THE WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC

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001-021-804

Alabama

THE WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC (AL)

G192A9HR62S5

4FVB8

2026-05-15

WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE INC

https://burke.weill.cornell.edu/

2025-05-16

2006-06-23

4FVB8

Obsolete

Non-Manufacturer

2025-05-16

2026-05-15

RAJIV RATAN

https://burke.weill.cornell.edu/

133434924

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2025-04-07

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Department of Health and Human Services

THE ROLE OF NEURONAL HYPEREXCITABILITY AND PROTEOSTASIS IN ALZHEIMER'S DISEASE - KEY PRODROMAL EVENTS IN ALZHEIMER’S DISEASE (AD) REVOLVE ON ALTERED ELECTRICAL SIGNALS AND BUILDUP OF GARBAGE PROTEINS IN VULNERABLE AREAS BEFORE SIGNS OF AD (LOCUS COERULEUS, LC)) AND AS DISEASE PROGRESSES TO BRAIN REGIONS THAT GOVERN MEMORY (HIPPOCAMPUS, HPC) AS DISEASE SEVERITY INCREASES. THIS STUDY BRIDGES THE POTENTIAL LIFESPAN OF DISEASE PROGRESSION USING A MOUSE MODEL OF AD PATHOLOGY TO EXAMINE HOW MODIFICATIONS IN BRAIN ACTIVITY CAN LEAD TO DISEASE. THE LC, WHILE NOT TRADITIONALLY ASSOCIATED WITH AD, IS THE SITE OF SOME OF THE EARLIEST PATHOLOGY IN AD, AS EARLY AS PEOPLE IN THEIR 20S. IT IS ALSO AN AREA REGULATING FLIGHT OR FIGHT RESPONSE AND AROUSAL. IN AD, THE HYPEREXCITATION OR UNREGULATED AROUSAL (HYPERAROUSAL) MAY BE A KEY EVENT IN MOVING THE DISEASE FROM AREAS LIKE THE LC, OR ANOTHER AREA WITH EARLY PATHOLOGY, THE ENTORHINAL CORTEX (EC) TO THE HIPPOCAMPUS OR OTHER CORTICAL REGIONS THAT ARE MORE COMMONLY ASSOCIATED WITH ALZHEIMER’S. IN AD, THE ACCUMULATION OF AGGREGATED PROTEINS DUE TO ALTERED CELLULAR PROCESSES, SPECIFICALLY, THE REGULATION OF PROTEIN LIFE CYCLE (PROTEOSTASIS) AND DYSFUNCTION OF AUTOPHAGIC-LYSOSOMAL AND UBIQUITIN-PROTEASOMAL SYSTEMS IS A KEY FEATURE OF NEUROPATHOLOGY. THESE PROCESSES ARE RESPONSIBLE FOR CLEARING THE GARBAGE IN CELLS AND DECLINES WITH AGE AND IS ACCELERATED IN DISEASE. WHILE WE KNOW LOSS OF PROTEOSTASIS CAN IMPAIR CELLULAR FUNCTION, HOW IT CAN IMPEDE NEURONAL ACTIVITY HAS NOT BEEN WELL ADVANCED. IN THIS APPLICATION, WE PROPOSE THAT A PRIMARY EVENT EARLY ON IS THE ALTERATION OF NEURAL NETWORKS IN THE LC (AND EC), LEADS TO THE PATHOLOGICAL HALLMARKS OF AD INCLUDING HIPPOCAMPAL PATHOLOGY. DEMONSTRATING HYPERACTIVATION AND PROTEOSTASIS DEFICITS IN THE LC AS INSTIGATORS OF HIPPOCAMPAL PATHOLOGY, PARTICULARLY, SELECTIVE NEURONAL LOSS PROVIDES MECHANISTIC INSIGHT AS TO WHY THESE ARE KEY NEURAL NETWORK CHANGES IN DISEASE. TO MODEL ALZHEIMER’S PATHOLOGY, WE FOCUS ON THE LC AND HPC TO IDENTIFY HOW THESE REGIONS ARE DISRUPTED WHEN PROTEOSTASIS SLOWS DOWN AND HOW HYPEREXCITATION IMPACTS THESE FUNCTIONS. WE WILL TRACK EARLY ELECTROPHYSIOLOGICAL CHANGES IN THE LC AND HPC WHEN PROTEINS LIKE BETA-AMYLOID (A) AND TAU START ACCUMULATING AND ASSESS HYPERAROUSAL/EXCITATION USING ELECTROPHYSIOLOGICAL MEASUREMENTS. OVER TIME, HYPEREXCITATION REDUCES CLEARANCE OF ABERRANT PROTEINS RESULTING IN A POSITIVE FEEDBACK LOOP OF PROTEOSTASIS LOSS AND HYPERAROUSAL, AND CASCADE TO HIPPOCAMPUS AND MEMORY LOSS. WE IDENTIFY THE TYPE OF NEURONS THAT ARE MOST VULNERABLE TO HYPEREXCITATION/AROUSAL-PROTEOSTASIS CHANGES IN THIS NETWORK, DESTABILIZING EXCITATORY-INHIBITORY HOMEOSTASIS. FINALLY, WE TEST IF DAMPENING HYPEREXCITATION OR PROTEOSTASIS RESTORATION IMPROVES COGNITIVE FUNCTION AND REVERSES PATHOLOGICAL CHANGES IN OUR MODEL. OUR GOAL IS TO USE OBSERVATIONS FROM ALL THE PARADIGMS TO IDENTIFY IF THESE BIOLOGICAL CHANGES AND PATHOLOGICAL SPREAD OF DISEASE CAN BE ANALYZED USING COMPUTATIONAL TOOLS TO PREDICT THE PATTERNS AND EVENTS LEADING TO AD AND TO TEST IF WE CAN USE AS A DISEASE RISK SCORE.

2075564.00

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2025-04-07

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Department of Health and Human Services

ASSESSING NEURONAL VULNERABILITY IN THE ENTORHINAL CORTEX DUE TO ALZHEIMER'S DISEASE PATHOLOGY - PROJECT SUMMARY UNDERSTANDING HOW SPECIFIC NEURONS IN A SELECTIVELY VULNERABLE REGION SUCH AS THE EC ARE AFFECTED IS CRITICAL TO UNRAVELING THE MECHANISMS UNDERLYING ALZHEIMER'S DISEASE ONSET. WE AND OTHERS HAVE SHOWN THAT NEURONAL HYPEREXCITABILITY IS THE KEY DRIVER THAT MAKES PATHOLOGIES AND SYMPTOMS WORSE AND AMELIORATING HYPEREXCITABILITY SLOWS DOWN AD-RELATED SYMPTOMS. HOWEVER, IT IS UNCLEAR IF THE HYPEREXCITABILITY IS DUE TO AN INCREASED FIRING OF EXCITATORY NEURONS OR DECREASED FIRING OF INHIBITORY NEURONS. WE AIM TO UNDERSTAND THE MECHANISMS UNDERLYING HYPEREXCITABILITY BY STUDYING THE EXCITATORY AND INHIBITORY NEURONS IN THE EC OF APP AND TAU KNOCKIN MICE. TO DETERMINE WHICH TYPE OF NEURONS ARE AFFECTED EARLY IN THE EC, WE WILL INVESTIGATE: AIM 1- EXCITATORY NEURONS IN THE APP KNOCKIN (APPNL-G-F) AND TAU KNOCKIN (HTAU-KI) MICE BY USING INTERSECTIONAL APPROACH WITH OPTOGENETICS AND CHEMOGENETICS IN COMBINATION WITH ELECTROPHYSIOLOGY RECORDINGS AND BEHAVIOR AND AIM 2- INHIBITORY NEURONS (PARVALBUMIN- PV AND SOMATOSTATIN- SST) IN THE APPNL-G-F AND HTAU-KI MICE AS IN AIM 1. USING CRE-SPECIFIC MICE TO TARGET EXCITATORY AND INHIBITORY NEURONS IN COMBINATION WITH OPTO- OR CHEMO- GENETIC APPROACH WE WILL NOT ONLY IDENTIFY SELECTIVELY VULNERABLE NEURON-TYPE, BUT WE WILL ALSO MODULATE THEIR ACTIVITIES TO RESTORE THEIR FUNCTION AND TEST IF BEHAVIORAL DEFICITS ARE REVERSED. WE WILL USE NOVEL COMPUTATIONAL APPROACHES SUCH AS DECODING AND REMAPPING TO DETECT SUBTLE CHANGES IN FIRING ACTIVITY OF EC NEURONS. WE WILL ALSO ASSESS HOW AMYLOID BETA OR TAU AFFECT DIFFERENT NEURON TYPES IN THE EC, AND IF DOWNSTREAM HIPPOCAMPAL NEURONS ARE AFFECTED TOO. THE RESULTS OF THE PROPOSAL WILL DEFINITIVELY ANSWER IF HYPEREXCITABILITY OF NEURONS DUE TO AD PATHOLOGIES IS CAUSED BY DYSFUNCTION OF EXCITATORY OR INHIBITORY NEURONS. THE SENSITIVE COMPUTATIONAL METHODS USED IN THIS PROPOSAL ALLOW FOR MEASUREMENT OF SUBTLE ELECTROPHYSIOLOGICAL CHANGES NOT POSSIBLE PREVIOUSLY AND THEREFORE MIGHT ALLOW FOR DEVELOPMENT OF BETTER DIAGNOSTIC TESTS THAT COULD BE TRANSLATED AND MODIFIED FOR CLINICAL USE IN HUMANS. OVERALL, THE PROPOSAL AIMS TO IDENTIFY WHICH NEURONS IN THE MEC ARE MOST VULNERABLE TO AD PATHOLOGY. THE PROPOSAL IS HIGHLY INNOVATIVE AS IT WILL USE A COMBINATION OF SOPHISTICATED IN VIVO RECORDING IN TWO AD MOUSE MODELS IN COMBINATION WITH OPTOGENETIC AND CHEMOGENETIC TOOLS TO IDENTIFY SPECIFIC CELL TYPE AND MODULATE NEURONAL FIRING TO RESTORE FUNCTION. THE RESULTS FROM THE STUDY WILL BE HIGHLY SIGNIFICANT AS THERAPEUTIC OR CLINICAL APPROACHES TO TARGET VULNERABLE CELL TYPE COULD BE IDENTIFIED. THE PROPOSAL BRINGS TOGETHER DIVERSE FIELDS (ELECTROPHYSIOLOGY, PATHOLOGY AND COMPUTATIONAL NEUROSCIENCE) APPLYING LARGE-SCALE RECORDING TECHNIQUES TO RECORD ENSEMBLE POPULATIONS OF NEURONS TO INTERROGATE WHAT CAUSES HYPEREXCITABILITY IN A VULNERABLE BRAIN REGION THAT IS DYSFUNCTIONAL IN ALZHEIMER’S DISEASE.

452375.00

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2024-05-06

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Department of Health and Human Services

AN ADVANCED, HIGH-THROUGHPUT IMAGING SYSTEM FOR THE BNI STRUCTURAL AND FUNCTIONAL IMAGING CORE - THIS APPLICATION IS A REQUEST FOR FUNDS TO ACQUIRE A ZEISS AXIOSCAN 7 SLIDE SCANNER FOR THE STRUCTURAL AND FUNCTIONAL IMAGING CORE AT THE BURKE NEUROLOGICAL INSTITUTE. THE INSTITUTE, DEDICATED TO FINDING CURES FOR CHRONIC NEUROLOGICAL DISABILITIES, REQUIRES AN AUTOMATED IMAGE ACQUISITION SYSTEM TO ADVANCE THEIR NIH-FUNDED RESEARCH. THE MANDATE OF THE IMAGING CORE FACILITY IS TO PROVIDE ACCESS TO A RANGE OF LIGHT MICROSCOPY SYSTEMS AND PROVIDE TECHNICAL ASSISTANCE WITH IMAGE ACQUISITION, PROCESSING, AND ANALYSIS TO ALL RESEARCH GROUPS WITHIN BNI. WHILE THE INSTITUTE HAS INVESTED IN HIGH-RESOLUTION CONFOCAL AND MULTIPHOTON MICROSCOPY SYSTEMS, IT LACKS MODERN EPIFLUORESCENCE AND BRIGHTFIELD IMAGING SYSTEMS. EXISTING MICROSCOPY SOLUTIONS ARE AGING AND LACK CRITICAL FEATURES FOUND IN THE PROPOSED AXIOSCAN 7 SYSTEM. THIS SCARCITY OF RESOURCES POSES A SIGNIFICANT BOTTLENECK FOR THE DIVERSE NIH-FUNDED RESEARCH PROGRAMS AT THE INSTITUTE. THE AXIOSCAN 7 SLIDE SCANNER, WITH ITS AUTOMATED FULL SLIDE WORKFLOW, UNLIMITED Z-STACK ACQUISITION PARAMETERS, AND ADVANCED DECONVOLUTION ALGORITHMS, OFFERS AN OPTIMAL COMBINATION OF FEATURES FOR LARGE AREA TISSUE SCANNING AND STITCHING. THE PROPOSED SYSTEM WILL GREATLY EXPEDITE RESEARCH PROGRESS BY REDUCING ACTIVE USER TIME DURING IMAGE ACQUISITION. FURTHERMORE, THE SURROUNDING AREA LACKS OTHER AUTOMATED, HIGH-THROUGHPUT MICROSCOPY RESOURCES ACCESSIBLE TO BNI INVESTIGATORS, MAKING THE AXIOSCAN 7 AN INDISPENSABLE ASSET. ITS IMPLEMENTATION WILL NOT ONLY BENEFIT CURRENTLY NIH-FUNDED RESEARCH PROGRAMS BUT ALSO CATALYZE THE PROGRESS OF STUDIES THAT ARE YET TO REACH THE MATURITY REQUIRED FOR NIH FUNDING. THE PROPOSED RESEARCH PROJECTS UNDERSCORE THE SHARED NEED FOR AN ADVANCED SLIDE SCANNING SYSTEM. IN CONCLUSION, THE EXTENSIVE CAPABILITIES AND EFFICIENT WORKFLOW OF THE AXIOSCAN 7 WILL EXERT A SUSTAINED, POWERFUL INFLUENCE ON THE CONDUCT OF NIH-FUNDED RESEARCH PROGRAMS AT THE BURKE NEUROLOGICAL INSTITUTE AND SUPPORT BREAKTHROUGHS IN THE UNDERSTANDING AND TREATMENT OF CHRONIC NEUROLOGICAL DISABILITIES.

272744.00

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2024-05-03

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Department of Health and Human Services

THE ROLE OF CORTICOSPINAL NEURONS IN THE RECOVERY OF DEXTEROUS FORELIMB FUNCTION AFTER SPINAL CORD INJURY - PROJECT SUMMARY: THE ADVERSE EFFECTS OF SPINAL CORD INJURY (SCI) ON CORTICOSPINAL FUNCTION ARE NOT RESTRICTED TO THE DAMAGED SPINAL CORD, BUT ALSO DISRUPT MOTOR REPRESENTATIONS WITHIN THE CORTEX. SCI RESULTS IN ALTERED CORTICAL MAPS THAT REPRESENT MOTOR OUTPUT, WITH REPRESENTATIONS ABOVE THE LEVEL OF INJURY EXPANDING INTO AFFECTED CORTICAL AREAS. REHABILITATION IS NECESSARY FOR BOTH THE RECOVERY OF CORTICOSPINAL-DEPENDENT FORELIMB FUNCTION AND THE COMMENSURATE REORGANIZATION OF DISRUPTED CORTICAL MOTOR MAPS. BOTH THE UNDERLYING CIRCUIT MECHANISMS THAT SUPPORT CORTICAL REORGANIZATION AFTER SCI AS WELL AS THE NECESSITY FOR THE REORGANIZED CIRCUITRY TO SUPPORT FUNCTIONAL RECOVERY, REMAIN UNKNOWN. FOR INJURED CORTICOSPINAL NEURONS TO CONTRIBUTE TO FUNCTIONAL RECOVERY, THEY MUST BE INTEGRATED INTO CORTICAL MOTOR NETWORKS. THE LONG-TERM GOAL IS TO DEVELOP THERAPEUTIC INTERVENTIONS FOR SUPPORTING FUNCTIONAL RECOVERY AFTER SCL THE OVERALL OBIECTIVE FOR THIS PROPOSAL IS TO DETERMINE HOW SPECIFIC REHABILITATION AFTER SCI PROMOTES REMODELING OF CORTICOSPINAL CIRCUITS AND THE CONTRIBUTION OF INJURED CORTICOSPINAL NEURONS TO MOTOR RECOVERY. THE CENTRAL HYPOTHESIS IS THAT CORTICOSPINAL-DEPENDENT REHABILITATION AFTER SCI DIRECTS THE STRUCTURAL REMODELING OF INJURED CORTICOSPINAL NEURONS RESULTING IN THEIR INCORPORATION INTO FUNCTIONAL MOTOR ENSEMBLES. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT DETERMINING THE PROPERTIES OF REHABILITATIVE TRAINING THAT PROMOTE SUCCESSFUL CORTICOSPINAL CIRCUIT INCORPORATION INTO CORTICAL MOTOR NETWORKS AFTER SCI WILL BE CRUCIAL FOR DEVELOPING EFFECTIVE REHABILITATIVE STRATEGIES. THE FOLLOWING THREE SPECIFIC AIMS ARE PROPOSED: 1) IDENTIFY THE NATURE OF STRUCTURAL AND CONNECTIVITY CHANGES THAT OCCUR IN INJURED CORTICOSPINAL NEURONS DURING REHABILITATION-MEDIATED RECOVERY FROM SCI; 2) IDENTIFY THE CHANGES IN THE FUNCTIONAL CONNECTIVITY OF INJURED CORTICOSPINAL NEURONS DURING REHABILITATION-MEDIATED RECOVERY FROM SCI; AND 3) IDENTIFY THE CONTRIBUTION OF INJURED CORTICOSPINAL NEURONS TO MOTOR RECOVERY AFTER SCL FOR THE FIRST AIM, THE APPROACH WILL BE TO IMAGE STRUCTURAL CHANGES OF INJURED CORTICOSPINAL DENDRITIC ARBORS IN RESPONSE TO REHABILITATION. IN THE SECOND AIM, THE APPROACHES WILL BE TO USE 2-PHOTON IMAGING TO RECORD THE ACTIVITY OF INJURED CORTICOSPINAL NEURONS DURING REHABILITATION AND TO USE RETROGRADE TRANSSYNAPTIC TRACING TO IDENTIFY PRESYNAPTIC INPUTS. IN THE THIRD AIM, THE APPROACH WILL BE TO OPTOGENETICALLY CONTROL INJURED CORTICOSPINAL NEURONS IN AWAKE, BEHAVING MICE TO DETERMINE THEIR CONTRIBUTION TO RECOVERY. THE PROPOSED STUDIES ARE INNOVATIVE IN THAT THEY SHIFT THE FOCUS OF SPINAL CORD REHABILITATION ONTO THE CIRCUIT MECHANISMS OF CORTICAL NETWORK PLASTICITY. THE PROPOSED STUDIES ARE SIGNIFICANT BECAUSE THEY WILL ELUCIDATE THE MECHANISMS BY WHICH CIRCUIT REMODELING INFLUENCES RECOVERY AND WILL INFORM COMBINATORIAL STRATEGIES THAT TARGET CORTICAL PLASTICITY TO FULLY REALIZE THE EFFECTS OF AXONAL SPROUTING AND REGENERATION. THE EXPECTATION IS THAT COMPLETION OF THE PROPOSED RESEARCH WILL DETERMINE THE ROLE FOR INJURED CORTICOSPINAL NEURONS IN THE RECOVERY OF FUNCTIONAL MOTOR NETWORKS AFTER SCI_ THESE FINDINGS WILL ESTABLISH A FOUNDATION TO GUIDE THE DEVELOPMENT OF THERAPEUTIC STRATEGIES TARGETING MOVEMENT RECOVERY AFTER CNS INJURY.

992986.00

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2024-01-31

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Department of Health and Human Services

MECHANISTIC LINKS BETWEEN THE BENEFITS OF PHARMACOLOGICALLY HIGH THIAMINE (VITAMIN B1) IN ALZHEIMER'S DISEASE TO ADVANCED GLYCATION ENDPRODUCTS (AGE) - EXPERIMENTAL DATA LINKING THIAMINE (VITAMIN B1) DEFICIENCY TO ALZHEIMER’S DISEASE (AD) INSPIRED OUR CLINICAL TRIAL, WHICH GENERATED PRELIMINARY EVIDENCE THAT PHARMACOLOGICAL THIAMINE PRODUCED BY THE DRUG BENFOTIAMINE PROVIDES CLINICAL BENEFIT. WE HYPOTHESIZE THAT PHARMACOLOGICAL THIAMINE IS PROTECTIVE BY DIMINISHING THE FORMATION OF ADVANCED GLYCATION ENDPRODUCTS (AGE). AGE ARE PROTEINS AND LIPIDS THAT BECOME GLYCATED AND HARMFUL FOLLOWING EXPOSURE TO REDUCING SUGARS. AGE CAUSE IRREVERSIBLE DAMAGE TO BIOLOGICAL MACROMOLECULES BY ALTERING THEIR STRUCTURAL AND FUNCTIONAL INTEGRITY. ABUNDANT EVIDENCE LINKS AGE TO AD. IN AD ANIMAL MODELS, THIAMINE DEFICIENCY INCREASES AGE AND EXACERBATES PLAQUES AND TANGLE FORMATION, WHILE INCREASED THIAMINE DIMINISHES AGE AND PATHOLOGY. IN OUR PILOT CLINICAL TRIAL, PHARMACOLOGICAL THIAMINE LEVELS DIMINISHED GLOBAL PLASMA AGE LEVELS AND IMPROVED SYMPTOMS IN PATIENTS WITH AD. INTERESTINGLY, IN AD PATIENTS, THE EFFECTS OF HIGH THIAMINE ARE DIMINISHED IN PATIENTS CARRYING THE APOE4 GENOTYPE, THE MOST SIGNIFICANT GENETIC RISK FACTOR FOR SPORADIC AD. WE POSTULATE THAT THIS IS BECAUSE APOE4 INCREASES UNIQUE AGE AT EARLIER STAGES. OPTIMIZING THIS THERAPEUTIC APPROACH REQUIRES A BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING THE ACTION OF BENFOTIAMINE. ALL PREVIOUS RELATED AD AND THIAMINE STUDIES HAVE UTILIZED AGE ANTIBODY SURVEYS. THIS DATA IS LIMITED TO A SMALL RANGE OF AGE AND PROVIDES NO DATA ON THE PROTEINS AND SPECIFIC SITES MODIFIED WITH GLYCATION. WE WILL PROVIDE THIS CRITICAL DATA BY USING MULTIPLE STATE-OF-THE-ART MASS SPECTROMETRIC MEASURES OF AGE. GLOBAL GLYCAPROTEOMICS WILL IDENTIFY GLYCATED PROTEINS AND SPECIFIC SITES OF AGE MODIFICATIONS AND AGE- OMICS WILL IDENTIFY A BROAD RANGE OF CROSSLINKING AND NON-CROSSLINKING AGE. A SECOND MAJOR GAP IS THE LACK OF OUR UNDERSTANDING ON HOW APOE4 MODIFIES THE RESPONSE TO THIAMINE. NOVEL APOE3 AND APOE4 HUMANIZED APP MOUSE MODELS WILL ALLOW US TO TEST THESE INTERACTIONS. WE WILL TEST OUR HYPOTHESES: (1) IN AD AUTOPSY BRAINS AT DIFFERENT STAGES OF THE DISEASE, AGE MODIFICATIONS ARE CRITICAL TO THE PATHOPHYSIOLOGY OF AD IN AN APOE-DEPENDENT MANNER. (2) IN MOUSE MODELS OF AD, THIAMINE DEFICIENCY DRIVES AD-LIKE PATHOLOGY AND MEMORY LOSS BY CAUSING SPECIFIC BRAIN AND BLOOD AGE MODIFICATIONS WHICH ARE MODIFIED BY APOE GENOTYPE. (3) IN MOUSE MODELS, BENFOTIAMINE IS BENEFICIAL BY DIMINISHING SPECIFIC AGE AND THE TREATMENT MUST BE INITIATED AT AN EARLIER STAGE OF DISEASE IN APOE4 MICE. THESE STUDIES WILL DRAMATICALLY IMPROVE OUR UNDERSTANDING OF THE ROLE OF AGE IN AD AND ITS LINK TO A TREATMENT OF PHARMACOLOGICAL THIAMINE LEVELS. DEFINING THE INTERACTION OF AGE AND THIAMINE IN THE ETIOLOGY AND PROGRESSION OF AD WILL ENABLE THE DEVELOPMENT OF SPECIFIC AGE SIGNATURES FOR TARGETS OF ENGAGEMENT FOR THERAPEUTIC TRIALS AND AS AD DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. THESE STUDIES WILL DEFINE THE DIFFERENTIAL EFFECTIVENESS OF THIAMINE BY APOE GENOTYPE AND DEFINE THE MOST EFFECTIVE THERAPEUTIC APPROACH FOR APOE3 AND CONSISTENTLY HARD TO TREAT APOE4 CARRIERS. WE THEREFORE EXPECT THIS STUDY WILL HAVE A HIGH IMPACT ON TRANSLATIONAL AD MEDICINE.

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