The Public Lecture Rudolph E. Tanzi, Ph.D. Joseph P. and Rose F. Kennedy Professor of Neurology Vice-Chair, Dept. of Neurology Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital Harvard Medical School Rudolph Tanzi, PhD, 2014
Rudolph Tanzi, PhD, 2014
Public Speaking: What is it Good For ?? • Educational Outreach: Public, Students, Foundations, Associations • Fund-Raising: Philanthropic Donors, Private Foundations, Industry • Community Service: Non-profits and Gov. Agencies • Public Awareness: Capital Hill, Media, AAAS, NIH 3 Rudolph Tanzi, PhD, 2014
4 Rudolph Tanzi, PhD, 2014
Public Speaking: Tips for Success • Begin and end with a “thank you”; they are there for you ! • Breath..and choose 4-6 people for eye contact • Keep it Simple: Try to explain your research to your uncle • Remember: you want to be there.. for audience (not yourself) • Try to keep it interactive - invite questions throughout talk • Avoid Jargon: Say “Nerve Cell” instead of “Neuron” • Slide Headings should be like headlines – tell a story • The Success Formula: • Describe the Problem - Clarity is vital! • Create the need for a solution • Explain how you are seeking a solution • Try to tell personal stories about your research • Acknowledge scientists in audience and their contributions • Stay calm, cool, and happy during the Q&A (no matter what!) 5 Rudolph Tanzi, PhD, 2014
Taking Control of Alzheimer's Through Research Rudolph E. Tanzi, Ph.D. Chair, Cure Alzheimer’s Fund Research Consortium Joseph P. and Rose F. Kennedy Professor of Neurology Vice-Chair, Dept. of Neurology Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital Harvard Medical School Rudolph Tanzi, PhD, 2014
Alzheimer’s Disease • Most common form of dementia in the elderly • Brain pathology of Alzheimer’s begins in almost everyone after 40 yrs old • Risk Factors: – Age : • 1/5 persons over 65 will get Alzheimer’s • Up to 50% over age 85 have AD – Family History : • Strong genetic component (inheritance) involved almost all cases – Other : • Gender: Females > Males • Traumatic Brain Injury • Stroke, Obesity, High Cholesterol, Diabetes • Social Isolation (Loneliness) • Depression • Emotional trauma, e.g. death of a spouse Rudolph Tanzi, PhD, 2014
The Disastrous Impact of Alzheimer’s 5.4 million victims in the USA 3.5 million deaths from Alzheimer’s in USA in past 10 years >13 million family members impacted >15 million unpaid caregivers Approximately 40,000,000 worldwide have Alzheimer’s … >>100,000,000+ by 2040 8 Date source: Alzheimer’s Disease International Rudolph Tanzi, PhD, 2014
Alzheimer’s could bankrupt the US healthcare budget between 2015 & 2020 if a cure is not found Medicare/Medicaid Costs per year (billions of dollars) 1,600 1,400 Tipping Point 1,200 1,000 800 600 400 200 - 2010 2015 2020 2025 2030 9 Rudolph Tanzi, PhD, 2014
2000-2010: Mortality Rates Decreased for Most Major Diseases Except Alzheimer’s 7 Rudolph Tanzi, PhD, 2014
Current Therapeutics for Alzheimer’s • Currently, no therapeutics are available to stop the progression of AD • FDA-approved AD drugs modestly alleviate symptoms.. temporarily. • Acetylcholinesterase inhibitors: Aricept, Exelon, Reminyl • NMDA glutamate receptor antagonist: Namenda × Rudolph Tanzi, PhD, 2014
Reducing risk for Alzheimer’s disease now • Physical exercise -At least a brisk walk everyday • Healthy diet -Mediterranean diet: Fruits/veggies, olive oil, less red meat • Social engagement -Hang out with friends • Learn new things - Attend more lectures • Reduce emotional stress -Meditation, Yoga • Get eight hours of sleep per night -Deep sleep consolidates memory: System back-up -Deep sleep clears protein debris from brain: Mental floss Rudolph Tanzi, PhD, 2014
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Alzheimer’s Disease: Catastrophic impairment of cognition (memory, learning, reasoning, judgment) to the point that everyday activities and quality of life are severely impacted. 15 Rudolph Tanzi, PhD, 2014
1906: Dr. Alois Alzheimer found his patient, Auguste D, 55 yrs old, sitting on a bed with a helpless expression. “What is your name?” he asked. “ Auguste ,” she replied. “Last name?” “ Auguste .” “What is your husband’s name?” “ Auguste , I think.” “How long have you been here?” “Three weeks.” (It was her second day in the hospital.) “I have lost myself ,” she told her doctor. Rudolph Tanzi, PhD, 2014
( Science Version ) The Stages of Alzheimer’s Disease Rudolph Tanzi, PhD, 2014
The Evolution of Memory (Based on the Triune Brain Model) Brainstem Limbic Neocortex No need for Acquired Memory Acquired Memory Acquired Memory of Pain/Pleasure of experiences Instinctive “ Self ” Emotional “ Self ” Intellectual “ Self ” Innate Memory Short-term Long-term Memory Memory Rudolph Tanzi, PhD, 2014
Ending Alzheimer’s: How Do We Use Genes? Early Early Early Early Prediction Prediction Detection Prevention Hit disease as early as possible! AD Genes show the way! Rudolph Tanzi, PhD, 2014
Milestones in Genetics Rudolph Tanzi, PhD, 2014
(Science version) Original Four AD Genes Pathogenic Biochemical Onset Gene Variant Phenotype ↑ Ratio of Aβ42:Aβ40 Fully Penetrant Early Mutations: ↑ Aggregation of Onset APP 24 (+Duplic) Aβ <60 yr PSEN1 184 PSEN2 15 ↑ Production of Aβ Late Susceptibilty Onset Factor: ↓ Aβ Clearance APOE ε4 - (3.7 to >10-fold) >60 yr Rudolph Tanzi, PhD, 2014
Ending Alzheimer’s: Starts with the Genes 1906 - 1986 1987 - 1995 Generic Disease Genetic Disease Brain Pathology Defects in 4 Genes APP PSEN1 PSEN2 Amyloid Plaques Tangles APOE Inflammation Rudolph Tanzi, PhD, 2014
Ending Alzheimer’s: What Do We Learn from AD Genes? Gene Drug Therapeutic Defects Targets Intervention APP PSEN1 PSEN2 APOE Rudolph Tanzi, PhD, 2014
Example: Target for Intervention HEART DISEASE: HIGH CHOLESTEROL Diet, Exercise, Weight Control, Statins, e.g. Lipitor, Crestor Rudolph Tanzi, PhD, 2014
Ending Alzheimer’s: Earliest Drug Target is A-Beta ALZHEIMER’S A-Beta DISEASE: Diet, Exercise, Weight Control, Drugs? Rudolph Tanzi, PhD, 2014
a -secretase (Science version) b -secretase -secretase APP A b Early-Stage Intervention Inhibit A b generation - (GSM, BSI – AZ, Novartis, A b 42 A b 40 Roche, Merck, Eisai Cu,Zn Early-Stage Intervention B Clear A b from brain - A b 42 B A b 40 A b (PBT2; Sola, Gant, Cren) A b 42 B b -amyloid (Cu-mediated) Mid-Stage Intervention - Prevent tau tangles NFT, Synaptic (Rember) Dysfunction Mid-Stage Intervention - Neuroprotection Neuronal (Growth factors) Cell Death Late-stage Intervention NP - Anti-inflammatory (CD33 inhibitors) Reactive microglia Inflammation Rudolph Tanzi, PhD, 2014
Alzheimer’s Disease Pathology b -Amyloid Pathology (EARLY-STAGE) Tangle Pathology (MID-STAGE) Inflammation (LATE-STAGE) Rudolph Tanzi, PhD, 2014
Alzheimer’s Genome Project Phase 1: Genome Wide Association Studies (Completed) - Identify new AD genes Phase 2: Whole Genome Sequencing (Ongoing) - Find functional variants in AD genes Phase 3: Functional Studies of New AD Genes (Ongoing) - Determine functional roles of new AD genes Model Systems Novel Therapeutics Cure Alzheimer’s Fund Rudolph Tanzi, PhD, 2014
Genome Wide Significant (22) Genome Wide Highly Suggestive (19) CD33 ZNF3 BIN1 IGHV1-67 PTK2B TP53INP1 CLU HLA-DRA ABCA7 HS3ST1 CR1 PICALM SQSTM1 MS4A6A TREML2 CD2AP NDUFAF6 HLA-DRB1/5 ECHDC3 SORL1 AP2A2 SLC24A4 ADAMST20 DSG2 INPP5D IGH@ MEF2C SPPL2A NME8 TRIP4 ZCWPW1 SCIMP CELF1 14Q Locus FERMT2 DLGAP1 EPHA1 ADAM10 CASS4 ATXN1 TREM2 Rudolph Tanzi, PhD, 2014
• ~3,000,000 variants/genome • A variant every ~1000 bp • Total: 51,000,000 DNA variants! Rudolph Tanzi, PhD, 2014
a -secretase (Science version) b -secretase -secretase APP A b A b production A b production/aggregation A b 42 A b 40 ATXN1 APP PICALM PSEN1 Cu,Zn A b aggregation SORL1 PSEN2 B ADAM10 APOE A b 42 B A b 40 A b A b 42 B b -amyloid deposition Tangles MAPT VCP Tangles GRN BIN1 (Spreading) SQSTM1 CHMP2B Neuronal Inflammation Cell Death APOE MS4A6E NP CR1 EPHA1 CD33 HLA-DRB Reactive microglia TREM2 INPP5D Inflammation TREM2L IGH Rudolph Tanzi, PhD, 2014
b -Amyloid Pathology (EARLY-STAGE) APP ATXN1 PSEN1 PICALM PSEN2 SORL1 APOE ADAM10 Tangle Pathology (MID-STAGE) Inflammation (LATE-STAGE) MAPT VCP APOE MS4A6E HLA-DRB GRN BIN1 CD33 EPHA1 INPP5D SQSTM1 CHMP2B CR1 TREM2 IGH Rudolph Tanzi, PhD, 2014
To end Alzheimer’s we will need a cocktail that will stop b -amyloid, tangles, and inflammation 33 Rudolph Tanzi, PhD, 2014
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