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Insulin Resistance, Obesity andBrain HealthJames E. Galvin, MD, MPHExecutive Director: Institute for Healthy Aging and LifespanDirector: Comprehensive Center for Brain HealthCharles E. Schmidt College of MedicineFlorida Atlantic UniversityDisclosures Clinical Trials Research Support Acadia, Amgen, Axovant, Biogen, Eisai,Genentech, Janssen, Novartis, Roche Alzheimer Disease Cooperative Study Alzheimer Prevention Initiative Alzheimer Therapeutic Research Institute National Institutes of Health Florida Department of Health Association for FrontotemporalDegeneration Lewy Body Dementia Association Alzheimer Drug Discovery Fund Mangurian Foundation Langbert Foundation Consultant Biogen, Axovant, Roche, Eisai, Lilly Royalties and License Agreements Eisai, Pfizer, Roche, Lilly, Biogen, Quintiles,AxovantI own no stocks or equities in any Pharmaceutical or Biotechnology CompaniesWhat is Alzheimer’s Disease (AD)?Acknowledgements New York University Stella Karantzoulis, PhD Victoria Raveis, PhD Ab Brody, PhD Licet Valois, MSW Yael Zweig, MSN, ANP, GNP Washington University John Morris, MD University of Kansas David Johnson, PhD Penn State University Marie Boltz, PhD Pace University Jean Bear‐Lehman, PhD Weill Cornell Medical College Lisa Mosconi, PhD Galvin Lab Magdalena Tolea, PhD Stephanie Chrisphonte, MD Stephanie Petrovich, MD Keri Greenfield, MSN, ANP, GNP Catherine Robson, MSN, FNP Marcia Walker, MSN, FNP Niurka Shkolnick, LCSW Amie Rosenfeld, DPT Katty Saravia Mary Lou Riccio Kadesha Chartie Marian Mirsky Joan Gould Angelina Kelly Most common cause of dementia AD Prevalence by Age in Adults 65 YearsAge ,000 8542%2,200,000 Annual treatment costs 200 billion Costs increase as disease progresses 3rd most expensive: heart, cancer Sixth leading cause of death (over age 70) Makes up 50% of all nursing home beds Median cost (2015) 88,000Chronic Diseases in South FloridaPrevalence of Chronic Disease in Medicare Beneficiaries (2013 Data)NationalFloridaPalm BeachCountyBeneficiaries34,126,305 2,243,566174,150Mean Age, y717375Gender, % Female55.154.756.2Dual‐eligible, %21.719.311.2Florida Statistics 5.4 million Americans have AD 250,000 age 65 years (early‐onset)6.5% of Medicare beneficiaries #1510,000 cases (2016)#2720,000 cases (2025)Per capita cases: 14%#15093 deathsMortality: 26/100,000 1 Million caregivers1.2 Million hours#3Care valued at 15MillionMedicaid: 2.3Billion#54Forecast of Alzheimer’s Disease s Disease (%)9.811.311.512.7Coronary Heart Disease (%)Diabetes (%)COPD (%)Hypertension (%)Hypercholesterolemia (%)Strokes 3020505.2 Million (est)7.7 Million (est)16.0 Million (est)85 Years75‐84 Years1. Hebert LE, et al. Arch Neurol. 2003;60(8):1119‐1122.2. Alzheimer’s Association. Alzheimer’s Disease Facts and Figures: 2009.65‐74 Years

Clinical Expression of AD may evolve fromdifferent esNeurofibrillarytanglesNeurodegeneration:Loss of synapses,neurons, dendrites,dendritic spinesCognitiveDeclineDiabetes and the Risk of ADClinicalADOtherpathology Can prevent or treat AD by addressing: AD pathology (plaques, tangles) Other pathologies and mechanismsAdapted from Galvin JE. J Am Geriatr Soc. 2017Ott A, et al Neurology 1999Diabetes is related to strokes but not AD pathology% InfarctsAD PathologyArvanitakis Z, et al. Neurology. 2006;67:1960–1965.Receptors for Advanced Glycation End‐Products(RAGE) RAGE and its ligands contribute toactivation, polarization, and maturationof T cells and antigen‐presenting cells AGEs are modified proteins, globulins,and nucleic acids associated withdiabetes risk May induce changes in adaptiveimmunity, islet cell function, oxidativestress, and systemic inflammation Lead to cross‐linking of intracellularand extracellular proteinsLeung et al, Current Diab Rep, 2017; Byun et al, Pharmacol Ther 2017.Regulation of Insulin Resistance in the Brain Brain insulin resistance appears to be an early and common feature of AD AD has been proposed as a “type 3 diabetes” representing a form ofdiabetes that selectively involves the brain Amyloid pathology as a major mediator of brain insulin resistance in AD Recently, tau protein has been identified as a modulator of brain insulinsignaling Insulin resistance markers such as insulin‐like growth factor (IGF‐1) andinsulin receptor substrate (IRS‐1) are associated with poor cognitiveperformance Insulin degrading enzyme (IDE) may play a role in degrading amyloidprotein in the brainStanley et al, 2016; de la Monte and Wands, 2008; Bomfim et al, 2012, Marcinak et al, 2017; Culberson 2017; Tundo et al 2017Link Between Obesity and Alzheimer’s Disease Obesity prevalence is increasing steadily throughout the world'spopulation in most countries and in parallel the prevalence ofmetabolic disorders including cardiovascular diseases and type 2diabetes is also rising Less is reported about excessive adiposity relationship with poorercognitive performance, cognitive decline and dementia The precise mechanisms that underlie the connections betweenobesity and the risk of cognitive impairment are still largely unknown insulin resistance the gut‐brain axis systemic mediators and central inflammation processes.Solas et al, 2017

Link between Diabetes and Alzheimer’s diseaseAdipokines and risk of Alzheimer Disease Adiponectin is an anti‐inflammatory adipokine Low levels are associated with vascular disease and diabetes Elevated levels are associated with neurodegenerative disease. Leptin is a pro‐inflammatory adipokine Elevation levels associated with diabetes and vascular disease Low levels associated with neurodegenerative disease.Walker and Harrison. Nutrients. 2015;7:7332‐7357.Obesity and risk of ADLipids and Dementia Cross‐sectional studies demonstrate HDL and ApoE levels areinversely associated with dementia Higher levels of ApoJ are marker of prevalent dementia notassociated with future dementia Polyunsaturated fatty acids may be neuroprotectiveProfenno et al, Biol Psych 2010Genetic Link Between Adiposity and AD Genome‐wide association meta‐analysis of body fat percentage (BF%) in100,716 individuals. Twelve loci reached genome‐wide significance (P 5 10‐8) Eight were previously associated with adiposity Four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novelassociations Seven loci showed a larger effect on BF% than on BMI, suggestive of aprimary association with adiposity, while five loci showed larger effects onBMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinctcross‐phenotype association signatures with a range of cardiometabolictraits revealing new insights in the link between adiposity and disease risk.Lu Y, et al Nat Commun 2016Koch and Jensen, Curr Opin Lipidol 2016; Grosso and Estruch, Maturitas 2016Nutrition and the Risk of Dementia Higher intake of vitamin B12, vitamin D and ω‐3 PUFA EPA from foodsources was associated with lower Aβ load Higher β‐carotene and folate intake was associated with higher brainglucose metabolism Higher consumption of saturated fats was associated with lower brainglucose metabolism Cross‐sectional studies demonstrate HDL and ApoE levels are inverselyassociated with dementia Polyunsaturated fatty acids may be neuroprotectiveMosconi L et al BMJ Open 2014; Mosconi et al J Prev Alzheimers Dis 2014

Mediterranean DietRelationship Between MeDi and AD Biomarkers Mediterranean Diet High in grains, olive oil, legumes,cereals, fish Low in saturated fats, red meats Moderate wine with meals Reduces risk of developingdementia Reduces mortality by 73% oncedementia develops Higher MeDi scores wereassociated with a smaller hip‐to‐waist ra o (β 0.25, p 0.03)MeDi scores weresignificantly associatedwith volumes oforbitofrontal cortex,entorhinal cortex andposterior cingulatecortexScarmeas N, et al. Neurology. 2007;69:1084‐1093, Galvin JE. Neurology. 2007;69:1072‐1073, Frsardi V et al, J Alz Dis 2010MIND Diet Brain Healthy Mediterranean‐DASH (Dietary Approachesto Stop Hypertension) Intervention forNeurodegenerative Delay Diet Combine two dietary plans Mediterranean: whole plant foods, grains,legumes, vegetables, fruit, nuts, fish,modest alcohol (red wine) DASH: fruit, vegetables, low‐fat dairyproduces, whole grains, poultry, fish, nutsMarcason W, J Acad Nutr Diet 2015 Green leafy vegetablesOther vegetablesNutsBerriesBeansWhole grainsFishPoultry UnhealthyOlive oil Red meatsWine Butter and stickmargarine Cheese Pastries and sweets Fried or fast foodsMulticultural Community Dementia ScreeningMosconi and McHugh, Curr Opin Nutr 2015MIND DietHigh MINDLow MINDMorris MC et al, Alzheimers Dem 2015Measurement Tools Supported by 2 grants from the National Institute on Aging Community‐based assessment of older adults (target goal 500) Demographics, financial resources, preferencesCognitive‐Behavioral Screening (memory, mood)Medical Screening (blood pressure, diabetes, lung disease, obesity)Physical assessment (balance, frailty, strength)Anthropometric measurementsSocial work follow‐up Subset have Gold Standard testing and biomarkers collected SphygmomanometerBlood pressureMRI scansPET scansEEGBlood and Spinal fluid Repository of multicultural medical, cognitive, and imaging biomarker data: 500 individualswith grant protocol (187,500 data points); a subset of 150 individuals with a Gold Standardevaluation (202,500 data points), structural and functional MRI, FDG‐PET (SUVR), and highdensity EEG (125,000 data points) raw and processed images.DynamometerGrip StrengthBody CompositionImpedanceBone(estimated)WaterLean MuscleFatHemoglobin A1C meterDiabetes RiskStopwatch/Tape MeasureSpirometerForced Expiratory VolumeBodyVisceral

BMI Increases Risk of Cognitive ImpairmentDifferences: Visceral and Body FatBody FatAdjusted Regression Model for BMIVisceral Fat95% CIAge1.041.01 – 1.07Gender.577.33 – 1.01BMI 25‐29.91.510.82 – 2.76BMI 302.201.13 – 4.32R ‐.415, p .003Lean BMI (1‐%body fat * BMI)R ‐.436, p .002Mini‐PPT r .13Adjusted Regression Model for Lean BMIExp(B)95% CIAge.9680.94 – 0.99Gender1.230.65 – 2.33Lean BMI1.000.89 – 1.14MoCA r .19MoCA r .03FDG SUVRExp(B)Mini‐PPT r .36BMIWorse Physical PerformanceDifferences: Visceral and Body FatBody FatWorse Cognitive PerformanceAbdomen/Hip Ratio as Proxy MarkerVisceral FatMoCA r .23FDG SUVRFDG SUVRR ‐.433, p .002Mini‐PPT r .07R .017, p .90R ‐.514, p .001R ‐.444, p .001R ‐.004, p .98R ‐.523, p .001Body Fat (%)Visceral Fat (Lbs)Elevated Hemoglobin A1C and Cognitive Impairment Hemoglobin A1C relates to average plasma glucose concentration over previous 2‐3 months Higher amounts of A1C indicates diabetes risk, poorer control of blood glucose, and risk of heart,kidney and retinal disease For diabetics, goal is below 6% Categories Normal (reference): 5.6% Pre‐diabetes: 5.7‐6.4% Diabetes: 6.5%Adjusted Regression ModelBStd ErrorSigExp(B)95% CIAge.019.030.5191.020.96 – 1.08Gender‐.421.606.49.6570.20 – 2.15Pre‐diabetes .129.675.851.140.30 – 4.27Diabetes.785.044.881.05 – 22.721.58Diabetes increases risk of cognitive impairment 4.8‐foldAbdomen/Hip RatioAbdomen/Hip RatioBlood Based BiomarkersLipid Profile Total cholesterol LDL‐C direct HDL‐C Non‐HDL‐C Triglycerides LDL‐p by NMR Small LDL‐p by NMR HDL‐p by NMRRenal Function Cystatin C Creatinine Est Glomerular Filtration RateMetabolic Electrolytes Glucose Hemoglobin A1C Est Average GlucoseInflammatory markers 25‐hydroxy‐vitamin D Homocysteine Hs‐CRP Vitamin B12 LP‐PLA2 Methlymalonic acid Myeloperoxidase Heart Type Fatty Acid Binding Protein RBC Folate Omega‐3 index Cortisol Adiponectin LeptinGenetic Markers Apolipoprotein E Factor V Leiden Prothrombin MTHFR C677T MTHFR A1298CEndocrine TSH T4 Total Free T3 Total Testosterone Total Free Sex Hormone Binding Protein

Clinical Expression of AD RevisitedLinks between Diabetes and Alzheimer’s Disease B‐Amyloid Insulin signaling Insulin degrading enzyme Inflammation Oxidative stress Mitochondrial dysfunction Advanced glycation end products ApoE4 ration:Loss of synapses,neurons, dendrites,dendritic spines Novel therapeutic approach usingintranasal insulin (INI) has shownpromise in short‐term clinical trials Provide evidence for the mechanismsthrough which INI may produce benefitsby examining key cerebral spinal fluid(CSF) biomarkers andhippocampal/entorhinal atrophy 240 people with aMCI or AD will be giveneither INI or placebo for 12 months,following an open‐label period of 6monthsCraft et al, 2012; ClinicalTrials.govTOMMorrow Study 3500 Individuals age 65‐83 with normal thinking andmemory were enrolled Have polymorphism of TOMM40 gene (possibly increasedrisk of AD) Five years of treatment with pioglitazone, an anti‐diabetesdrugToba et al, 2016; Geldmacher et al, 2011Summary Multiple medical conditions increase the risk of neurodegeneration May be multiple pathways to get Alzheimer’s, Parkinson’s, and related disorders May also be multiple pathways to diagnose, treat, cure or prevent Detection of and interventions addressing root causes (diabetes, obesity) may offer novelapproaches to diagnosing, treating, curing, or preventing Alzheimer’s disease A number of exciting pharmaceutical approaches are attempting to modify AD pathology Many are now targeting pathways related to diabetes Modifiable risk factors (lifestyle, exposure, environment, co‐morbid disease) are excellenttargets to personalize approach to medical care AD and PD are diseases of a lifetime; may be many ways to build a better brain as we age At FAU, we are spearheading game‐changing approaches to improve the lives of ourpatients and their families“An Ounce of Prevention is Worth a Pound of Cure”‐ Benjamin FranklinClinicalAD APOE leads to clinical AD through AD pathology Diabetes may lead to clinical AD through infarctions Obesity may lead to clinical AD through inflammationAdapted from Galvin JE. J Am Geriatr Soc. 2017Study of Nasal Insulin in the Fight AgainstForgetfulness (SNIFF) TrialCognitiveDecline

Licet Valois, MSW Yael Zweig, MSN, ANP, GNP Washington University John Morris, MD University of Kansas David Johnson, PhD Penn State University Marie Boltz, PhD Pace University Jean Bear‐Lehman, PhD Weill Cornell Medical College Lisa Mosconi, PhD What is Alzheimer's Disease (AD)?