treatments for common ailments and diseases.According to the latest research,the Chilean maqui berry,Aristotelia chilensis,has been shown to reduce postprandial insulin levels by as much as fifty percent.The berry,which has been shown to be as effective as metformin at increasing insulin sensitivity and controlling blood glucose levels,follows a simple mechanism of action that involves the inhibition of sodium dependent glucose transporters in the small intestine,slowing the rate at which sugars enter the bloodstream and thereby decreasing blood sugar spikes and the corresponding increase in insulin levels.Chronically high blood glucose levels have been proven to play a significant role in the development of cancers,as diabetics and prediabetics have been proven to have elevated risk of developing cancerous growth.Consistent dietary supplementation with maqui berry may therefore indirectly reduce the risk of cancer,as well as other diseases which respond negatively to hyperglycemia and hyperinsulinemia.

Hyperinsulinemia and insulin resistance in a patient with type 2 diabetes complicated with myelofibrosis

Inflammation induces insulin resistance and hyperinsulinemia due to elevation of serum cytokines such as tumor necrosis factor-α and interleukins. Chronic myeloproliferative diseases including myelofibrosis show higher serum interleukin levels than healthy subjects, which has been suggested to be the useful markers for disease activity. However, an association between myelofibrosis and insulin resistance has not ever been discussed anywhere. Here we report a case of type 2 diabetes showing remarkable hyperinsulinemia and insulin resistance possibly due to myelofibrosis.

An androgen induced hyperinsulinemic and hyperandrogenic anovulatory rat model

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Atherogenic lipids profile relates to postprandial hyperglycemia and hyperinsulinemia due to whole body insulin resistance in prediabetic subjects

Backgrounds: Differences in serum lipids profiles in different type of glucose intolerance are unclear. Aims: To characterize lipid profiles in different type of glucose intolerance, and to assess relationships between serum lipids profile and disturbance of glucose metabolism in prediabetic subjects. Methods: Using the measurements in medical check-up with 75 goral glucose tolerance test (OGTT), total of 620 male subjects, who are not on medications for metabolic diseases or hypertension, were divided into normal fasting glucose and glucose tolerance (NFG/ NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined IFG and IGT (IFG/IGT) based on results of the OGTT. Results: Age and body mass index (BMI) were similar in the four groups. Matsuda index (an index of whole body insulin sensitivity) was lower in iIFG, iIGT and IFG/IGT as compared with NFG/NGT. Plasma insulin excursion during the OGTT was significantly higher in IFG/IGT versus NFG/NGT. Serum triglyceride level (TG) and TG to HDL ratio (TG/HDL) were higher in IFG/IGT versus NFG/NGT. Matsuda index was positively correlated with HDL and was inversely correlated with TG, LDL, non-HDL, TG/ HDL and LDL to HDL ratio (LDL/HDL). Backward stepwise multiple regression analysis indicated that increases in BMI, plasma insulin level at 60 min (PI60) and plasma glucose level at 120 min in the OGTT were independently associated with increases in TG and TG/HDL. Increases in BMI and PI60 were related to an increase in non-HDL and LDL/HDL and a decrease in HDL. Conclusions: These results indicate that postprandial hyperglycemia and hyperinsulinemia based on advanced insulin resistance are closely related to lipid risk factors of atherosclerotic macrovascular disease in prediabetic subjects.

Influence of physiological and supraphysiological hyperinsulinemia on skin microcirculation in healthy volunteers

AIM:To examine skin perfusion in dependency on insulinemia in healthy subjects.METHODS:All volunteers were informed in detail about the procedures and signed informed consent.The protocol of this study was approved by the ethical committee.In our study,a two stage hyperinsulinemic euglycemic clamp was performed,with insulinemia 100and 250 mIU/mL and glycemia 5.0 mmol/L(3%standard deviation).Before the clamp and in steady states,microcirculation was measured by laser Doppler flowmetry and transcutaneous oximetry and energy expenditure was measured by indirect calorimetry.Results(average and standard deviation)were evaluated with pairedt-test.RESULTS:Physiological(50 mIU/L)insulinemia led to higher perfusion in both tests;hyperemia after heating to 44%-1848%(984-2046)vs 1599%(801-1836),P<0.05,half time of reaching peak perfusion after occlusion release 1.2 s(0.9-2.6)vs 4.9 s(1.8-11.4),P<0.05.Supraphysiological(150 mIU/L)insulinemia led to even higher perfusion in both tests;hyperemia after heating to 44%-1937%(1177-2488)vs 1599%(801-1836),P<0.005,half time to reach peak perfusion after occlusion release 1.0 s(0.7-1.1)vs 4.9 s(1.8-11.4),P<0.005.A statistically significant increase occurred in tissue oxygenation in both insulinemia.The difference in perfusion and oxygenation between physiological and supraphysiological hyperinsulinemia was not statistically significant.CONCLUSION:The post occlusive hyperemia test in accordance with heating test showed significantly increasing skin perfusion in the course of artificial hyperinsulinemia.This effect rises non-linearly with increasing insulinemia.Dependency on the dose was not statistically significant.

Role of Estradiol, Progestins, Insulines and Adipocytokines in Breast Cancer Promotion in Post-Menopausal Women

Estrogens and artificial progestins used in hormone replacement therapy increase breast cancer risk. This seems to bedue to a promoting and not initiating effect. A synergic effect of estradiol and hyperinsulinism has been shown. Insulinplays a role in the increase of breast cancer risk when associated with android obesity, sedentariness, type II diabetes,and high glycemic index food, alcohol and trans fatty acids intake. Natural menopause induces insulin resistance anddoes not induce a risk decrease. The role of insulin gives a new outlook on the influence of HRT in breast cancer promotion:estradiol alone, which improves insulin-sensitivity, does not increase breast cancer risk. Artificial progestinsassociated with estrogens increase the risk, whereas estrogens associated with progesterone do not. This could be dueto the fact that artificial progestins increase insulin resistance, whereas natural progesterone does not. Adipose tissue,which is an endocrine gland, is insulin dependant. Breast cancer and its seriousness are correlated to adipocytokincirculating levels such as resistin, leptin, interleukin 1, adipocyte fatty acid-binding protein, and are inversely correlatedto the level of adiponectin. Insulin could play a synergic role with sexual steroids by a direct effect and by increasingadipose tissue secretions.

The Effects of a Hyperinsulinemic-Euglycemic Clamp on Milk Fat Synthesis and the Expression of Fat Synthesis-Related Genes in the Mammary Gland Tissues of Lactating Goats

To determine whether insulin exerts an effect on milk fat yield through the direct regulation of milk fat synthesis in the mammary gland, the hyperinsulinemic-euglycemic clamp procedure was performed in lactating goats in the present study. The effects of the hyperinsulinemic-euglycemic clamp on milk yield, milk composition, milk fatty acid yield and the expression levels of mRNAs of milk fat synthesis-related genes were examined. The results revealed that the hyperinsulinemiceuglycemic clamp had no significant effect on the milk yield, the milk protein yield, the yield and content of lactose or the yield and content of solids-not-fat (SNF) (P > 0.05). In contrast, the milk fat percentage and milk fat yield were decreased by 35.3% and 33.6%, respectively (P < 0.01). Among the 19 fatty acids examined, the yields of 9 fatty acids were significantly reduced (P < 0.05) following the clamp procedure, including C16:0 (hexadecanoic acid), 3 fatty acids derived from blood (>C16) and 5 fatty acids synthesized de novo in the mammary gland ( 0.05), including acetyl-coenzyme A carboxylase (ACC), fatty acid synthase (FAS), fatty acidbinding protein (FABP), lipoprotein lipase (LPL), stearoyl-CoA desaturase (SCD) and glycerol-3-phosphate acyltransferase (GPAT). However, the expression level of the SCD gene was significantly reduced during the post-procedure period (P < 0.05) but returned to a normal level at 48 h after termination of the clamp procedure. It was concluded that the hyperinsulinemic-euglycemic clamp exerted a direct effect on milk fatty acid desaturation.

EFFECT OF ACUPUNCTURE ON HYPERLEPTINAEMIA AND HYPERINSULINEMIA IN OBESITY RATS

Objective: To observe the effect of acupuncture on hyperleptinaemia and hyperinsulinemia for studying its underlying mechanism about anti-obesity and reducing blood lipid in obesity rats. Methods: A total of 80 SD rats were randomized into normal control, model, acupuncture and medication groups, with 20 cases in each group. Hypothalamic obesity model was established by subcutaneous injection of 15% sodium glutamate (0.2 mL/10 g body weight), once daily and continuously for 5 days. “Zusanli” (足三里 ST 36), “Sanyinjiao”(三阴交 SP 6), “Guanyuan”(关元 CV 4) and “Zhongwan”(中脘 CV 12) were punctured and stimulated electrically (100 Hz, dense-sparse waves, and a suitable strength inducing local muscular tremor) for 15 min, once daily. In medication group, rats were fed with Sibutramine 4 mg/kg, once daily. After 4 weeks’ treatment, Lee’s index was detected, and serum leptin and insulin contents were determined by radioimmunoassay (RIA). Results: Compared with normal control group, Lee’s index, serum leptin and insulin contents of model group increased significantly (P<0.01). Comparison between acupuncture and model groups, Lee’s index and serum leptin of acupuncture group decreased significantly (P<0.01), and serum insulin level also lowered. In comparison with model group, Lee’s index, serum leptin and insulin levels of medication group also lowered. Comparison between acupuncture and medication groups showed that Lee’s index and serum leptin level of acupuncture group were significantly lower than those of the later group (P<0.01), displaying that the therapeutic effect of acupuncture is better than that of Sibutramine in lowering Lee’s index and serum leptin. No significant differences were found between acupuncture and medication groups in body weight and length and serum insulin(P>0.05). Conclusion: Acupuncture can effectively reduce Lee’s index, serum leptin and insulin contents in fasting obese rats, which may contribute to its effect in anti-obesity.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Decoding the nexus:branched-chain amino acids and their connection with sleep,circadian rhythms,and cardiometabolic health

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.

Role of metabolic dysfunction and inflammation along the liver-brain axis in animal models with obesity-induced neurodegeneration

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship.Peripheral lipid accumulation,particularly in the liver,initiates a cascade of inflammatory processes that extend to the brain,influencing critical metabolic regulatory regions.Ceramide and palmitate,key lipid components,along with lipid transporters lipocalin-2 and apolipoprotein E,contribute to neuroinflammation by disrupting blood–brain barrier integrity and promoting gliosis.Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation.Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models.However,translating these findings to clinical practice requires further investigation into human subjects.In conclusion,metabolic dysfunction,peripheral inflammation,and insulin resistance are integral to neuroinflammation and neurodegeneration.Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

Microplastic and nanoplastic exposure and risk of diabetes mellitus

The issue of plastic pollutants has become a growing concern.Both microplastics(MPs)(particle size<5 mm)and nanoplastics(NPs)(particle size<1μm)can cause DNA damage,cytotoxicity,and oxidative stress in various organisms.The primary known impacts of microplastic/nanoplastic are observed in the liver and respiratory system,leading to hepatotoxicity and chronic obstructive pulmonary disease.Although research on the effects of MPs and NPs on diabetes is still in its early stages,there are potential concerns.This editorial highlights the risk to diabetics from co-exposure to contaminants and MPs/NPs,supported by evidence from animal studies and the various chemical compositions of MPs/NPs.

BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes

Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Enteric neuropathy in diabetes:Implications for gastrointestinal function

Diabetes,commonly known for its metabolic effects,also critically affects the enteric nervous system(ENS),which is essential in regulating gastrointestinal(GI)motility,secretion,and absorption.The development of diabetes-induced enteric neuropathy can lead to various GI dysfunctions,such as gastroparesis and irregular bowel habits,primarily due to disruptions in the function of neuronal and glial cells within the ENS,as well as oxidative stress and inflammation.This editorial explores the pathophysiological mechanisms underlying the development of enteric neuropathy in diabetic patients.Additionally,it discusses the latest advances in diagnostic approaches,emphasizing the need for early detection and intervention to mitigate GI complications in diabetic individuals.The editorial also reviews current and emerging therapeutic strategies,focusing on pharmacological treatments,dietary management,and potential neuromodulatory interventions.Ultimately,this editorial highlights the necessity of a multidisciplinary approach in managing enteric neuropathy in diabetes,aiming to enhance patient quality of life and address a frequently overlooked complication of this widespread disease.

Muscle strength and non-alcoholic fatty liver disease/metabolicassociated fatty liver disease

This editorial comments on an article published in a recent issue of World Journal of Gastroenterology,entitled“Association of low muscle strength with metabolic dysfunction-associated fatty liver disease:A nationwide study”.We focused on the association between muscle strength and the incidence of non-alcoholic fatty liver disease(NAFLD)and metabolic-associated fatty liver disease(MAFLD),as well as the mechanisms underlying the correlation and related clinical applications.NAFLD,which is now redefined as MAFLD,is one of the most common chronic liver diseases globally with an increasing prevalence and is characterized by malnutrition,which may contribute to decreased muscle strength.Reduction of muscle strength reportedly has a pathogenesis similar to that of NAFLD/MAFLD,including insulin resistance,inflammation,sedentary behavior,as well as insufficient vitamin D.Multiple studies have focused on the relationship between sarcopenia or muscle strength and NAFLD.However,studies investigating the relationship between muscle strength and MAFLD are limited.Owing to the shortage of specific medications for NAFLD/MAFLD treatment,early detection is essential.Furthermore,the relationship between muscle strength and NAFLD/MAFLD suggests that improvements in muscle strength may have an impact on disease prevention and may provide novel insights into treatments including dietary therapy,as well as tailored physical activity.

Body composition and metabolic syndrome in patients with type 1 diabetes

BACKGROUND In recent years,the prevalence of obesity and metabolic syndrome in type 1 diabetes(T1DM)patients has gradually increased.Insulin resistance in T1DM deserves attention.It is necessary to clarify the relationship between body composition,metabolic syndrome and insulin resistance in T1DM to guide clinical treatment and intervention.AIM To assess body composition(BC)in T1DM patients and evaluate the relationship between BC,metabolic syndrome(MS),and insulin resistance in these indi-viduals.METHODS A total of 101 subjects with T1DM,aged 10 years or older,and with a disease duration of over 1 year were included.Bioelectrical impedance analysis using the Tsinghua-Tongfang BC Analyzer BCA-1B was employed to measure various BC parameters.Clinical and laboratory data were collected,and insulin resistance was calculated using the estimated glucose disposal rate(eGDR).RESULTS MS was diagnosed in 16/101 patients(15.84%),overweight in 16/101 patients(15.84%),obesity in 4/101(3.96%),hypertension in 34/101(33.66%%)and dyslip-idemia in 16/101 patients(15.84%).Visceral fat index(VFI)and trunk fat mass were significantly and negatively correlated with eGDR(both P<0.001).Female patients exhibited higher body fat percentage and visceral fat ratio compared to male patients.Binary logistic regression analysis revealed that significant factors for MS included eGDR[P=0.017,odds ratio(OR)=0.109],VFI(P=0.030,OR=3.529),and a family history of diabetes(P=0.004,OR=0.228).Significant factors for hypertension included eGDR(P<0.001,OR=0.488)and skeletal muscle mass(P=0.003,OR=1.111).Significant factors for dyslipidemia included trunk fat mass(P=0.033,OR=1.202)and eGDR(P=0.037,OR=0.708).CONCLUSION Visceral fat was found to be a superior predictor of MS compared to conventional measures such as body mass index and waist-to-hip ratio in Chinese individuals with T1DM.BC analysis,specifically identifying visceral fat(trunk fat),may play an important role in identifying the increased risk of MS in non-obese patients with T1DM.

Polyoxidovanadates a new therapeutic alternative for neurodegenerative and aging diseases

Aging is a natural phenomenon characterized by a progressive decline in physiological integrity,leading to a deterioration of cognitive function and increasing the risk of suffering from chronic-degenerative diseases,including cardiovascular diseases,osteoporosis,cancer,diabetes,and neurodegeneration.Aging is considered the major risk factor for Parkinson’s and Alzheimer’s disease develops.Likewise,diabetes and insulin resistance constitute additional risk factors for developing neurodegenerative disorders.Currently,no treatment can effectively reverse these neurodegenerative pathologies.However,some antidiabetic drugs have opened the possibility of being used against neurodegenerative processes.In the previous framework,Vanadium species have demonstrated a notable antidiabetic effect.Our research group evaluated polyoxidovanadates such as decavanadate and metforminium-decavanadate with preventive and corrective activity on neurodegeneration in brain-specific areas from rats with metabolic syndrome.The results suggest that these polyoxidovanadates induce neuronal and cognitive restoration mechanisms.This review aims to describe the therapeutic potential of polyoxidovanadates as insulin-enhancer agents in the brain,constituting a therapeutic alternative for aging and neurodegenerative diseases.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.