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ALZHEIMER'S PREVENTION INITIATIVE APOE4 TRIAL

ADUCANUMAB ALZHEIMER'S PREVENTION TRIAL

APOE IN THE PREDISPOSITION TO, PROTECTION FROM AND PREVENTION OF ALZHEIMER'S DISEASE

ALZHEIMER'S PREVENTION INITIATIVE ADAD COLOMBIA TRIAL PROGRAM - PROJECT SUMMARY/ABSTRACT WHEN THE API AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE (ADAD) COLOMBIA TRIAL (NCT01998841) WAS ANNOUNCED IN 2012, IT LAUNCHED A NEW ERA IN AD PREVENTION RESEARCH. THE TRIAL LED US TO IDENTIFY ~6,000 PERSONS FROM THE WORLD'S LARGEST ADAD KINDRED, INCLUDING NEARLY 1,200 PRESENILIN 1 (PSEN1) E280A MUTATION CARRIERS, WHO ARE VIRTUALLY CERTAIN TO DEVELOP AD AND BECOME COGNITIVELY IMPAIRED AT 44 (SD ± 5) YEARS OF AGE; ESTABLISH THE CLINICAL TRIALS, INFUSION CAPABILITY, PET, AND MRI INFRASTRUCTURE COLOMBIA NEEDED TO CONDUCT INTERVENTIONAL STUDIES IN THE KINDRED; AND INTRODUCE PRECEDENT SETTING SCIENTIFIC, ETHICAL, SOCIAL SUPPORT, AND LOGISTICAL PARADIGMS AS WELL AS PIONEERING SAMPLE SHARING AGREEMENTS. MOREOVER, IT DEMONSTRATED THE ABILITY TO EVALUATE AN EXPERIMENTAL TREATMENT IN A VULNERABLE POPULATION FROM A DEVELOPING COUNTRY IN WAYS THAT THE PARTICIPANTS VALUED, SUCH THAT 94% OF PARTICIPANTS COMPLETED THE 5-8 YEAR TRIAL. IN RECENT LANDMARK PIVOTAL TRIALS, THE AΒ PLAQUE-CLEARING ANTIBODY (PCA) TREATMENTS LECANEMAB AND DONANEMAB WERE ASSOCIATED WITH A SIGNIFICANT CLINICAL BENEFIT IN MILDLY IMPAIRED LATE-ONSET AD (LOAD) PATIENTS, WITH DRAMATIC AΒ PET AND PLASMA PTAU REDUCTIONS, AND SIGNIFICANT EFFECTS ON OTHER AΒ, TAU, NEURODEGENERATIVE, AND INFLAMMATORY (A/T/N/I) BIOMARKERS. THESE DATA PROVIDED COMPELLING SUPPORT FOR THE ROLE OF AΒ AGGREGATES IN THE DEVELOPMENT, TREATMENT, AND PREVENTION OF AD AND SUPPORT THE USE OF BIOMARKER ENDPOINTS THAT ARE LIKELY TO BE ASSOCIATED WITH A CLINICAL BENEFIT. HERE, WE PROPOSE TO CONDUCT A TWO-PART CLINICAL TRIAL IN 200 COGNITIVELY UNIMPAIRED AND MILDLY IMPAIRED PSEN1 MUTATION CARRIERS AND 40 PLACEBO-TREATED NON-CARRIERS FROM THIS REMARKABLE KINDRED. IN PART 1, CARRIERS WILL RECEIVE UP TO 18 MONTHS OF A PLAQUE-CLEARING ANTIBODY (PCA) TREATMENT (EXEMPLAR: DONANEMAB), PERMITTING US TO COMPARE THE MAGNITUDE OF AΒ PET AND PLASMA PTAU REDUCTIONS IN THIS ADAD KINDRED TO THAT OBSERVED IN TRIALS OF THE SAME DRUG IN AΒ+ MILDLY IMPAIRED LOAD PATIENTS AND COGNITIVELY UNIMPAIRED OLDER ADULTS. IN PART 2, CARRIERS WILL BE RANDOMIZED TO RECEIVE 1) CONTINUED PCA TREATMENT, 2) AN ORAL GAMMA SECRETASE MODULATOR (GSM) TREATMENT (EXEMPLAR: RG6289) WITH THE POTENTIAL TO MINIMIZE THE RE-ACCUMULATION OF AΒ AGGREGATES IN A COMPLEMENTARY, POTENTIALLY LESS EXPENSIVE, AND MORE SCALABLE WAY, 3) COMBINED PCA/GSM TREATMENT, AND 4) PLACEBO TREATMENT FOR 18 MONTHS. THIS SEAMLESS, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOUBLE-DUMMY STUDY OF A PCA AND A GSM IN COGNITIVELY UNIMPAIRED AND MCI/MILD AD PSEN1 E280A MUTATION CARRIERS WILL EFFICIENTLY ADDRESS A NUMBER OF KEY QUESTIONS INCLUDING (1) DETERMINING THE EFFICACY OF A PCA IN REDUCING BRAIN AMYLOID LEVELS IN ADAD; (2) EXAMINING THE RELATIVE EFFICACY OF COMBINATION TREATMENT FOLLOWING PCA TREATMENT VERSUS PCA MONOTHERAPY VERSUS GSM MONOTHERAPY VERSUS PLACEBO TO FURTHER LOWER OR MAINTAIN LOW BRAIN AMYLOID LEVELS AS WELL AS ON DOWNSTREAM BIOMARKERS; (3) ESTIMATING HOW LONG PLACEBO-TREATED MUTATION CARRIERS REMAIN AMYLOID NEGATIVE FOLLOWING PCA- INDUCED AMYLOID CLEARANCE; (4) PROVIDING A FOUNDATION FOR UNDERSTANDING THE LONGER TERM CLINICAL IMPACT OF THE INTERVENTIONS LEVERAGING THE COLOMBIAN API REGISTRY; AND (5) PROVIDING INVALUABLE DATA AND SAMPLES FOR THE FIELD.

PET, APOE & THE PRECLINICAL COURSE OF ALZHEIMER'S DISEASE

ALZHEIMER'S PREVENTION INITIATIVE

ALZHEIMER'S PREVENTION INITIATIVE ADAD COLOMBIA TRIAL

ESTABLISHING THE SCIENCE BEHIND ALZHEIMER'S RECRUITMENT REGISTRIES: OPPORTUNITIES FOR INCREASING DIVERSITY AND ACCELERATING ENROLLMENT INTO TRIALS

NATIONAL BRAIN AND TISSUE RESOURCE FOR PARKINSON'S DISEASE AND RELATED DISORDERS

CYCLOTRON PET AND MRI FACILITY IMPROVEMENT: A SCIENTIFIC RESOURCE FOR ARIZONA

OPTIMIZING RESEARCH INFRASTRUCTURE OF REGISTRIES TO ACCELERATE PARTICIPANT RECRUITMENT INTO ALZHEIMER'S FOCUSED STUDIES - PROJECT SUMMARY/ABSTRACT THE SUFFERING CAUSED BY ALZHEIMER'S DISEASE (AD) IS ONE OF THE GREATEST MEDICAL CHALLENGES OF OUR TIME. WITH A HEIGHTENED SENSE OF URGENCY, NUMEROUS AD PREVENTION TRIALS ARE BEING LAUNCHED, REQUIRING AN UNPRECEDENTED NUMBER OF HEALTHY OLDER ADULTS TO BE SCREENED TO IDENTIFY THE THOUSANDS ELIGIBLE TO PARTICIPATE. AT THE SAME TIME, THE NUMBER OF TRIALS IN AFFECTED INDIVIDUALS AND THEIR CARE PARTNERS CONTINUES TO RISE. IN 2019, THERE WERE 156 TRIALS FOR THE TREATMENT OF AD, AN INCREASE FROM 2018. NOTABLY, THIS NUMBER DOES NOT INCLUDE OBSERVATIONAL STUDIES, WHICH ARE ALSO IMPORTANT TO UNDERSTANDING AD AND DEVELOPING NEW INTERVENTIONS TO TREAT OR PREVENT IT. IMPROVING PARTICIPANT RECRUITMENT METHODS HAS BECOME A CRITICAL PRIORITY FOR THE FIELD. INITIATIVES SUCH AS THE NATIONAL PLAN TO ADDRESS AD CALL FOR GREATER ATTENTION TO INCREASING ENROLLMENT INTO CLINICAL TRIALS AND OTHER CLINICAL RESEARCH. AN OUTGROWTH OF THE NATIONAL PLAN IS THE NATIONAL STRATEGY FOR RECRUITMENT AND PARTICIPATION IN ALZHEIMER'S DISEASE CLINICAL RESEARCH WHICH ENUMERATED FOUR GOALS, ONE OF WHICH IS FOCUSED SPECIFICALLY ON THE NEED TO “BUILD AND IMPROVE RESEARCH INFRASTRUCTURE OF REGISTRIES IN ORDER TO RECRUIT AND RETAIN MORE AND MORE DIVERSE QUALIFIED STUDY PARTICIPANTS.” THE OBJECTIVE OF THIS PROPOSAL IS TO DEVELOP, DEPLOY, OPTIMIZE AND AUTOMATE NEW WEBSITE DESIGN/CONTENT, INFRASTRUCTURE AND FUNCTIONALITY TO SUPPORT AND SUSTAIN ONLINE RECRUITMENT, ENGAGEMENT, AND RETENTION OF ADULTS INTERESTED IN PARTICIPATING IN AD-FOCUSED STUDIES, CREATING A SUSTAINABLE AND ENDURING RESOURCE TO RESEARCHERS. TO ACCOMPLISH THIS, WE WILL BUILD OFF OUR SUCCESSFUL ALZHEIMER'S PREVENTION REGISTRY (APR), AN ONLINE REGISTRY LAUNCHED IN 2012 WITH >350,000 MEMBERS, INCLUDING ~90,000 ENROLLED IN ITS GENEMATCH (GM) PROGRAM LAUNCHED IN 2015 VIA THE FOLLOWING AIMS: 1) DEVELOP, DEPLOY, OPTIMIZE AND AUTOMATE A REFRESHED AND SUSTAINABLE WEBSITE PLATFORM FOR THE RECRUITMENT INTO AND ENGAGEMENT OF MEMBERS IN THE APR AND ITS GM PROGRAM; 2) DEVELOP, DEPLOY, OPTIMIZE AND AUTOMATE A REFRESHED WEBSITE PLATFORM SUPPORTING RESEARCHERS' EFFORTS TO RECRUIT APR AND GM MEMBERS; AND 3) DEVELOP, DEPLOY, OPTIMIZE AND AUTOMATE NEW FUNCTIONALITY AND PROCESSES FOR REFERRING APR AND GM MEMBERS TO AD- FOCUSED STUDIES. WE HYPOTHESIZE THAT THE A) REFRESHED WEBSITE WILL INCREASE ENROLLMENT INTO THE APR AND GM AS WELL AS ENGAGEMENT AND RETENTION OF MEMBERS; B) ENHANCED AD-RESEARCHER EXPERIENCE WILL INCREASE THE NUMBER OF RESEARCHERS / STUDY SPONSORS LEVERAGING THE APR/GM FOR THEIR PARTICIPANT RECRUITMENT NEEDS, ALLOWING THEM TO COMPLETE ENROLLMENT FASTER; AND C) NEW FUNCTIONALITY WILL INCREASE THE PERCENTAGE OF APR AND GM MEMBERS SCREENING FOR AND ENROLLING IN AD-FOCUSED STUDIES.

THE GE PETTRACE CYCLOTRON: A SCIENTIFIC RESOURCE FOR THE STATE OF ARIZONA

BLINDED COMPARISON OF DIFFERENT ALPHA-SYNUCLEIN SEEDING ASSAYS AS CUTANEOUS BIOMARKERS OF LEWY BODY DEMENTIAS - ABSTRACT WITH INCREASING LONGEVITY IN OUR POPULATION, DEMENTIA IS WIDELY RECOGNIZED AS AN IMPENDING PUBLIC HEALTH CRISIS. LEWY BODY DEMENTIA (LBD), ENCOMPASSING DEMENTIA WITH LEWY BODIES (DLB) AND PARKINSON DISEASE DEMENTIA (PDD), IS THE SECOND MOST COMMON CAUSE. LBD IS CHARACTERIZED BY ABNORMAL AGGREGATION AND ACCUMULATION OF A PROTEIN, A-SYNUCLEIN (ASYN). PDD AND DLB ARE CLINICALLY SEPARATED ONLY BY THE RELATIVE TIMING OF THE ONSET OF PARKINSONISM AND DEMENTIA. AT PRESENT, ADVANCES IN THE TREATMENT OF THESE CONDITIONS ARE CRITICALLY HAMPERED BY THE LACK OF NON-INVASIVE, INEXPENSIVE BIOMARKERS THAT CAN PROVIDE ACCURATE DIAGNOSTIC AND PROGNOSTIC INFORMATION. THIS SITUATION MAY SOON BE RESOLVED, AS IN RECENT YEARS IT HAS BECOME APPARENT, THROUGH OUR OWN STUDIES AND THOSE OF OTHERS, THAT BIOPSIES OF PERIPHERAL TISSUE SITES CAN DETECT DIAGNOSTICALLY SIGNIFICANT ASYN. OUR PROJECT WILL ASSESS ASYN IN PUNCH BIOPSIES OF THE SKIN. OUR PRELIMINARY DATA FROM NEW “SEEDING ASSAY” METHODS INCLUDING REAL-TIME QUAKING-INDUCED CONVERSION (RT-QUIC) AND PROTEIN MISFOLDING CYCLIC AMPLIFICATION (PMCA), FROM AUTOPSY-CONFIRMED LBD SUBJECTS, INDICATE HIGH SENSITIVITY AND SPECIFICITY FOR PREDICTING THE PRESENCE OF ASYN IN THE SKIN OF AFFECTED SUBJECTS. FURTHER WORK IS NECESSARY TO CONFIRM THESE RESULTS IN LIVING SUBJECTS WITH THESE CONDITIONS, WHICH IS THE OBJECTIVE OF THIS PROPOSED PROJECT. WE WILL BIOPSY, TWICE DURING A FOUR YEAR PERIOD, 90 SUBJECTS WITH ASYN DISEASE, 30 EACH WITH PD, PDD AND DLB, AS WELL AS 30 NORMAL CONTROL SUBJECTS. TWO INDEPENDENT LABORATORIES WILL BLINDLY PERFORM SEPARATELY-DEVELOPED SEEDING ASSAYS, RIGOROUSLY TESTING THE INTERLABORATORY RELIABILITY AND PROVIDING ESTIMATES OF ASYN DENSITY CHANGE OVER TIME. THE SEEDING ASSAY RESULTS WILL BE COMPARED WITH THOSE OBTAINED BY THE CURRENT GOLD-STANDARD BIOPSY METHOD, IMMUNOHISTOCHEMISTRY (IHC). ALL SUBJECTS WILL RECEIVE COGNITIVE AND MOVEMENT DISORDER ASSESSMENTS AT TWO TIMEPOINTS IN THIS FOUR YEAR PROJECT, ENABLING COMPARISONS OF ASSAY MEASURES WITH COGNITIVE AND MOTOR DECLINE RATES. MANY OF THE SUBJECTS WILL BE ENROLLED IN THE ARIZONA STUDY OF AGING AND NEURODEGENERATIVE DISORDERS (AZSAND), A LONGITUDINAL CLINICOPATHOLOGICAL STUDY WITH AN AUTOPSY RATE EXCEEDING 90%. THIS WILL ALLOW, IN A SUBSTANTIAL SUBSET, EVENTUAL NEUROPATHOLOGICAL CONFIRMATION OF THE MOLECULAR CAUSE OF PARKINSONISM AND DEMENTIA IN EACH SUBJECT.

TRACER HARMONIZATION FOR AMYLOID AND TAU PET IMAGING USING STATISTICAL AND DEEP LEARNING TECHNIQUES - PROJECT SUMMARY/ABSTRACT AMYLOID AND TAU ARE TWO HALLMARK PATHOLOGIES OF ALZHEIMER'S DISEASE (AD), WHICH START TO ACCUMULATE IN THE BRAIN LONG BEFORE CLINICAL SYMPTOM ONSET. WITH THE RECENT DEVELOPMENT OF POSITRON EMISSION TOMOGRAPHY (PET) TRACERS, IN VIVO MEASUREMENTS OF THESE TWO PATHOLOGIES BECAME POSSIBLE AND PLAY IMPORTANT ROLES IN IMPROVING OUR UNDERSTANDING OF AD PATHOGENESIS AND PROGRESSION, AND PROVIDE CRITICAL DIAGNOSTIC AND PROGNOSTIC INFORMATION THAT CAN FACILITATE THE TREATMENT DEVELOPMENT EFFORT NOW AND IMPROVE PATIENT OUTCOME WHEN EFFECTIVE TREATMENTS BECOME AVAILABLE. HOWEVER, MULTIPLE PET TRACERS EXIST FOR BOTH AMYLOID AND TAU IMAGING AND GENERATE IMAGES THAT HAVE DIFFERENT VISUAL APPEARANCES AND QUANTITATIVE CHARACTERISTICS. THESE DIFFERENCES LEAD TO DIFFICULTIES IN COMPARING DIFFERENT STUDIES, LEVERAGING THE LARGE VOLUME OF DATA THAT HAVE BEEN COLLECTED TO DATE, AND DEFINING A COMMON CRITERION FOR POSITIVITY. IN THIS PROJECT, WE WILL FOCUS ON THE DEVELOPMENT OF NOVEL TECHNIQUES THAT CAN HARMONIZE PET IMAGING DATA AND GENERATE HIGHLY COMPATIBLE IMAGING DERIVED MEASUREMENTS. WE ARGUE THAT BY ADOPTING ADVANCED STATISTICAL AND DEEP LEARNING TECHNIQUES AND DEVELOPING NOVEL QUANTIFICATION STRATEGIES THAT TAKE FULL USE OF THE AVAILABLE INFORMATION IN IMAGING DATA, SUCCESSFUL HARMONIZATION CAN BE ACHIEVED VIA GENERALIZABLE APPROACHES. SEVERAL LINES OF RESEARCH SUPPORT THIS ARGUMENT: 1) WE RECENTLY DEMONSTRATED THAT USING PARTIAL VOLUME CORRECTION TECHNIQUE TO REDUCE WHITE MATTER SIGNAL CONTAMINATION, IMPROVED AGREEMENTS IN AMYLOID BURDEN MEASUREMENTS DERIVED FROM PIB AND FLORBETAPIR CAN BE OBTAINED; 2) IN OUR PRELIMINARY ANALYSIS, USING MACHINE LEARNING TECHNIQUE, WE CAN SUBSTANTIALLY IMPROVE BETWEEN-TRACER AGREEMENTS IN GLOBAL AMYLOID BURDEN; 3) RECENT ADVANCEMENT IN DEEP LEARNING RESEARCH DEMONSTRATED THE ABILITY TO “IMPUTE” ONE IMAGING MODALITY FROM ANOTHER BY TAKING ADVANTAGE OF THE INHERENT INFORMATION IN LARGE IMAGING DATASETS, AND OUR PRELIMINARY RESULTS DEMONSTRATED ITS POTENTIAL IN IMAGE HARMONIZATION TASKS. IN THIS PROJECT, WE WILL CONTINUE THIS RESEARCH AND DEVELOP A SET OF TECHNIQUES THAT CAN BE USED TO HARMONIZE AMYLOID IMAGING DATA FROM DIFFERENT TRACERS AND EXTENT THIS APPROACH FOR TAU PET HARMONIZATION. OUR SPECIFIC AIMS ARE 1) TO DEVELOP DEEP LEARNING MODELS THAT CAN GENERATE IMPUTED AMYLOID PET IMAGES FROM ONE TRACER BASED ON THE IMAGES FROM ANOTHER TRACER; 2) TO DEVELOP STATISTICAL LEARNING APPROACHES THAT CAN GENERATE HARMONIZED AMYLOID BURDEN MEASUREMENTS; 3) TO ACQUIRE HEAD-TO-HEAD COMPARISON TAU PET IMAGING DATA AND EXAMINE STATISTICAL AND DEEP LEARNING APPROACHES TO THE HARMONIZATION OF TAU PET IMAGING DATA.

DNA METHYLATION IN ALZHEIMER?S DISEASE AND NORMALLY AGED BRAIN

SOCIALLY RELEVANT KNOWLEDGE BASED TELEMEDICINE

SEE NOTICE OF AWARD, ATTACHMENT 1 - TERMS AND CONDITIONS, ATTACHMENT D, STATEMENT OF WORK, ABSTRACT

TRACER HARMONIZATION FOR AMYLOID AND TAU PET IMAGING USING STATISTICAL AND DEEP LEARNING TECHNIQUES - PROJECT SUMMARY/ABSTRACT AMYLOID AND TAU ARE TWO HALLMARK PATHOLOGIES OF ALZHEIMER'S DISEASE (AD), WHICH START TO ACCUMULATE IN THE BRAIN LONG BEFORE CLINICAL SYMPTOM ONSET. WITH THE RECENT DEVELOPMENT OF POSITRON EMISSION TOMOGRAPHY (PET) TRACERS, IN VIVO MEASUREMENTS OF THESE TWO PATHOLOGIES BECAME POSSIBLE AND PLAY IMPORTANT ROLES IN IMPROVING OUR UNDERSTANDING OF AD PATHOGENESIS AND PROGRESSION, AND PROVIDE CRITICAL DIAGNOSTIC AND PROGNOSTIC INFORMATION THAT CAN FACILITATE THE TREATMENT DEVELOPMENT EFFORT NOW AND IMPROVE PATIENT OUTCOME WHEN EFFECTIVE TREATMENTS BECOME AVAILABLE. HOWEVER, MULTIPLE PET TRACERS EXIST FOR BOTH AMYLOID AND TAU IMAGING AND GENERATE IMAGES THAT HAVE DIFFERENT VISUAL APPEARANCES AND QUANTITATIVE CHARACTERISTICS. THESE DIFFERENCES LEAD TO DIFFICULTIES IN COMPARING DIFFERENT STUDIES, LEVERAGING THE LARGE VOLUME OF DATA THAT HAVE BEEN COLLECTED TO DATE, AND DEFINING A COMMON CRITERION FOR POSITIVITY. IN THIS PROJECT, WE WILL FOCUS ON THE DEVELOPMENT OF NOVEL TECHNIQUES THAT CAN HARMONIZE PET IMAGING DATA AND GENERATE HIGHLY COMPATIBLE IMAGING DERIVED MEASUREMENTS. WE ARGUE THAT BY ADOPTING ADVANCED STATISTICAL AND DEEP LEARNING TECHNIQUES AND DEVELOPING NOVEL QUANTIFICATION STRATEGIES THAT TAKE FULL USE OF THE AVAILABLE INFORMATION IN IMAGING DATA, SUCCESSFUL HARMONIZATION CAN BE ACHIEVED VIA GENERALIZABLE APPROACHES. SEVERAL LINES OF RESEARCH SUPPORT THIS ARGUMENT: 1) WE RECENTLY DEMONSTRATED THAT USING PARTIAL VOLUME CORRECTION TECHNIQUE TO REDUCE WHITE MATTER SIGNAL CONTAMINATION, IMPROVED AGREEMENTS IN AMYLOID BURDEN MEASUREMENTS DERIVED FROM PIB AND FLORBETAPIR CAN BE OBTAINED; 2) IN OUR PRELIMINARY ANALYSIS, USING MACHINE LEARNING TECHNIQUE, WE CAN SUBSTANTIALLY IMPROVE BETWEEN-TRACER AGREEMENTS IN GLOBAL AMYLOID BURDEN; 3) RECENT ADVANCEMENT IN DEEP LEARNING RESEARCH DEMONSTRATED THE ABILITY TO “IMPUTE” ONE IMAGING MODALITY FROM ANOTHER BY TAKING ADVANTAGE OF THE INHERENT INFORMATION IN LARGE IMAGING DATASETS, AND OUR PRELIMINARY RESULTS DEMONSTRATED ITS POTENTIAL IN IMAGE HARMONIZATION TASKS. IN THIS PROJECT, WE WILL CONTINUE THIS RESEARCH AND DEVELOP A SET OF TECHNIQUES THAT CAN BE USED TO HARMONIZE AMYLOID IMAGING DATA FROM DIFFERENT TRACERS AND EXTENT THIS APPROACH FOR TAU PET HARMONIZATION. OUR SPECIFIC AIMS ARE 1) TO DEVELOP DEEP LEARNING MODELS THAT CAN GENERATE IMPUTED AMYLOID PET IMAGES FROM ONE TRACER BASED ON THE IMAGES FROM ANOTHER TRACER; 2) TO DEVELOP STATISTICAL LEARNING APPROACHES THAT CAN GENERATE HARMONIZED AMYLOID BURDEN MEASUREMENTS; 3) TO ACQUIRE HEAD-TO-HEAD COMPARISON TAU PET IMAGING DATA AND EXAMINE STATISTICAL AND DEEP LEARNING APPROACHES TO THE HARMONIZATION OF TAU PET IMAGING DATA.

ARE THE SUPPRESSORS OF CYTOKINE SIGNALING INVOLVED IN ALZHEIMER'S DISEASE?

CARDIOVASCULAR GENOTYPE AND APOE ?4 CARRIER STATUS INTERACTION EFFECTS ON AMYLOID LOAD IN PRE-CLINICAL ALZHEIMER'S DISEASE - PROJECT SUMMARY RESEARCH AND TREATMENT APPROACHES IN PRE-CLINICAL ALZHEIMER'S DISEASE (AD) HAVE FOCUSED PRIMARILY ON THE DEPOSITION AND CLEARANCE OF BETA-AMYLOID WHICH LEADS TO THE FORMATION OF CORTICAL PLAQUES AND NEUROFIBRILLARY TANGLES, A HALLMARK OF AD PATHOLOGY. HOWEVER, THE ROLE THAT VASCULAR FACTORS MAY HAVE IN THE DEVELOPMENT OF THESE PATHOLOGIES IS NOT CLEAR. EPIDEMIOLOGICAL STUDIES HAVE SUGGESTED THAT RISK FACTORS SUCH AS HIGH CHOLESTEROL, HYPERTENSION, TYPE 2 DIABETES, AND INFLAMMATION ARE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING AD. SEVERAL STUDIES HAVE DEMONSTRATED THAT CERTAIN CARDIOVASCULAR GENETIC MARKERS ARE ASSOCIATED WITH CLINICAL AD AND ITS PATHOLOGICAL HALLMARKS. SPECIFIC POLYMORPHISMS OF THE CRP GENE (RS3091244, AND RS3093075) ARE ASSOCIATED WITH GREATER PLAQUE LOAD WHILE THE RS1205 AND RS2794521 POLYMORPHISMS APPEARS TO PROTECT AGAINST AMYLOID DEPOSITION. THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE HAS BEEN IMPLICATED AS A SUSCEPTIBILITY MARKER FOR AD AND IS ALSO RECOGNIZED AS AN IMPORTANT FACTOR IN CARDIOVASCULAR DISEASE DUE TO ITS ROLE IN REGULATING HOMOCYSTEINE. THE MTHFR C677T (RS1801133) POLYMORPHISM IS A MARKER OF INTEREST IN BOTH THE AD AND CARDIOVASCULAR CONTEXTS AND IT IS NOTED THAT THIS POLYMORPHISM INTERACTS WITH APOE CARRIER STATUS ON CARDIOVASCULAR OUTCOMES. THERE IS ALSO EVIDENCE THAT THE RS1801131 POLYMORPHISM INFLUENCES THE RISK OF AD AND HAS SHOWN TO MODERATE THE EFFECT OF APOE ON AD RISK. VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) HAS ALSO BEEN IMPLICATED IN AD AS THE C2578A ALLELE (RS699947) HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR AD IN WHICH A SIGNIFICANT VEGF BY APOE INTERACTION MAY PLAY A ROLE. THE G1154A (RS1570360) POLYMORPHISM OF VEGF HAS SHOWN TO HAVE A PROTECTIVE EFFECT FOR AD. THE KINESIN FAMILY MEMBER 6 (KIF6) GENE'S 719ARG POLYMORPHISM (RS20455) HAS BEEN STRONGLY IMPLICATED IN THE RISK FOR CARDIOVASCULAR EVENTS, BUT ITS POSSIBLE ROLE IN AD HAS NOT BEEN FULLY INVESTIGATED. THE RS3025039 POLYMORPHISM HAS ALSO SHOWN CONSISTENT ASSOCIATIONS WITH CARDIOVASCULAR DISEASE HOWEVER ITS LINK WITH AD RISK OR PATHOLOGY IS UNKNOWN. THE AIM OF THIS STUDY WILL BE TO EXAMINE THE EFFECTS OF THESE CARDIOVASCULAR GENE MARKERS ON IMAGING-BASED MEASURES OF AMYLOID IN COGNITIVELY UNIMPAIRED OLDER ADULTS. THIS STUDY WILL ALSO EXPLORE WHETHER THE INTERACTIONS BETWEEN APOE E4 CARRIER STATUS AND THESE ALLELES ARE ASSOCIATED WITH IN VIVO PLAQUE AND TANGLE LOAD.

BOLD AND PERFUSION FMRI OF ALZHEIMER'S DISEASE RISK

RURAL HEALTH NETWORK DEVELOPMENT PLANNING GRANT PROGRAM

RURAL HEALTH NETWORK DEVELOPMENT PLANNING GRANT PROGRAM

INTEGRATIVE ONCOLOGY: FROM RESEARCH TO PRACTICAL APPLICATIONS

PET APOE & THE PRECLINICAL COURSE OF ALZHEIMER DISEASE