Alzheimer’s Disease: A woman’s health issue, a woman’s health cure

Alzheimer’s Disease: A woman’s health issue, a woman’s health cure


>>GOOD AFTERNOON. I’M VERY HAPPY TO SEE ALL OF YOU HERE. THE I’M MARIE BERNARD, CO-CHAIR OF THE TRANS-NIH WOMEN OF COLOR COMMITTEE WHICH IS A SUBCOMMITTEE THE WORKING GROUP OF WOMEN IN BIOMEDICINE. AND WE WERE VERY HONORED TO BE ABLE TO NOMINATE AND FIND SELECTION ROBERTA DIAZ AS TODAY’S WALS LECTURER. DR. BRITON IS THE CHAIR AND THERAPEUTIC DISCOVERY AND DEVELOPMENT AT THE UNIVERSITY SOUTHERN CALIFORNIA WHERE SHE IS PROFESSOR OF PHARMACOLOGY AND PHARMACEUTICAL SCIENCES, BIOMEDICAL ENGINEERING AND NEUROLOGY. SHE DIRECTS THE NORRIS FOUNDATION LABORATORY FOR NEUROSCIENCES RESEARCH AND THE U IS. C STAR SCIENCE EDUCATION PROGRAM. SHE IS INTERNATIONALLY RECOGNIZED AS AN INNOVATIVE LEADER IN ALZHEIMER’S RESEARCH AND DEVELOPMENT OF THERAPEUTICS TO PREVENT, DELAY AND TREAT THE DISEASE. RESEARCH IN HER LAB FOCUSES ON DISCOVERY OF WHY THE BRAIN CAN DEVELOP ALZHEIMER’S AND ON TRANSLATING THOSE DISCOVERIES INTO THERAPEUTICS TO TREAT THE DISEASE. OF PARTICULAR FOCUS IS THE AGING FEMALE BRAIN AND ELUCIDATED MECHANISMS THAT UNDERLIE THE TWO-FOLD GREATER LIFETIME RIFFING OF ALZHEIMER’S DISEASE IN WOMEN. YOU CAN UNDERSTAND WHY THE WOMEN AND BIOMEDICAL CAREERS COMMITTEE WOULD BE INTERESTED IN HAVING HER TALK. SHE DEVELOPED THERAPEUTICS THAT RESTORE ENERGY PRODUCTION AND NEUROSTEM CELL REGENERATION IN THE BRAIN TO PREVENT AND TREAT ALZHEIMER’S. OUS COMES OF HER DISCOVERY AND TRANSLATE RESEARCH LED TO TWO NINETY FIVE-FUNDED CLINICAL TRIALS. SHE HAS BEEN CONTINUOUSLY FUNDED BY THE NINETY FIVE FROM HER PREDOCTORAL YEARS TO THE PRESENT SUPPORT THROUGH MYINS FUT, NATIONAL INSTITUTE ON AGING. SHE HAS OVER 180 PUBLICATIONS AND HOLDS MULTIPLE PATENTS FOR THERAPEUTICS FOR ALZHEIMER’S AND DISEASES AND SUSTAINING NEUROLOGICAL HEALTH DURING AGING. SHE COMMUNICATES HER IMPACT OF SCIENCE TO THE PUBLIC THROUGH MEDIA WHERE HER WORK APPEARED IN THE NEW YORK TIMES IN OVER WOB00 GLOBAL MEDIA OAT LETS, ABC, CBS, SCIENCE FRIDAY ONWARD. SHE WAS AWARDED THE ALZHEIMER’S DRUG DISCOVERY FOUNDATION SCIENTIST OF THE YEAR, WOMAN OF THE YEAR BY THE CALIFORNIA STATE SENATE, SCIENCE EDUCATOR OF THE YEAR BY THE SOCIETY FOR NEUROSCIENCES AND L.A. MAGAZINE WOMAN OF THE YEAR. SHE IS ALSO RECOGNIZED AS ONE OF THE 10 BEST MINDS BY U.S. US.>>WORLD REPORT. AND VERY IMPORTANTLY, FOR HER DECADES OF COMMITMENT TO SCIENCE, EDUCATION FOR INNER CITY YOUTH OF L.A., SHE RECEIVED THE PRESIDENTIAL CITIZEN’S MEDAL. SO WITH GREAT PLEASURE THAT I BRING TO YOU DR. ROBERTA DIAZ BRITON. [ APPLAUSE ]>>THANK YOU DR. BERNARD, AND TO THE WOMEN OF COLOR COMMITTEE FOR NOMINATING ME FOR THIS PRESTIGIOUS AND HONORED SYMPOSIUM SEMINAR, WEDNESDAY AFTERNOON LECTURE. I ALSO WOULD LIKE TO THANK THE NIA AND ALL THE PROGRAM OFFICERS WHO WORKED VERY CLOSELY WITH ME. DR. WISE IS IN THE AUDIENCE, AND MUCH OF WHAT I’M GOING TO BE PRESENTING TODAY IS IN HIS PORTFOLIO OF GRANTS TO MANAGE. SO, WHAT I’M GOING TO BE TALKING WITH YOU ABOUT TODAY IS THE JOURNEY THAT WE HAVE MADE IN TRYING TO UNDERSTAND WHY THE BRAIN DEVELOPS ALZHEIMER’S DISEASE. AND I’LL START WITH A BIT OF A SUMMARY. AND REVIEW THAT AGE IS THE GREATEST RISK FACTOR FOR DEVELOPING ALZHEIMER’S DISEASE. THE OTHER GREATEST RISK FACTOR FOR DEVELOPING ALZHEIMER’S DISEASE IS BEING FEMALE, BEING APOE4 POSITIVE OR HAVING A MOTHER WITH ALZHEIMER’S DISEASE. SO THERE IS A DISTINCTLY FEMININE CHARACTER TO THE RISK OF DEVELOPING ALZHEIMER’S DISEASE. WE KNOW THAT THERE ARE MULTIPLE EAT APOLOGIES TO LATE ONSET ALZHEIMER’S DISEASE AND THEREFORE THERE WILL BE MULTIPLE PRODROMAL PHENOTYPE AND MULTIPLE PROGRESSION TRAJECTORIES. THE FIELD MOVED ON FROM A SINGLE MECHANISTIC HYPOTHESES OF ALZHEIMER’S DISEASE TO UNDERSTANDING THAT THERE WILL BE MULTIPLE PHENOTYPES AND GENOTYPES OF RISK AND THAT THEREFORE THERE WILL HAVE TO BE A PORTFOLIO OF THERAPEUTICS THAT TARGET THESE GENOTYPES AND PHENOTYPES. THE CHALLENGE FOR US NOW IN THIS AGE S TO DEVELOP ANIMAL MODELS AND CELLULAR MODELS THAT ARE PREDICTIVE OF THE PHENOTYPES OF RISK. AND THE DIFFERENT STAGES OF TRAJECTORY IN THE DISEASE, AND THEN TO DEVELOP TARGETS THAT WE CAN THEN INTERROGATE CHEMICAL SPACE, THAT HIT THOSE TARGETS, AND APPLY THAT TO THE APPROPRIATE GENOTYPE AND PHENOTYPE. THE LESSONS THAT WE LEARNED DURING OUR DECADES OF RESEARCH IN THIS DOMAIN, IS THAT THE AGING BRAIN IS CHARACTERIZED BY TRANSITIONS AND IN THE FEMALE AGING BRAIN, TRANSITIONS IN THE BIOENERGETIC PHENOTYPE THAT INVOLVE A SET OF SEQUENTIAL SYSTEM-LEVEL ADAPTATIONS. THE AGING BRAIN IS NOT A LINEAR DECLINING BRAIN. IT’S IN FACT A VERY DYNAMIC BRAIN. IT IS A BRAIN WITH SURVIVAL BACKUP MECHANISMS, WHICH IT ACTUALLY BRINGS ONLINE. THAT FEMALE AND MALE BRAINS BIOENERGETICALLY AGE DIFFERENTLY, AND THAT PERTURBING ONE COMPONENT OF THIS SYSTEM DOES NOT CREATE A SYSTEM CORRECTION T CREATES A SYSTEM ADAPTATION. AND THAT IS IMPORTANT WHEN WE THINK ABOUT THE DEVELOPMENT OF THERAPEUTICS. THAT IN FACT, MOST LIKELY WHAT WE HAVE TO DO IN ALZHEIMER’S DISEASE IS TO DEVELOP SYSTEMS BIOLOGY THERAPEUTICS. AND LASTLY, THERE ARE WINDOWS OF OPPORTUNITY. THERE ARE TRANSITIONS OF AGING IN WHICH THERE IS AN OPPORTUNITY FOR A THERAPEUTIC INTERVENTION TO PREVENT OR DELAY ALZHEIMER’S DISEASE, AND THERE WILL BE TRANSITIONS FOR TREATMENT OF THE DISEASE. FURTHER, ONE SIZE THERAPEUTIC WILL NOT FIT ALL AND WILL NOT FIT FOR ALL-TIME. SO THOSE ARE THE TAKE HOME MESSAGEES FROM MY TALK THAT I’LL START WITH REMINDING EVERYONE THAT PRECISION MEDICINE ACTUALLY STARTS WITH SEX. EVERY CELL, EVERY SINGLE CELL HAS A SEX IN OUR BODIES, INCLUDING THE BRAIN. SO WHEN WE LOOK AT THE PREVALENCE OF ALZHEIMER’S DISEASE, 33% OF PERSONS WITH ALZHEIMER’S DISEASE ARE MEN AND 67% ARE FEMALE. AND IT IS THAT FEMALE COHORT OF PERSONS WITH ALZHEIMER’S DISEASE OR AT RISK FOR DEVELOPING ALZHEIMER’S DISEASE, THAT HAS TAUGHT US A GREAT DEAL ABOUT THE DISEASE, WHY IT STARTS, HOW IT PROGRESSES, AND PERHAPS HOW WE CAN TREAT IT. SO HOW DID WE BEGIN THIS PROCESS? WELL, WE KNOW THE AVERAGE AGE OF DIAGNOSIS FOR ALZHEIMER’S DISEASE IS AGE 75. FURTHER, WE KNOW THAT THERE IS A 20-YEAR PRODROMAL PHASE TO THIS DISEASE. SO WE STARTED TO BEGIN TO LOOK BACK IN TIME TO TRY TO UNDERSTAND WHAT WAS HAPPENING IN THE AGING FEMALE BRAIN THAT WOULD ELUCIDATE THE RISK FOR DEVELOPING THIS NEURODEGENERATIVE DISEASE. AND IT TURNS OUT THAT ABOUT 20 YEARS BEFORE THE AGE OF 75, WOMEN UNDERGO THE MENOPAUSAL TRANSITION. AND WE THINK ABOUT THE MENOPAUSAL TRANSITION IN A REPRODUCTIVE PERSPECTIVE BUT I WILL SHOW YOU THAT THE MENOPAUSAL AND PERIMENOPAUSAL TRANSITION ACTUALLY A LARGE TRANSITION. FURTHER, WE BEGIN TO LOOK AT THE TRANSITION STATE OF THAT PRECEDES THE PERIMEN — OR THE MENOPAUSE, AND THAT’S THE PERIMENOPAUSE. BECAUSE IT IS THIS TRANSITION STATE THAT WE THINK IS THE HARSHEN GER OF RISK FOR DEVELOPING ALZHEIMER’S DISEASE. SO LET’S THINK ABOUT TRANSITION STATES. SO WE ARE ALL VERY FAMILIAR WITH THE TRANSITION STATE OF PURSUANTY. PURSUANTY IS AN ENDOCRINE TRANSITION STATE RELATED TO REPRODUCTIVE CAPACITY IN BOTH FEMALES AND MALES, HOWEVER, THE SYMPTOMS OF PURSUANTY THAT BECOME PROBLEMATIC — PUBERTY — ARE NOT REPRODUCTIVE, THEY ARE NEUROLOGICAL. INCREASED RISK OF SCHIZOPHRENIA IN MALES AND INCREASED RISK OF DEPRESSIVE ILLNESS IN FEMALES. WOMEN CAN ALSO UNDERGO A SECOND TRANSITION AND THAT IS PREGNANCY WHICH LASTS ALMOST A YEAR. THE LAST AGING TRANSITION IS THE PERIMENOPAUSE TO THE MENOPAUSE IN THE FEMALE SO WHILE EVERYONE GOES THROUGH THE PUBERTY, WOMEN UNIQUELY EXPERIENCE THE TRANSITION STATES OF PREGNANCY AND PERIMENOPAUSE. AND WHEN WE THINK ABOUT TRANSITION STATES, WE THINK ABOUT THE DEFINITION OF TRANSITION STATES IN WHICH THERE ARE POPULATIONS THAT ARE TIGHTLY CONTROLLED AND IN THIS CASE, I’LL BE TALKING ABOUT MEN BOLLIC CONTROL. AND THEN THERE WERE POPULATIONS THAT BEGIN TO HAVE OR BEGIN TO MOVE AWAY FROM THAT TIGHTLY CONTROLLED SYSTEM AND THEY BEGIN TO BECOME MORE AND MORE AT RISK FOR MOVING INTO A DISEASE TRANSITION STATE. AND IT IS THIS TRANSITION STATE I WILL SPEND MOST OF MY TIME TALKING ABOUT. WHEN THE BRAIN UNDERICOSE THE PERIMENOPAUSAL TRANSITION, THERE IS INCREASING IN THE VARIABILITY OF BRAIN RESPONSES IN THE FEMALE AGING BRAIN AND WITH THAT VARIABILITY IN NEUROLOGICAL FUNCTION IS DECLINE IN BRAIN METABOLISM REPRESENTED BY FTG PET. IT’S NOT A LINEAR DECLINE, IT’S A STEP FUNCTION AND THAT TURNS OUT TO BE IMPORTANT TO CONSIDER. WE KNOW THAT ABOUT 80% OF WOMEN ARE TRANSITIONING THROUGH THE PERIMENOPAUSE ARE SYMPTOMATIC AND 20% ARE NOT AND THAT OF THOSE SYMPTOMS OF THE PERIMENOPAUSE AND MENOPAUSE, 30% OF THIS 80% WILL EXPERIENCE HOT FLASHES ONLY AND 70% OF WOMEN WILL EXPERIENCE SYMPTOMS OF COGNITIVE DYSFUNCTION PLUS INSOMNIA, MOOD DISTURBANCE, CAN HAVE SEVERE CASES SUICIDAL IDEATION AND DEPRESSION. SO THESE ARE ALL NEURLANGUAGE CALL SYMPTOMS ASSOCIATED WITH WHAT WE TYPICALLY THINK IS A REPRODUCTIVE TRANSITION. SO FOR US, THE PERIMENOPAUSE IS IN FACT A NEUROLOGICAL TRANSITION. WE SPENT MANY YEARS UNDERSTANDING ESTROGEN ACTION IN THE BRAIN AS OBVIOUSLY BECAUSE THE ESTROGEN IS A IMPORTANT STARED HORMONE RELATED TO ENDOCRINE FUNCTION AND REPRODUCTION IN THE FEMALE AND WHAT WE FIND OR FOUND OVER MANY YEARS OF RESEARCH IS, ESTROGEN IS A SYSTEMS BIOLOGY REGULATOR OF THE BIOENERGETIC SYSTEM OF THE BRAIN. I CALL ESTROGEN THE QUEEN OF DARWIN. SHE HAS LEFT NOTHING TO CHANCE. ESTROGEN IS REGULATING GLUE COWS UPTAKE INTO THE BRAIN. GLUCOSE METABOLISM IN THE BRAIN AND GENERATION OF ASEATAL KOA TO GENERATE THROUGH THE TCA CYCLE AND ULTIMATELY TO GENERATE NNDH TO GENERATE ELECTRONS TO MOVE DOWN THE ELECTRON TRANSPORT CHAIN AND ULTIMATELY TO GENERATE ATP. AND I WILL COME BACK TO THIS WHOLE BIOENERGETIC SYSTEM THROUGHOUT THIS LECTURE. MOREOVER, ESTROGEN IS SUPPRESSING THE KETOGENIC SYSTEM OF THE BRAIN. ESTROGEN IS MAINTAINING THE ABILITY OF THE BRAIN TO UTILIZE GLUCOSE AS ITS SOLE BIOENERGETIC FUEL AND THAT TURNS OUT TO HAVE SIGNIFICANT IMPLICATIONS. SO HOW DID WE ACTUALLY BEGIN TO THINK ABOUT THE PERIMENOPAUSE AS THIS VULNERABLE TRANSITION STATE? SO, FOR MANY YEARS, WE HAVE BEEN CONDUCTING ANALYSIS IN WILDTYPE MICE AND IN THE TRIPLE TRANSGENIC ALZHEIMER’S MOUSE, AND WHAT WE SEE HERE ON MITOCHONDRIAL RESPIRATION IS THE WELL-RECOGNIZED, REPRODUCIBLE DECLINE AND I SHOULD MENTION ALL MY EXPERIMENTS ARE CONDUCTED IN FEMALES. EXCEPT FOR THE HUMAN BIOINFORMATIC ANALYSIS I’LL TALK ABOUT AT THE END. SO ALL OF THIS WORK IS GENERATED FROM THE FEMALE AND AS IN THE MALE, AND THE FEMALE, BOTH SHOW AN AGE RELATED DECLINE IN MITOCHONDRIAL RESPIRATION. IN THE TRIPLE TRANSGENIC MOUSE MODEL FEMALE, WE SEE THAT EVEN AT AN EARLY AGE, THERE IS A DEFICIT IN MITOCHONDRIAL RESPIRATION THAT IS MAXIMAL AT 12 MONTHS OF AGE. SO FOR A LONG TIME, WE ASKED, WHY IS IT THAT THIS TRIPLE TRANSGENIC MOUSE HAS SUCH A GOOD RESPIRATION? BECAUSE IT LOOKS JUST LIKE THE WILDTYPE. WHY ISN’T IT MORE OF A LINEAR DECLINE? THAT TURNED OUT TO BE THE WRONG QUESTION TO ASK. THE RIGHT QUESTION IS, WHY IS IT THAT THIS NORMAL MOUSE LOOKS LIKE A TRIPLE TRANSGENIC ALZHEIMER’S MOUSE IN TERMS OF MITOCHONDRIAL RESPIRATION? AND IT WAS THEN THAT WE UNDERSTOOD THAT IN FACT, THIS IS EXACTLY THE TIME WHEN THESE ANIMALS UNDERGO THEIR MOUSE PERIMENOPAUSE AND THEIR TRANSITION TO REPRODUCTIVE SUNNIESENCE. THESE EARLY STUDIES LEAD TO A VERY EXTENSIVE ANALYSIS THAT WE RECENTLY PUBLISHED IN NEUROBIOLOGY OF AGING, IN WHICH WE GENERATED A CUSTOM TARGETED ARRAY AROUND THE BIOENERGETIC INFLAMMATORY AND REDOX SYSTEM OF THE BRAIN. AND YOU CAN’T READ THIS. BUT ESSENTIALLY, WHAT I HOPE YOU CAN SEE IS HERE IN THIS BIOENERGETIC COMPONENT OF THE ARRAY FROM GLUCOSE METABOLISM TO MITOCHONDRIAL FUNCTION, WE LOOK HERE AND THIS IS THE FIRST LINE IS A 6-MONTH-OLD ANIMALS AND THEN WE CONTROLLED FOR AGE. WE LOOKED AT ANIMALS THAT WERE 9 MONTHS OF AGE AND THEY WERE EITHER REGULAR SUCKLERS, IRREGULAR SUCKLERS OR MENOPAUSAL AND NO LONGER CYCLING. AND I THINK WHAT YOU CAN SEE, VED HIGH AND GREEN IS LOW RELATIVE GENE EXPRESSION AND I THINK WHAT CAN YOU SEE IS THAT IN THE CASE OF THE IRREGULAR CYCLING FEMALES, THERE IS A CONSISTENT AND PERSISTENT DECLINE IN THE BIOENERGETIC SYSTEM OF THE BRAIN. THEN IT WILL RECOVER, AND I’LL TALK MORE ABOUT THAT IN A MOMENT. SO THERE ARE A NUMBER OF GENES THAT REACH STATISTCATH SILLS AND WHAT WE SEE AGAIN HERE IS IN TERMS OF THE BIOENERGETIC GENES, THEY ARE PRIMARILY DOWN REGULATED AND THAT THERE IS A RECOVERY OF GENE EXPRESSION IN THE BIOENERGETIC SYSTEM. ONCE THIS TRANSITION COMPLETED AND I’LL TALK MORE ABOUT THAT IN A MOMENT. HERE IS A PRINCIPAL COMPONENT ANALYSIS IN WHICH WE SEE BETWEEN THESE ANIMALS 6 MONTHS OF AGE AND THEN THERE IS THE CHRONOLOGICAL AGE DECLINE IN BIOENERGETIC FUNCTION AT NINE MONTHS OF AGE BOTH ANIMALS ARE REGULAR CYCLERS. THIS IS NOT ENDOCRINE, THIS IS CHRONOLOGICAL AGING AND HERE THE ANIMALS ARE THE SAME AGE AND WE SEE A DRAMATIC DROP IN THE BIOENERGETIC GENE EXPRESSION THAT RECOVERS IN TERMS OF THE NUMBER OF GENES THAT ARE BEING ACTIVATED HERE. AND THEN, AT THE 16 MONTHS WHEN THESE ANIMALS AGAIN ARE IN CHRONOLOGICAL AGING, THIS PERIMENOPAUSAL MOUSE AGED 9-MONTH-OLD ANIMAL, HAS A BIOENERGETIC PROFILE OF A 16-MONTH-OLD ANIMAL SUGGESTING THAT THIS IS AN ACCELERATED AGING EVENT IN THE FEMALE AGING BRAIN. SO IN TERMS OF WHETHER THESE GENES ACTUALLY PREDICTIVE OF CHANGES IN PROTEIN, WE SEE THAT THE TRANSPORTER FOR GLUCOSE INTO THE BRAIN, GLUTE 3, IS SIGNIFICANTLY REDUCED DURING THIS IRREGULAR CYCLING AS IS PHOSPHODEHYDROGENASE, AS IS ATP SYNTHASE ACT 2 SUBUNIT. MOREOVER, THE INSULIN SIGNALING PATHWAY IS ALSO DECLINED DURING THIS TRANSITION. AND THE PHOSPHOCRAB IRK PATH WAY IS ALSO DECREASED DURING THIS TRANSITION. SO THIS WHOLE SYSTEM OF ESTROGEN REGULATION OF THE BIOENERGETIC SYSTEM HAS DECLINED DURING THIS REPRODUCTIVE TRANSITION. AND WHAT IS ALSO INTERESTING IS THAT THERE WAS A DECLINE IN TWO MARKERS OF THE IMMUNE SYSTEM NF-KAPPA B AND ICAPPAB. I’LL COME BACK TO THE IMMUNE SYSTEM BUT WE DID SEE THAT DURING THIS TIME WHEN THE BIOENERGETIC SYSTEM IS SUPPRESSED IN THE HIPPOCAMPUS, SO IS THE IMMUNE SYSTEM. SO WE ASKED WHETHER THIS GENE EXPRESSION WAS CORRELATED, ASSOCIATED WITH THE DECLINE IN THE UPTAKE OF GLUCOSE INTO THE BRAIN, HERE YOU SEE FTG PET SIGNAL AND INDEED, DURING THIS TRANSITION THERE IS A DECLINE IN GLUCOSE UPTAKE INTO THE BRAIN AND THE EMERGENCE OF WHAT APPEARS TO BE GLUCOSE INNOCENCE ACTIVITY IN THE PERIPHERY. GLUCOSE INTOLERANCE. AGAIN, THERE IS DECLINE IN MITOCHONDRIAL RESPIRATION AND COMPLEX 4 ACTIVITY AND ATP SYNTHASE ACTIVITY, AND A RISE IN FREE RADICAL PRODUCTION. SO, ESSENTIALLY THE BRAIN, THE BIOENERGETIC SYSTEM FROM THE HIPPOCAMPUS, BUT ALSO IN WHOLE BRAIN AND IN THE PERIPHERY, THERE SEEMS TO BE THE SWITCH FROM A HIGHLY EFFICIENT GLUCOSE METABOLISM SYSTEM IN THE BRAIN TO AN INEFFICIENT GLUCOSE METABOLISM SYSTEM AND THE EMERGENCE OF INSULIN RESISTANCE IN THE PERIPHERY. SO WHAT ABOUT THESE ARE ALL RELEVANT TO GENES THAT ARE CODED BY THE NUCLEAR GENOME. WHAT ABOUT THE MITOCHONDRIAL GENOME? AND WHAT WE KNOW FROM A NUMBER OF STUDIES IS THAT ESTROGEN REGULATES NOT ONLY THE NUCLEAR GENOME BUT ALSO THE MITOCHONDRIAL GENOME. SO, LET’S THINK A MOMENT ABOUT THE MITOCHONDRIAL GENOME. THE MITOCHONDRIAL — EVERY CELL HAS A MITOCHONDRIAL DNA DERIVED FROM THE MOTHER. SO IT IS MITOCHONDRIAL DNA AND MATERN. THOUSANDS OF COPIES OF MITOCHONDRIAL DNA PER CELL AS YOU ALL KNOW. MITOCHONDRIAL DNA ENCODES FOR 13 PROTEINS OF THE ELECTRON TRANSPORT CHAIN AND THAT THE MITOCHONDRIA ARE DEPENDENT UPON ABOUT 1000 TO 2000 OF THE NUCLEAR ENCODED PROTEINS THAT THEN ARE TRANSPORTED INTO THE MITOCHONDRIA. SO I WON’T GO THROUGH A LOT OF MORE ABOUT THE MITOCHONDRIA EXCEPT TO REMIND PEOPLE THAT THE MITOCHONDRIA ARE ACTUALLY THE STARTING PLACE FOR STARED SYNTHESIS AND FATTY ACID OXIDATION, THAT BOTH OF THESE OCCUR IN THE MITOCHONDRIA, MOREOVER GAMMA SEEK TAZE THAT ENZYME THAT WILL GENERATE BETA AMYLOID, IN SOLUBLE BITTA AN LLOYD IS ENRICHED IN THE MITOCHONDRIAL, RETICULUM MEMBRANE. SO THERE IS LOTS THEY WANT YOU TO ENCODE WHILE WE GO ALONG HERE. AND SO, WHEN WE EXAMINED THE IMPACT OF THIS PERIMENOPAUSABLE TRANSITION ON MITOCHONDRIAL GENE EXPRESSION OF THESE 13 PROTEINS WITHIN THE ELEC TRON TRANSPORT CHAIN, WE SEE AGAIN THAT IS THERE A STEP FUNCTION, A DECLINE ACROSS THESE MITOCHONDRIAL ENCODED GENES ASSOCIATED WITH THE IRREGULAR TO REGULAR CYCLING AND THESE GENES DO NOT RECOVER. AND AGAIN, WHAT WE SEE IS THAT THERE IS A STEP FUNCTION THAT IN MITOCHONDRIAL GENE EXPRESSION IS SUSTAINED. SO MUCH EARLIER WORK HAD SHOWN THAT PERSONS WITH A MATERNAL HISTORY OF ALZHEIMER’S DISEASE ACTUALLY HAD A SUBSTANTIAL INCREASED RISK OF DEVELOPING ALZHEIMER’S DISEASE RELATIVE TO THOSE WITH A PATERNAL HISTORY OF DISEASE. MOREOVER WORK HAS SHOWN THAT INDIVIDUALS WHO HAVE A MATERNAL HISTORY OF ALZHEIMER’S DISEASE HERE ESSENTIALLY HAVE RELATIVE TO PEOPLE WITH NO FAMILY HISTORY, ALREADY SHOW EARLY IN LIFE, EARLY IN THEIR ADULT YEARS, REGIONS OF HYPOMETABOLISM IN THE BRAIN, AND THIS IS ALSO TRUE IF IT IS RELATIVE TO PEOPLE WITH A PATERNAL HISTORY OF ALZHEIMER’S DISEASE SUGGESTING THAT THERE IS A RELATIONSHIP BETWEEN MATERNAL INHERITANCE AND THAT UNIQUE GENOME THAT IS INHERITED FROM THE MOTHER. SO 75% OF ALL ATP GENERATED IN THE BRAIN IS UTILIZED FOR TO RESET THE MEMBRANE POTENTIAL. SO, WHY IS THAT IMPORTANT? WELL, IF YOU DON’T RESET THE MEMBRANE POTENTIAL, ESSENTIALLY MOVE SODIUM IONS AND POTASSIUM IONS AGAINST CONCENTRATION AND GRADIENT, AN ATP DEPENDENT PROCESS, YOU’RE NOT ABLE TO RESET THE MEMBRANE POTENTIAL WHICH MEANS YOU’RE NOT ABLE TO AGAIN FIRE AN ACTION POTENTIAL. SO IT TAKES MORE ACTION POTENTIALS TO GENERATE A SYNAPTIC TRANSMISSION. SO DECLINE IN ATP GENERATION WILL IN THE BRAIN, WILL BE EVIDENT IN SYNAPTIC TRANSMISSION PARTICULARLY IN BRAIN REGIONS WHERE THERE IS HIGH SYNAPTIC ACTIVITY. LIKE THE AREAS OF THE BRAIN YOU’RE USING RIGHT NOW. HIPPOCAMPUS IN PARTICULAR. SO IT’S NO WONDER THAT THE FIRST SYMPTOMS OF ALZHEIMER’S DISEASE ARE IN FACT AN INABILITY TO ENCODE NEW INFORMATION WHICH IS A HIPPOCAMPAL FUNCTION AND THEREFORE, THERE IS AN INABILITY TO REMEMBER WHAT HAS NOT BEEN ENCODED. SO WITH OTHER LABS, WE CONDUCTED ANALYSIS OF THE IMPACT OF THIS TRANSITION ON THE LTP, LONG TERM POE POTENTIATION. WHAT YOU SEE HERE ON THE INPUT OUTPUT RELATIONSHIP IS THAT IN FACT THERE IS NO DIFFERENCE IN THE INPUT-OUTPUT EXPORT I OF EITHER REGULAR OR IRREGULAR CYCLERS. THE DIFFERENCE COMES IN NOT WHETHER THEY CAN REACH MAXIMUM WHICH THEY DO, IS WHICH THEY CAN SUSTAIN MAXIMUM AND THEY CANNOT. AND THAT TURNS OUT TO HAVE A SIGNIFICANT IMPACT ON THE ABILITY OF THE BRAIN TO MAINTAIN HIGH SYNAPTIC TRANSMISSION. SO TO SUMMARIZE THIS PART OF MY TALK, ESTROGEN PROMOTES THE GLUCOSE METABOLISM SYSTEM OF THE BRAIN FROM UPTAKE TO METABOLISM TO ULTIMATELY ATP GENERATION. WOULD THE EVIDENCE THUS FAR INDICATE THAT THIS SUBSEQUENT DECLINE IN GLUCOSE METABOLISM IN THE BRAIN LEADS TO AN ADAPTIVE RESPONSE T LEADED TO RESPONSE THAT IS CONSISTENT WITH THE BRAIN STARVING AND THAT IS NOW THE DEPUTIESY ON THE UTILIZATION OF KETONE BODIES AS AN ALTERNATIVE FUEL — DEPENDENCY. NOW THE BRAIN IS A DUAL FUEL SYSTEM OF BOTH GLUCOSE AND KETONE BODIES. ULTIMATELY, THE BRAIN WILL ESSENTIALLY UTILIZE ALL PERIPHERAL STORES OF LIPIDS TO GENERATE KETONE BODIES. THE BRAIN, HOWEVER, IS UNDER THE ABILITY TO NOW UTILIZE KETONE BODIES AND REMEMBER, THAT ESTROGEN WAS SUPPRESSING THIS SYSTEM AND IS NO LONGER SUPPRESSED. AND OUR HYPOTHESES THAT WE GENERATED SEVERAL YEARS AGO, ACTUALLY ABOUT A DECADE AGO, IS THAT THE BRAIN WILL ULTIMATELY UTILIZE ITS OWN SOURCE OF LIPIDS, IT’S WHITE MATTER, AS A SOURCE OF KETONE BODIES TO SUSTAIN BRAIN FUNCTION. AND TO REMIND YOU, AGAIN, THAT ESTROGEN IS SUPPRESSING THIS SYSTEM OF UTILIZATION OF KETONE BODIES IN THE BRAIN, AND THAT THE LOSS OF ESTROGEN ESSENTIAL ELICITS THIS SUPPRESSION OF THIS KETOGENIC SYSTEM IN BRAIN. SO WITH LAUREN, GRADUATE STUDENT IN THE LAB, CONDUCTED HER DOCTORAL THESIS TO TEST THIS HYPOTHESES THAT IN FACT, THIS INCREASE IN H202 FREE RADICAL PRODUCTION ACTUALLY LEADS TO THE ACTIVATION IN ASTROCYTES OF THE CYTOPLASMIC PHOSPHOLIPASE A2 WHICH ACTIVATES ACID WHICH THEN ACTIVATES IF ANYTHINGO MILE ENAISE WHICH THEN LEADS TO THE CATABOLISM OF WHITE MATTER FOR FUEL THAT THEN IS TRANSPORTED AS FATTY ACIDS INTO ASTROCYTES AND THEN GENERATED BY BETA OXIDATION TO GENERATE KETONE BODIES TO FEED STARVING NEURONS. SO WHAT IS THE IN EVIDENCE SUPPORT OF THAT HYPOTHESES? SO FIRST OF ALL, WE REPLICATED THE DECLINE IN MITOCHONDRIAL RESPIRATION AND THE RISE IN HYDROGEN PEROXIDE FROM THESE NOW INEFFICIENT MITOCHONDRIA, AND THE ACTIVATION OF PHOSPHOLIPASE A2 IN THE BRAIN. AND THAT THIS ACTIVATED PHOSPHOLIPASE A2 IS OCCURRING HERE IN ASTROCYTES AS SHOWN ASTROCYTES LABELED FOR GFAP IN RED FOR PHOSPHOLIPASE A2 AND THE COLOCALIZATION OF THE GFA. AND PHOSPHOLIPASE A2 IN THESE ASTROCYTES. AND THAT THIS ISEST IN WHITE MATTER REGIONS OF THE FILM BRIIA, SING LUMAND SCHAFER COLLATERAL PATHWAY. AND SO DO WE HAVE EVIDENCE FOR CATABOLISM OF MILE IN WHITE MATTER? AND ESSENTIALLY, WHAT WE FIND IS A STAGE DEPENDENT CATABOLISM THAT FIRST ISEST IN THE ACCUMULATION OF SERA MIDES IN THE REPRODUCTIVELY IN COMPITANT, PERIMENOPAUSAL ANIMALS AND THEN IN THE AGED ANIMALS, WE SEE THE RISE IN FATTY ACIDS. AND A CHANGE IN THE MITOCHONDRIAL TCA PANEL CONSISTENT WITH THE UTILIZATION OF FATTY ACIDS. SO IF THAT IS TRUE, IF THESE LIPIDS ARE BEING FORMED FROM MY LIN, THERE SHOULD BE EVIDENCE FOR MILE IN DEGENERATION. AND THAT IS SHOWN HERE. THIS IS ELECT TROP MICROGRAPH FROM EUGENIA TRA SIN SKI — SORRY. AT MAYO CLINIC. SO, THIS IS A LOWER MEG AND HIGHER MEG OF MILE IN SURROUNDING AXONS AND THIS IS IN ANIMALS THAT ARE REPRODUCTIVELY IRREGULAR. SO AT THIS POINT, IN THE ENDOCRINE AGING PROCESS, THE MILE IN REMAINS INTACT. ONCE THESE ANIMALS HAVE BECOME REPRODUCTIVELY INCOMPETENT AND THESE ANIMALS ARE NINE MONTHS OF AGE, WHAT WE SEE IS THAT THERE IS AN UNRAVELING OF THE MILE IN. THAT THEN ULTIMATELY APPEARS AS A LOSS IN MILE IN ACTUAL DENSITY HERE IN THE AGED ANIMALS. AND THAT IS SHOWN HERE IN TERMS OF THE NUMBER OF AXONS AFFECTED IN THE COLLATERAL PATHWAY, SCHAFER COLLATERAL PATHWAY, AN TEAR AND CHORPUS CLOSE OM SHOW THIS CHANGE IN A NUMBER OF AXON THAT IS NOW SHOW THIS DECLINE IN WHITE MATTER INTEGRITY AND WHITE MATTER DENSITY. SO IF THIS MILE IN IS BEING CATABALIZED TO GENERATE LIPIDS, WE SHOULD SEE AN ACCUMULATION OF LIPID DROP LETS. AND AGAIN, MY ELECTRON MICROSCOPY, WHAT WE SEE IS THAT THERE IS AIC AND DRAMATIC RISE IN THE NUMBER OF LIPID DROP LETS IN BOTH THESE — IN THE CHORPUS CALLOSUM AND AN TEAR COM SER AND THESE ARE LIPID DROP LETS AND WE SEE THAT IN THESE REPRODUCTIVELY INCOMPETENT ANIMALS, WE SEE A DRAMATIC RISE IN THE GENERATION OF LIPID DROP LETS. SO, IF LIPID DROP LETS ARE BEING UTILIZED, AND LIPIDS, FATTY AGES IDS ARE BEING GENERATEDDED FROM THESE LIPIDS, THERE SHOULD BE EVIDENCE IN THE MITOCHONDRIA FOR TRANSPORT OF THESE FATTY ACIDS AND METABOLISM OF THESE FATTY ACIDS, AND WHAT WE SEE HERE IS THAT THE CPT1, FATTY ACID TRANSPORTER IS GREATLY INCREASED IN THE AGED ANIMALS THE ENZYME WHICH CATAB LIESES LONG CHAIN FATTY ACIDS IS GATELY INCREASED AND ABAD ALSO SHORT CHAIN FATTY ACID DEHYDROGENASE IS ALSO INCREASED IN THESE AGED ANIMALS. THE ABILITY TO TRANSPORT AND METABOLIZE LONG AND MEDIUM AND SHORT CHAIN FATTY ACIDS IN THE MITOCHONDRIA IS EVIDENCE ESSENTIALLY WHAT WE SEE HERE IS THAT THE BRAIN IN THE HIPPOCAMPUS AND CORTEX, WHAT WE SEE IS A LINEAR RISE IN HIPPOCAMPAL KETONE BODIES AND IN THE CORTEX, A INCREASE IN THE AMOUNT OF KETONE BODIES IN THE CORTEX AND A COM CONINANT DECLINE IN THE ABILITY OF THE PLASMA TO MAINTAIN KETONE BODY CONCENTRATIONS. SO THESE DATA ARE CONSISTENT WITH THE TRAJECTORY THAT THE BRAIN PRIOR TO THIS TRANSITION IS USING GLUCOSE AS PRIMARY FUEL. THE BRAIN UNDERGOES A STARVATION RESPONSE TO UTILIZE KETONE BODIES AND THE SUPPRESSION OF THE UTILIZATION OF KETONE BODIES IS LIFTED AND ULTIMATELY THERE IS EVIDENCE THAT THE AGING FEMALE BRAIN WILL CATAB LIES ITS WHITE MATTER AS A SOURCE OF KETONE BODIES. AND THIS IS SHOWN HERE AGAIN WHITE MATTER INTEGRITY DURING THIS EARLY PHASE AND THAT A LOSS OF INTEGRITY BOTH OF THE MILE IN AND ALSO OF THE AXON IS EVIDENT IN THE MENOPAUSAL ANIMALS AND THEN IS GREATLY EXACERBATED IN THE AGING ANIMALS. SO IF THIS IS TRUE IN THE MOUSE, WHAT IS THE EVIDENCE THAT THIS ACTUALLY HAS RELEVANCE TO THE HUMAN? SORRY. FORGOT IMMUNE PART. SO WE SAW IN THE INFORMATION COMPONENT THERE WERE CHANGES IN THE NF-KAPPA B AREA DURING THIS TRANSATION. AND THIS CHANGE WAS COINCIDENT WITH THIS RISE IN UTILIZATION OF THE INACTIVATION OF THE FATTY ACID METABOLISM SYSTEM. SO WE CONDUCTED AN RNA-SEQ ANALYSIS TO DETERMINE THE TRANSCRIPTOME FROM THE PERIMENOPAUSAL ANIMALS AND USING ALUMINA HIGH RNA-SEQ, WE WERE ABLE TO DETECT AROUND 30,000 GENES. 20,000 OF WHICH WERE MAPPED AND ESSENTIALLY WE SEE ABOUT 300 GENES CHANGED HERE AND THEN WHEN WE LOOKED AT WHERE THE SIGNIFICANT NUMBER OF GENES WERE CHANGED, IT WAS ESSENTIALLY DURING THIS TRANSITION, DURING THE IRREGULAR, FROM THE REGULAR CYCLERS TO IRREGULAR CYCLERS. AND HERE WHAT WE SEE IS AGAIN, A LITTLE OVER 200 GENES BEING CHANGED DURING THIS IRREGULAR CYCLER. THIS PERIMENOPAUSAL TRANSITION ESSENTIALLY THIS IS DURING THIS TRANSITION THAT MOST OF THE GENETIC CHANGES ARE HAPPENING RELATIVE TO WHEN THESE ANIMALS ARE NOW TRANSITIONING TO BEING ACYCLIC. SO WHAT WAS SURPRISING TO US IS THE ACTIVATION OF THE IMMUNE SYSTEM ESSENTIALLY WHAT THE GENE EXPRESSION DATA SUGGESTS IS THAT DURING CHRONOLOGICAL AGING, THERE IS A SIGNAL THAT EMERGES FROM THE BRAIN TO THEN ATTRACT T LYMPHOCYTES TO NOW INVADE THE BRAIN AND THIS CHEMOTAXIS ESSENTIALLY, THIS CHEMOTAXIS SYSTEM IS ACTIVATED IN CHRONOLOGICAL AGING AND THEN DURING THE REPRODUCTIVE AGING, ESSENTIALLY WHAT WE SEE IS THE UPREGULATION AND ACTIVATION OF ANTIGEN PRESENTATION AND THEN ULTIMATELY DOWNREGULATION OF THE T-CELL PROLIFERATION RESPONSE THAT OCCURS EARLY IN THIS PROCESS AND THAT ESSENTIALLY THE AGING PROCESS WE SEE THAT THERE IS T-CELL ACTIVATION AND DIFFERENTIATION IN THE BRAIN. THIS IS IN THE HIPPOCAMPUS. SO THESE T LYMPHOCYTES WE DON’T KNOW WHAT THEY ARE DOING BUT THEY HAVE CLEARLY INVADED THE BRAIN TO DO SOMETHING. AND THAT IS AN AREA OF ACTIVE INVESTIGATION BY MANY. OKAY, SO, NOW, WHAT DOES THIS MEAN? IS THERE EVIDENCE THIS ACTUALLY HAPPENS IN THE HUMAN FEMALE AGING BRAIN? AND THIS IS WORK THAT WE CONDUCTED WITH LISA MUSCONEY AT NYU IN WHICH SHE DID A RETROSPECTIVE ANALYSIS. SHE WENT BACK INTO HER DATASET OF WOMEN IN WHICH SHE HAD CONDUCTED BOTH FTG PET AND BETA AMYLOID PLAQUE IMAGING WITH THE PICK COMPOUND. AND WE HAD ABOUT 16 WOMEN IN EACH GROUP SO WOMEN OF PERIMENOPAUSAL AGE WITHOUT SYMPTOMS, WOMEN OF PERIMENOPAUSAL AGE WITH SYMPTOMS AND THEN MENOPAUSAL AGE WOMEN. AND HERE IS JUST A COUPLE OF EXAMPLES. THIS IS A 49-YEAR-OLD FEMALE AND ESSENTIALLY 14 YEARS OF EDUCATION. SHE REPORTS SUBJECTIVE MEMORY DEFICITS AND MILD DEPRESSION. AND WHAT SHE ALREADY SHOWS IS MILD HYPOMETABOLISM RELATIVE TO THE SAME AGE SET OF WOMEN WITHOUT SYMPTOMS. THIS WOMAN WITH SYMPTOMS SHOWS ALREADY MILD HYPOMETABOLISM IN THE MEDIAL TEMPORAL DORE TEXT. THIS WOMAN IS 53 YEARS OLD. AGAIN, REPORTS SUBJECTIVE MEMORY DEFICITS, HOT FLASHES AND IN SOMNOIA AND SHOWS MILD HYPOMETABOLISM IN THE MEDIAL TEMPAL CORTEX AND PRY TALL TEMPAL CORTEX. IN A WOMAN WHO IS APOE34 POSITIVE, ESSENTIALLY SHE TOO SHOWS, SHE REPORTS SUBJECTIVE MEMORY COMPLAINT SHE TOO SHOWS MILD HYPOMETABOLISM IN THE PRY TALL TEMPAL, POSTERIOR CINGULATE AND THE MEDIAL TEMPAL CORTEX OF BOTH HEMISPHERES. SO HYPOMETABOLISM IS EXACERBATED IN WOMEN WHO IN THIS PARTICULAR WOMAN WHO IS POSITIVE, ONE ALLELE OF THE APOE GENE AND ALREADY BEGINNING TO SHOW SIGNS OF ATROPHY IN THE HIPPOCAMPUS. SO, THE EARLY ANALYSIS OF THESE WOMEN SHOWS THAT THERE IS AGAIN A STEP FUNCTION AND DECLINE IN FDG PET SIGNAL IN THE BRAIN THAT THEN IS SUSTAINED IN THE MENOPAUSE. SO IT’S MORE LIKE A STEP FUNCTION AND IT’S NOT LINEAR DECLINE IN THIS CASE. WHAT WAS SURPRISING TO US WAS THE FACT THAT WHEN SHE LOOKED AT THE PICK LABELING FOR BETA AMYLOID PLAQUE, SHE SAW THE REVERSE. SO NOW THERE IS A RISE IN PICK LABELING IN THE BRAIN IN PERIMENOPAUSAL ANIMALS — SORRY PERIMENOPAUSAL HUMAN WOMEN, AND THAT NOW INCREASES OR APPEARS TO BE INCREASING LINEARLY. WE HAVE A ONGOING PROJECT TO STUDY THIS FURTHER. BUT THIS IS SOMEWHAT DISCONCERTING THAT EARLY IN THIS AGING PROCESS, THERE IS ALREADY EVIDENCE FOR A MODEST DECLINE IN GLUCOSE METABOLISM AND A MODEST RISE IN BETA AMYLOID GENERATION. SO, WHEN WE LOOKED AT — AND HERE IS THE QUANTITATIVE ANALYSIS OF THE FTG PET SIGNAL AND AGAIN, IT’S MODEST BUT THE MAXIMUM THAT IS ACHIEVED TYPICALLY IN ALZHEIMER’S BRAIN IS 25%. SO, ALREADY IN THIS EARLY PROCESS OF AGING THAT WE CAN SEE THERE IS ALREADY A 6 TO 7 PERCENT DECLINE. WHEN SHE LOOKED AT THE DISTRIBUTION OF THE PICK LABELING ACROSS THE BRAIN, THERE WAS A SURPRISING RISE IN THE CUE TAME EN AND ORBITAL FRONTAL CORTEX. ALTHOUGH IT WAS NOT SO SURPRISING BUT THE PEW TAME EN WAS SOMEWHAT SURPRISING UNTIL WE ASKED WHAT IS THERE SOMETHING THAT LINKS YOU UP WITH THE ORAL FRONTAL CORTEX? THIS SUGGESTS THAT THIS AREA OF THE BRAIN IS ALREADY VULNERABLE, THE WHITE MATTER THIS BRAIN IN THIS REGION IS ALREADY VULNERABLE AND THESE LONG WHITE MATTER TRACKS. SO NOW HOW CAN WE TRANSLATE THIS BASIC SCIENCE AND EARLY CLINICAL SCIENCE INTO DETECTING WOMEN WHO ARE AT RISK? WHO HAVE NOT YET DEVELOPED SYMPTOMS OF ALZHEIMER’S DISEASE BUT IN FACT HAVE RISKS? AND SO WITH WENDY MACK AND HOWARD HOEDIS, WE CONDUCTED AN ANALYSIS OF THE EARLY VERSUS LATEST JEN INTERVENTION TRIAL AND TOOK ADVANTAGE OF THIS COHORT OF CONVENIENCE AND TO ASK THE QUESTION WITHIN A HEALTHY POPULATION, WITHIN A POPULATION OF HEALTHY WOMEN, CAN WE USE CLINICALLY FAMILIAR RAPIDLY DEPLOYABLE BIOENERGETIC BIOMARKERS TO DETECT WOMEN AT RISK FOR COGNITIVE DECLINE? WE CONDUCTED A PRINCIPAL COMPONENT ANALYSIS THAT ALLOWED US TO IDENTIFY THE POTENTIAL VARIABLES THAT EXPLAINED THE VARIANCE AND THE DATASET AND K MEANS CLUSTERING TO ESSENTIALLY ALLOW US TO LINK SUBJECTS WHO HAD COMPARABLE PROFILES INTO THESE DIFFERENT CLUSTERS. THE CLUSTERS WERE NOT PREDEFINED. IT WAS THE DATA THAT DROVE THE CLUSTERS. WE HAD 14 DIFFERENT BYO MARKERS AND NINE OF THEM TURNED OUT TO EXPLAIN 85 OR 87% OF THE VARIABILITY. SO, IN THIS POPULATION OF HEALTHY WOMEN, NO ONE HAS BEEN DIAGNOSED WITH DISEASE. WE FIND THREE CLUSTERS OF WOMEN. THERE IS THE HEALTHY WOMEN WHO HAVE HEALTHY METABOLIC CONTROL. THERE IS WOMEN WHO APPEAR TAB AT CARDIOVASCULAR RISK AND A THIRD POPULATION AT RISK FOR METABOLIC DYSFUNCTION. AND WHEN WE ASSOCIATED WE DID CORRELATION ANALYSIS WITH THEIR COGNITIVE FUNCTION, WHAT WE FOUND IS THAT ON GLOBAL COGNITION VERBAL MEMORY AND EXECUTIVE FUNCTION, THE GREEN ARE THE HEALTHY POPULATION OF WOMEN. THE RED ARE THE WOMEN AT CARDIOVASCULAR RISK, AND THE WOMEN WHO ARE AT METABOLIC RISK ALREADY SHOW A SIGNIFICANT DECLINE IN COGNITIVE FUNCTION. SUGGESTING THAT IT IS THIS METABOLIC FUNCTION THAT IS DRIVING SOME OF THIS COGNITIVE DECLINE. MOREOVER WHEN WE LOOKED AT THE ETHNIC COMPOSITION OF THESE CLUSTERS, THAT’S DISAPPEARED. WHEN WE LOOKED AT THE ETHNIC COMPOSITION, THE HEALTHY GROUP WAS LARGELY NOT EXCLUSIVELY BUT LIBERALLY POPULATED BY CAUCASIAN AND ASIAN WOMEN. THE WOMEN AT CARDIOVASCULAR RISK WAS LARGELY BUT NOT EXCLUSIVELY POPULATED BY WOMEN OF AFRICAN ORIGIN. AND THIS POPULATION WAS LARGELY BUT NOT EXCLUSIVELY POPULATED BY WOMEN OF HISPANIC ORIGIN. SUGGESTING THAT THOSE ETHNIC GENOTYPES AFFECTIONATELY CREATE OR CAN CREATE A PHENOTYPE OF RISK FOR COGNITIVE DECLINE. SO HOW DO WE ACTUALLY ADDRESS THIS PROBLEM OR THIS INTERVENTION OR INTERVENING IN THIS PROCESS? SO, WE DEVELOPED A ESTROGEN RECEPTOR BETA SELECTIVE FORMULATION BECAUSE WE HAD SHOWN FOR MANY YEARS IN PRECLINICAL STUDIES THAT TARGETING ESTROGEN RECEPTOR BETA, FIRST OF ALL IT IS LOCALIZED TO THE MITOCHONDRIA WHEREAS ESTROGEN RECEPTOR ALPHA IS NOT. AND THAT ESTROGEN RECEPTOR BETA INHIBITS PROLIFERATION OF IN THE BREAST WHILE PROMOTING NEUROGENESIS IN THE BRAIN, AS WELL AS PROMOTING MITOCHONDRIAL FUNCTION AND MULTIPLE INDICATORS OF BIOENERGETIC SYSTEM IN THE BRAIN. SO WE THEREFORE ADDRESS A UNMET NEED IN WOMEN’S HEALTH AND THAT IS FOR A SAFE AND EFFECTIVE ALTERNATIVE TO HORMONE THERAPY. WE DID THIS BY USING IN SILL CO, CHEMISTRY STRATEGIES THAT ALLOWED US. WE DEVELOPED A PHARMACO4 WE INTERROGATED A DATABASE OF 50,000 NATURAL SOURCE COMPOUNDS THEN REDUCED OUR SEARCH INTO 25 OF THOSE — 25,000 OF THOSE AND THROUGH AN IN SILL COAPPROACH, NARROWED THAT ESTROGEN RECEPTOR BETA SET TO 30 COMPOUNDS WHICH WE THEN TESTED AT THE BENCH. AND THAT TESTING LED TO THE DEVELOPMENT OF OUR PHYTOSERUM FORMALATION THAT IS COMPOSED OF GENOSTEIN DADE SIGN AND S EQUAL, ALL ESTROGEN RECEPTOR BETA PREFERRING MOLECULES AND ALL ON THE GRASS LIST GENERALLY RECOGNIZED AS SAFE. WE WERE AWARDED A GRANT FROM THE NIA TO CONDUCT A CLINICAL TRIAL AND THIS IS THE FIRST REPORT OF DATA FROM THAT CLINICAL TRIAL. AND ESSENTIALLY, IT WAS INTERESTING, ALTHOUGH SOMEWHAT DISAPPOINTING. WHAT WE FIND IS THAT IS THERE NO STATISTICALLY DIFFERENCE OF PHYTOSERUMS AT 50 OR 100 MILLIGRAMS RELATIVE TO PLACEBO ON HOT FLUSH ON A COMPOSITE SCORE OF HOT FLUSH. BUT I WILL NOTE THAT MORE IS NOT BETTER. TYPICAL OF ESTROGENS AND STEROIDS. MORE IS NOT BETTER. AND THEN WHEN WE BEGAN TO LOOK AT THE DATA THAT EMERGED FROM THIS HOT FLASH DIARY, THESE ARE THE DATA FROM TWO PARTICIPANTS AND ESSENTIALLY YOU SEE THE DATA ON A PHYSIOLOGICAL OUTCOME, HOT FLASHES, IS HIGHLY VARIABLE. AND THAT THERE ARE DIFFERENT PHENOTYPES OF RESPONDERS. SO HERE, IT TURNS OUT THAT A SCORE OF TWO IS EQUAL TO ZERO. WHAT WE SEE IS THAT THERE ARE TWO WOMEN HERE WHO ESSENTIALLY ARE VERY RAPID RESPONDERS THAT EARLY IN THE CLINICAL TRIAL THEY WERE RAPID RESPONDERS AND THEN STAYED FREE OF HOT FLASHES. THIS WOMAN, ESSENTIALLY THIS WOMAN HERE, IS A LATE RESPONDER AND APPEARS TO BE MOVING TO A HOT FLASH FREE ZONE. AND THEN, OVER HERE, WHAT YOU SEE IS THAT THERE ARE MULTIPLE WOMEN WHO CYCLE FROM HAVING HOT FLASHES HERE TO NO HOT FLASHES AND BACK AGAIN. SO THIS IS VERY DYNAMIC DATA. WHEN WE LOOKED AT THE ONE — WE HAD MULTIPLE COGNITIVE MEASURES. WHEN WE — THIS IS LOGICAL MEMORY DELAYED RECALL. WHAT WE SEE IS THAT THERE IS A HINT BUT NOT STATISTICALLY SIGNIFICANT. SO WE THEN CONDUCTED A SECONDARY ANALYSIS. FIRST OF ALL LET ME SAY THAT THE PHARMACOKINETIC ARE CONSISTENT WITH A 50 MILLIGRAM AND 100 MILLIGRAM DOSE OF PHYTOSERUM SO THERE IS GOOD, RELIABLE PHARMACOKINETICS ACROSS ALL THESE WOMEN AND THAT THERE WERE MULTIPLE MORE MEASURES OF SAFETY ALL OF WHICH WERE MET. WHEN WE BEGAN TO THEN DO A SECONDARY ANALYSIS ON RESPONDERS, WHAT WE FIND IS THAT THERE ARE ABOUT 10% OF WOMEN IN THE PLACEBO GROUP WHO WILL SPONTANEOUSLY CEASE HAVING HOT FLASHES LIKE 90% OF WOMEN DO DURING THE THREE MONTH TRIAL. BUT THAT ABOUT 30% OF WOMEN WHO ARE TREATED WITH THE PHYTOSERUMS ACTUALLY HAD CESSATION OF THEIR HOT FLASHES. SUGGESTING THERE IS A SUB POPULATION OF WOMEN WHO ARE RESPONSIVE TO THIS INTERVENTION WITHIN THREE MONTHS. WE CAN’T SAY WHETHER THEY WOULD — OTHERS WOULD HAVE RESPOND YOU BUT WITHIN THREE MONTHS ABOUT 30% OF THE WOMEN ON THE PHYTOSERUM AND THE LOW DOSE PHYTOSERUM WERE RESPONSIVE. MOREOVER, THAT CORRELATED WITH A SIGNIFICANT INCREASE IN LOGICAL MEMORY AND DELAYED RECALL. SO, THIS IS VERY TYPICAL FOR ALL CLINICAL TRIALS THAT THERE ARE A SUBSTANTIAL NUMBER OF PEOPLE WITHIN A CLINICAL TRIAL WHO WILL BE NONRESPONSIVE AND THEN A SUBSET OF THOSE PEOPLE IN THE CLINICAL TRIAL WILL BE RESPONDERS. SO WE HAVE MOVED THIS APPROACH INTO ANOTHER ARENA AND IN THIS CASE, THIS IS AROUND OUR TRANSLATIONAL CENTER CURE ALZHEIMER’S DISEASE. AND ESSENTIALLY OUR GOAL IN THE CENTER IS TO CREATE PERSONALIZED PRECISION AND PREDICTIVE THERAPEUTICS TO CURE ALZHEIMER’S DISEASE THROUGH A WIDE STRATEGY FROM BIG DATA LETTING BIG DATA DRIVE OUR SYSTEMS PHARMACOLOGY STRUCTURE-BASED DRUG DESIGN AND METABOLOMICS AND GENOMICS ANALYSIS AND THEN DEVELOPING MODELS COMPUTATIONAL MODELS TO TEST THE EFFICACY AND FAILURE TO PREDICT EFFICACY AND FAILURE AND UTILIZING IPS GENERATED NEURAL STEM CELLS AS A STRATEGY TO SCREEN THERAPEUTICS. SO, IN COLLABORATION WITH OTHERS AT UCSF, UTILIZING A DATASET DERIVED FROM SNYDER, WE CONDUCTED A METANALYSIS FOR RESPONDERS IN FAILED PHASE III CLINICAL TRIALS IN ALZHEIMER DISEASE. AND THESE WERE STUDIES OR DATA DERIVED FROM 19 STUDIES FROM THE ALZHEIMER’S DISEASE CONSORTIUM STUDY AND THE ALZHEIMER’S DISEASE IMAGING INITIATIVE. THEY WERE INTEGRATED INTO A SINGLE DATASET. THIS IS WORK DONE BY SNYDER, KENNEDY AND CUTTER. AND THE COMBINED DATASET HAS OVER 6000 INDIVIDUALS. THERE ARE MULTIPLE TREATMENT ARMS IN THIS DATASET. AND THAT IT INCLUDES PERSONS WITH ALZHEIMER’S DISEASE AND PERSONS WITH MYOCOGNITIVE IMPAIRMENT. LARGELY PEOPLE WITH LATE STAIN ALZHEIMER’S DISEASE. IN AN ANALYSIS OF RESPONDERS, IN THIS COMBINED DATASET, THE DOCTOR WAS ABLE TO DETECT THAT WOMEN, ESSENTIALLY HAD OVERALL ONE OF THE COGNITIVE PERFORMANCE THAN MEN AND COMPARABLE AGE DISTRIBUTION. SO THIS IS NOT A NOVEL FINDING. THIS IS ACTUALLY CONSISTENT WITH THE INCREASED BURDEN OF PATHOLOGY IN THE FEMALE BRAIN AND BOTH IN APOE4 NEGATIVE INDIVIDUALS AS WELL AS IN APOE4 POSITIVE INDIVIDUALS. AND THAT IS SHOWN HERE RELATIVE TO MEN, WOMEN HAVE IN THIS CASE, IN THE COG, A HIGHER SCORE IS WORST PERFORMANCE. SO, WHEN SHE BEGAN TO DETERMINE WHETHER THERE WERE RESPONDERS ANYWHERE IN IN DATASET, WHAT SHE DISCOVERED WAS IN FACT THERE WERE RESPONDERS AND THE RESPONDERS WERE ON STATENS. THAT THERE WERE MULTIPLE PHASE III CLINICAL TRIALS OF STATENS THAT ALL FAILED BUT WITHIN THIS DATASET, THERE WERE RESPONDERS AND THEY WERE MALE. THERE WAS IN THIS LARGE DATASET, THERE WERE NO STATISTICALLY SIGNIFICANT DIFFERENCE IN THE FEMALES. AND THEN, LOOKING AT SPECIFIC GENOTYPES, IT TURNS OUT THAT THE MALE RESPONDERS WERE ACTUALLY APOE34 POSITIVE. SUGGESTING AGAIN THAT THIS GROUP OF INDIVIDUALS, MALES IN THIS CASE, THAT GENOTYPE CAN INFLUENCE THERAPEUTIC INTERVENTION EFFICACY. IN THE CASE OF WOMEN, ESSENTIALLY, THERE WAS NO STATISTICAL DIFFERENCE IN WOMEN TREATED WITH LIPITOR IN THIS CASE, ACTUALLY LET ME BACK UP A STEP. SAY THAT THIS IS SIM BOW STATEN. THIS IS A RESPONSE AND THESE APOE34 MALES TO THIS WHEREAS THERE WAS A STATISTICALLY SIGNIFICANT AFFECT OF LIPITOR IN FEMALES AND ONLY IN THE APOE44 FEMALES. AND THERE WAS A 4.1 DIFFERENCE IN THE ADAS COG. FOR A CLINICAL TRIAL IN ALZHEIMER’S DISEASE TO BE SUCCESSFUL, THERE NEEDS TO BE A MOVEMENT OF TWO POINTS. ON THE ADAS COG. SO IN THIS CASE, IN THE APOE44 POSITIVE WOMEN, LIPITOR WAS GENERATING A 4 POINT DIFFERENCE IN THE ADAS COG SUGGESTING AGAIN THAT THERE ARE SEX DIFFERENCES NOT ONLY TO A CLASS OF COMPOUNDS BUT TO SPECIFIC COMPOUNDS, IN THIS CASE, STATENS AND LIPITOR. SO GOING FORWARD, WE HAVE ALREADY STARTED TO INVESTIGATE THE ELECTRONIC MEDICAL RECORDS AT UCSF. WE ARE CONDUCTING ANALYSIS FROM THE RUSH STUDIES, RELIGIOUS ORDERS AND MEMORY AND AGING PROJECT WITH RACHEL WHIT MERAT KAISER-PERMANENTE NORTHERN CALIFORNIA. SHE WILL BE INVESTIGATING THE IMPACT TO SEE WITH SHE CAN AFFECTIONATELY SEE THE SAME AFFECT IN HER POPULATION AND THE POPULATION FROM THE KAISER-PERMANENTE GROUP. WE ARE ALSO LOOKING IN THE U.K. BIOBANK AND JULIE AT USC IS INTERROGATING MEDICARE RECORDS TO ASK THE QUESTION OF PERSONS WHO ARE ON THESE STATENS, WHAT IS THE RISK OF DEVELOPING OR BEING DIAGNOSED WITH ALZHEIMER’S DISEASE? IF YOU’RE DIAGNOSED WITH ALZHEIMER’S DISEASE, WHAT ANAL ARE YOU DIAGNOSED? SUGGESTING WE HAVE EVIDENCE TO SUGGEST THAT WE CAN ACHIEVE POTENTIALLY ACHIEVE THAT VERY MUCH SOUGHT AFTER FIVE-YEAR DELAY. BUT ESSENTIALLY WE ARE GOING FROM A RELATIVELY SMALL MEGADATASET TO ALL THE WAY TO MILLIONS OF ELECTRONIC MEDICAL RECORDS IN THE MEDICARE SYSTEM. SO, THE LESSONS THAT WE HAVE LEARNED FROM THE 67% IS THAT THERE IS DECLINE IN GLUCOSE METABOLISM IN THE BRAIN THAT HAPPENS EARLY IN THE AGING TRANSITION IN THIS ENDOCRINE AGING TRANSITION OF THE PERIMENOPAUSE THAT LEADS TO A RELIANCE ON ALTERNATIVE FUEL PATHWAY KETONE BODIES AND THAT RELIANCE ON ALTERNATIVE FUEL PATHWAY, SETS THE BRAIN UP FOR UTILIZATION OF ITS OWN STORM OF LIPIDS AS A SOURCE OF FUEL SUPPLY. AND OUR MOST RECENT DATA SUGGESTS THAT THERE IS ACTIVATION OF BOTH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS. SO THE LESSONS LEARNED ARE THAT THE TRANSITIONS OF THE FEMALE AGING BRAIN INVOLVE A SET OF SEQUENTIAL SYSTEM LEVEL ADAPTATIONS AND A CHANGE IN YOUR BRAIN AND YOUR VOICE. THAT PERTURBING ONE COMPONENT OF THE SYSTEM INDUCES ADAPTATIONS. THE ONE COMPONENT OF THE SYSTEM DOES NOT RESULT IN THIS A COURSE CORRECTION. IT RESULTS IN A COURSE ADAPTATION. AND THAT THE FEMALE AGING BRAIN IS A DYNAMIC ADAPTING BRAIN. IT’S A SURVIVING BRAIN. SUGGESTING THAT ALZHEIMER’S DISEASE IN THIS AGED POPULATION MAY IN FACT BE DUE TOAGE ACTIVATION OF SURVIVAL RESPONSES IN THE AGING FEMALE BRAIN. THERAPEUT IWILL HAVE WINDOWS OF OPPORTUNITY ONE TYPE OF THERAPEUTIC WILL NOT FIT ALL FOR ALL-TIME SO THE KEY POINTS IS OVER 60% OF PERSONS WITH ALZHEIMER’S DISEASE ARE WOMEN PREVENTING DELAYING AND CURING ALL HEIMERS DISEASE IN WOMEN. WILL YIELD A 60% ACHIEVEMENT OF THE GOAL. IT’S IMPORTANT FOR US TO CONSIDER THE RIGHT DATA, SEX, THE RIGHT INFORMATICS, THE RIGHT QUESTIONS, BASED ON SEX, AND THE CORRECT SEX BASED THERAPEUTICS AT THE RIGHT TIME. TO CREATE PRECISION MEDICINE FOR ALZHEIMER’S DISEASE STARTS WITH SEX. THANK YOU. [ APPLAUSE ] I WANT TO RECOGNIZE MY TEAM. PHENOMENAL GROUP OF PEOPLE SHOWN HERE. I WANT TO PARTICULARLY RECOGNIZE FAY YEN AND OTHERS WHO DID THIS WORK AND MY COLLABORATORS AND THE NATIONAL INSTITUTES ON AGING. THANK YOU. [ APPLAUSE ]>>WE HAVE A FEW MINUTES FOR QUESTIONS BEFORE WE ADJOURN TO THE LIBRARY WHERE THERE ARE COOKIES PROVIDED BY FAES. SO, AND I SEE THAT THERE ARE PEOPLE LINED UP SO WE’LL JUST START DOWN THE LEFT.>>THANK YOU VERY MUCH FOR YOUR INTERESTING PRESENTATION. I FOLLOWED YOUR WORK ON METABOLISM AND THE BRAIN FOR A LONG TIME. I WORKED WITH DR. DUCKELS AND COURTHOUSE AT UC IRVINE AND CITED YOUR WORK EXTENSIVELY IN OUR OWN STUDIES. NOW I’M WORKING ON A PROJECT INVOLVING KETONE BODIES AND EXOGENOUS SOURCES. HAVE YOU LOOKED INTO JUST GIVING IT TO HOME.>>THAT’S A GOOD QUESTION AND IT’S A VERY GOOD POINT. SO THERE IS PRODUCTS ON THE MARKET THAT ARE KETOGENIC. IT’S BEEN KNOWN THE ALZHEIMER’S BRAIN IS KETOGENIC BRAIN AND THE TRIPLE TRANSGENIC MOUSE IS BORN A KETOGENIC BRAIN. SO IT’S ALREADY DEPENDENT ON KETONE BODIES SO, THE CHALLENGE WITH FEEDING THE BRAIN THIS MAY WORK. THERE IS DATA THAT IT DOESN’T.>>CTs DON’T DO MUCH.>>IT’S VERY MODEST AND PART OF THE PROBLEM IS THE TRANSPORTERS OF FUEL ARE DECLINING SO WE KNOW THAT TRANSPORT OF GLUCOSE INTO NEURONS IS FIRST AFFECTED AND THEN, THERE IS A CHANGE IN TRANSPORTERS FOR BOTH GLUCOSE AND MONOCAR BOX LAIDS AT THE BLOOD BRAIN BARRIER. SO ESSENTIALLY WHAT I THINK IS HAPPENING, IS THAT THERE IS THIS FEEDBACK SYSTEM BETWEEN THE BRAIN AND THE PERIPHERY. SO, AGAIN HIGH POG SCIZZ HERE, WE KNOW THAT THERE IS AN INEXPLICABLE WEIGHT LOSS 10 YEARS PRIOR TO THE DIAGNOSIS OF ALZHEIMER’S DISEASE IN WOMEN AND MEN. THAT INEXPLICABLE WEIGHT LOSS ESSENTIALLY IS ASSOCIATED WITH THE UTILIZATION OF ALL PERIPHERAL STORIES OF FAT. THAT SEEMS TO WORK BUT I THINK THAT IT IS TIME LIMITED. AND ONE OF THE THINGS I THOUGHT IS THAT THE WHITE MATTER CATABOLISM WOULD HAPPEN AT A UNIFORMED RATE ACROSS THE BRAIN. IT DOESN’T. IT HAPPENS MORE LIKE AN ATM. SO THE BRAIN IS GOING THROUGH ITS ATM STORE OF LIPIDS AND THEN IT GOES ON TO THE NEXT. AND THEN IT GOES TO THE NEXT. SO, THE WHOLE PROCESS OF WHEN THE BRAIN STARTS UTILIZING ITS OWN LIPIDS, IT’S JUST LIKE IN THE PERIPHERY, THERE ARE CHANGES IN TRANSPORTERS AND ENZYME SYSTEM SYSTEM THAT MAY MAKE IT INEFFECTIVE TO GIVE PERIPHERAL EITHER GLUCOSE OR KETONE BODIES OF THE IT’S AN AREA THAT IS CRITICAL FOR INVESTIGATION.>>WE HAD SOME SUCCESS BOTH IN HUMANS AND IN ANIMALS FEEDING EXOGENOUS KETONE BODIES. IT’S SOMEWHAT IMPORTANT THEY BE THE RIGHT STEREO ISOMERS BUT ANYWAY, I CAN SEND YOU THOSE REFERENCE FIST YOU’RE INTERESTED.>>AND I THINK TIMING WILL BE CRITICAL.>>I WOULD AGREE WITH THAT.>>THANK YOU.>>YOU DIDN’T SAY ANYTHING ABOUT THE SPACE OCCUPYING LESIONS NAMELY PLAQUES AND TANGLES. I KNOW THAT YOU’RE NOT GOING TO BE ABLE TO STUDY AUTOPSY BRAINS BECAUSE THE PEOPLE AREN’T DEAD AS OF YET. BUT IN ANIMALS MODELS FOUND ANY COMPARISON OR IN METANALYSIS WHERE YOU MAY HAVE SEEN SOME OF THEM REFER TO AUTOPSY BRAINS QUANTIFYING OR CHARACTERIZING THE NEUROFIBRILLARY PLAQUES AND TANGLES, SPACE OCCUPYING LESIONS OF ALZHEIMER’S. ANY RELATIONSHIP BETWEEN THAT AND YOUR HYPOTHESES ABOUT YOU’RE PUTTING FORTH?>>SO, I THINK IT IS A VERY GOOD POINT AND I THINK IT IS — I’M NOT CLEAR ON HOW TO GO ABOUT THAT. CAN WE TRACK THE BURDEN OF GENERATION OF PATHOLOGY WITH THE CHANGE IN EITHER ENZYMES REQUIRED FOR UTILIZATION OF KETONE BODIES AND/OR THE DEPOSITION OR THE LOSS OF WHITE MATTER, GENERATION OF WHITE MATTER OR HYPERINTENSITIES.>>AND IN TERMS OF PEOPLE WHO HAD TRANSPLANTATION OF MALE WHO HAD LIKE A FEMALE ORGAN PUT IN, WOULD THAT PUT THEM IN ADVANCED CATEGORY BECAUSE NOW THEY ARE HAVING MORE OF A X CHROMOSOME BURDEN? IF A MALE GETS A HEART TRANSPLANT, FROM A FEMALE CADAVER, HE IS ESSENTIALLY GETTING A FEMALE ORGAN SO HE BECOMES A CAME ERA? I KNOW THAT’S A STRANGE SITUATION BUT IT IS SOMETHING TO THINK ABOUT.>>IN THAT CASE, I WOULD SUGGEST ESTROGEN THERAPY. THAT’S A JOKE.>>THANK YOU.>>SINCE YOU DID MRI AND IMAGING TECHNIQUES DID YOU MEASURE THE THICKNESS –>>THAT’S ACTUALLY -A – WE PUBLISHED THAT. WE DID THAT FIRST AND YOU KNOW WHAT WAS VERY STRANGE, AND WE DIDN’T — AND THAT LED TOO THE ELECTRON MICROSCOPY, IS THAT WE SAW EXPANSION IT WAS THE UNRAVELING OF THE WHITE MATTER. SO YES WE DID THE MEASUREMENT OF THE AREA.>>YOU HAVE THE MOUSE MODEL. DID YOU GIVE THEM ESTROGEN IN THE AREA WHERE THEY MIGHT BE HAVING THE PROBLEMS? AND DOES IT HELP THEM TO REDUCE THE DISEASE OR DELAY?>>SO THAT’S A VERY GOOD POINT AND SO, THE REALITY IS IS THAT THE BRAIN IS DISCONNECTING FROM ESTROGEN. RECEPTORS ARE STILL THERE. AND WE DON’T KNOW SO WE ARE INVESTIGATING THIS NOW. WHAT IS THE PROCESS BY WHICH THERE IS A DISCONNECTING OF THE BIOENERGETIC SYSTEM FROM THE ESTROGENIC CONTROL? AND THE MOREOVER, IN TERMS OF UTILIZING OR INTERVENING WITH ESTROGEN, YOU CAN SEE THAT THE TIMING OF INTERVENTION IS CRITICAL. TIMING PERHAPS DURING THE TRANSITION WILL BE BENEFICIAL BUT TIMING MUCH LATER INTERVENING MUCH LATER ESSENTIALLY THAT SYSTEM HAS DISCONNECTED. SO IT WOULD NOT BELIEVE EFFECTIVE. I THINK YOUR POINT IS VERY WELL MADE. WHEN IS THIS INTERVENTION ACTUALLY APPROPRIATE AND WHEN IS IT INAPPROPRIATE OR INEFFECTIVE AT BEST?>>THANK YOU. GOOD LUCK.>>THANK YOU.>>SO PLEASE AGAIN JOIN ME IN THANKING DR. DIAZ AND JOIN US IN THE LIBRARY FOR REFRESHMENTS. [ APPLAUSE ]

2 comments

  1. Rates of Alzheimers disease went up in direct correlation with the increase consumption of sugar/high carbs and the lowering of healthy fats in our diet over the last 100+ years. In the year 1900, the average person consumed around 5 pounds of sugar per year, today it is well over 100 pounds of sugar per year. Cancer rates too have increased dramatically with increase sugar rates…….1 out of 20 contracted cancer in year 1900, one in two/three today. Cancer requires sugar/gluscose in order to thrive/survive. The brain requires far more Ketones from healthy fat to survive than it ever does from glucose. You can blame scientist Ancel Keys for creating the Food Pyramid of today. The High carbs, low fats. Flip pyramid upside down and watch Alzheimer rates plummet.

Leave a Reply

Your email address will not be published. Required fields are marked *