Rudolph E. Tanzi


Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, and Co-Director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital. Dr. Tanzi has been investigating the genetics of neurological disease since a student in the 1980s when he participated in the first study that used genetic markers to find a disease gene. Dr. Tanzi co-discovered all three familial early-onset Alzheimer's disease genes and several other neurological disease genes including that responsible for Wilson’s disease. As the leader of the Cure Alzheimer's Fund Alzheimer’s Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer’s families leading to the identification of novel AD candidate genes, including CD33 and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led to clinical trials at Prana Biotechnology. He is also working on gamma secretase modulators for the prevention and treatment of Alzheimer's. He also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and Director the Cure Alzheimer’s Fund Alzheimer’s Genome Project™.
Dr. Tanzi’s team was the first to use human stem cells to create three-dimensional cell culture organoids of AD, dubbed “Alzheimer’s-in-a-Dish”. This model was the first to recapitulate all three key AD pathological hallmarks in vitro, and first to definitively show that amyloid plaques directly cause neurofibrillary tangles. The 3-D model also made drug screening for AD faster and more cost-effective. Using this system, Dr. Tanzi has developed several novel therapies for AD including gamma secretase modulators targeting amyloid pathology, ALZT-OP1 targeting neuroinflammation and a neuroprotective drug combination, AMX0035, which was successful in a clinical trial of ALS. Dr. Tanzi also discovered that beta-amyloid plays a functional role in the brain as an anti-microbial peptide, supporting a role for infection in AD pathology. Dr. Tanzi serves as Chair of the Cure Alzheimer’s Fund Research Leadership Group and numerous advisory and editorial boards, He has published roughly 600 research papers and has received the highest awards in his field, including the Metropolitan Life Foundation Award, Potamkin Prize, Ronald Reagan Award, Silver Innovator Award, the Smithsonian American Ingenuity Award, and the Brain Research Foundation Award. In 2015, he was named to TIME magazine’s list of TIME100 Most Influential People in the World. He co-authored the books Decoding Darkness, and the three international bestsellers, Super Brain, Super Genes, and The Healing Self, with Dr. Deepak Chopra. Dr. Tanzi has hosted three shows public television, regularly appears on television news programs, has testified to Congress on both Alzheimer’s disease and brain health, and on occasion serves as a studio keyboard player for Aerosmith, and other musicians.

Publications

Dr. Tanzi has published over 550 scientific papers including the top three most cited papers in the field of Alzheimer's disease research. Dr. Tanzi also co-authored the books "Decoding Darkness: The Search the Genetic Causes of Alzheimer's Disease, the New York Times Best Seller book “Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being" Paperback – October 22, 2013” and "Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being", "The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life" with Deepak Chopra. Tanzi has made numerous television appearances on shows such as CBS This Morning, The NBC Today Show, NBC Nightly News, Nova, and Dr. Oz. He also hosts the shows "Super Brain with Dr. Rudy Tanzi" "Super Genes with Dr. Rudy Tanzi" and "The Brain Body Mind Connection with Dr. Rudy Tanzi and Dr. Deepak Chopra" on PBS television.

Education

Dr. Tanzi received his B.S. in microbiology and B.A.in history from the University of Rochester in 1980. In 1990, he received his Ph.D. in neurobiology at Harvard Medical School, where his doctoral thesis was on the discovery and isolation of the first Alzheimer's disease gene - the amyloid precursor protein, published in 1987 in Science.

Research and Awards

At the start of his career in 1980, Dr. Tanzi worked as a research technologist for Dr. James Gusella at Massachusetts General Hospital where he assisted in localizing the Huntington’s disease gene, published in Nature in 1983. This was the first human disease gene to be found using genetic linkage and the first set of human genetic markers based on single nucleotide variants.
In 1987, based on his doctoral studies at Harvard Medical School, he was lead author of seven papers published in Science and Nature between 1987 and 1988, describing the initial cloning, mapping and characterization of the gene encoding the amyloid beta-protein precursor. Two other groups reported the cloning of APP at that time, and the gene was shown in 1990 to contain a mutation causing Dutch cerebral hemorrhage with amyloidosis and later in 1991, a mutation causing early-onset familial AD. In 1992, Dr. Tanzi and ex-trainee, Dr. Wilma Wasco, discovered the two APP family members, APLP1 and APLP2.
In 1995, Dr. Tanzi collaborated with Dr. Peter Hyslop and Dr. Jerry Schellenberg to discover the two other EO-FAD genes, presenilin 1 and 2. He has published many key studies characterizing the role of the EO-FAD genes in health and disease. All three genes remain among the most highly studied drug targets in the field of AD, especially with regard to therapeutic strategies aimed at reducing beta-amyloid deposition. In 1993, Dr. Tanzi also first discovered the gene for the neurodegenerative disease, Wilson’s disease, published in Nature Genetics. In that same year, he contributed significantly to the discovery of the first familial amyotrophic lateral sclerosis gene, SOD1, by providing the key genetic and physical mapping data for chromosome 21 used to find the gene defect, published in Nature, 1993.
As the leader of the Cure Alzheimer’s Fund Alzheimer’s Genome Project, Dr. Tanzi several other AD genes, most notably, CD33, reported in 2008 with his ex-trainee, Dr. Lars Bertram, in the American Journal of Human Genetics. In that study, Dr. Tanzi reported the first family-based genome-wide association study of AD, which most notably to the identification of the first innate immune AD gene, CD33, which encodes a cell-surface receptor on monocytes and microglia. Three years later, in 2011, in a large case-control AD GWAS consortium study, the National Institute on Aging Alzheimer's Disease Genetic Consortium independently confirmed association of AD with CD33. When first identified as an AD gene, nothing was known about CD33 in the brain or AD pathology. In 2013, Dr. Tanzi and his ex-trainee, Dr. Ana Griciuc first reported in Neuron that increased expression of CD33 in microglial cells in AD brain and showed that a protective CD33 gene variant was associated with reductions in CD33 expression and Abeta levels in AD brain. Importantly, they showed CD33 inhibits microglial phagocytosis and clearance of Abeta and induces pro-inflammatory cytokine release leading to neuroinflammation. They also elucidated the molecular mechanism by which sialic acid binds to CD33 to induce neuroinflammation. In a follow up study published in Neuron in 2019, Dr. Tanzi and Dr. Griciuc compared the neuroinflammatory effects of CD33 gene to another AD-associated innate immune gene, TREM2. Knockout of CD33 in AD mice attenuated amyloid-beta pathology and improved cognition while knockout of TREM2 led to opposite effects. They then showed that TREM2 functions downstream of CD33 and that crosstalk between CD33 and TREM2 involves the neuroinflammation-related IL-1beta/IL-1RN axis cluster. Since Dr. Tanzi’s discovery and characterization of CD33 as the first microglial AD gene, ~700 publications have been published on AD innate immune genes. CD33 has now emerged as the primary target for novel drug discovery programs aimed at curbing neuroinflammation, at over a dozen pharmaceutical and biotech companies.
Other AD genes Dr. Tanzi has discovered include, among others, ADAM10, UBQLN1, IDE, A2M, ITGB3, and ATXN1. In 2019, Dr. Tanzi, his ex-trainee, Dr. Jaehong Suh, and Dr. Huda Zoghbi led a study published in the journal, Cell, showing that ATXN1 controls production of the amyloid beta protein by regulating expression of the gene BACE1.
Over the past two decades, Dr. Tanzi has also contributed greatly to the development of novel therapeutics for AD. Beginning in 1994, in a study published in Science with Dr. Ashley Bush, his post-doctoral fellow at the time, Dr. Tanzi demonstrated a key role for zinc, copper, and iron in beta-amyloid deposition and Lewy body formation. This finding has led to the initiation of AD clinical trials of metal chaperones targeting metal-induced aggregation of beta-amyloid in AD and of alpha-synuclein and Lewy bodies in Parkinson disease.
Based on numerous studies co-authored by Dr. Tanzi, showing that most familial AD mutations increase the ratio of Abeta42:Abeta40, the key driver of amyloid plaque formation ". GSM's reverse the Abeta42:Abeta40 ratio and thereby prevent the “seeding” of amyloid plaques. Notably, they do not inhibit gamma secretase. Dr. Tanzi and Dr. Wagner have published several pioneering papers on these compounds, and their ongoing drug development efforts, supported by the NIH Neurotherapeutics Blueprint Program and the Cure Alzheimer's Fund, have led to a clinical candidate GSM that is now slated for AD clinical trials in 2021. Many in the field believe that in comparison to beta-secretase inhibitors and Abeta immunotherapy, GSMs may represent one of the safest and economically feasible ways for long-term therapeutic intervention in beta-amyloid deposition.
Also in 2000, Dr. Tanzi collaborated with cell biologist, Dr. Dora Kovacs, to show that blocking the enzyme acetyl-coA acetyltransferase 1, responsible for storing cholesterol as lipid droplets in intracellular rafts, prevents the generation of Abeta. Most recently, this led to their discovery that ACAT1 promotes the palmitoylation of APP dimers in lipid rafts, rendering them more susceptible to beta-secretase cleavage and Abeta production. They are now testing anti-palmitoylation drugs as well as their own ACAT1 inhibitors as potential drugs for preventing axonal release of Abeta and reducing beta-amyloid deposition.
In 2005, Dr. Tanzi and his ex-trainee and late colleague, Dr. Robert Moir, reported in J. Biol. Chem. the existence of auto-antibodies against oligomeric Abeta, which they showed to protect against risk for AD. This discovery inspired Dr. Roger Nitsch and the Swiss biotech, Neurimmune to develop an AD therapy based on isolating those auto-antibodies from memory B-cells and reverse translating them into the promising beta-amyloid immunotherapy, known as aducanumab, which was recently successful in a phase 3 AD clinical trial by Biogen and Eisai.
In 2014, Dr. Tanzi, and his ex-trainees, Dr. Doo Yeon Kim and Dr. Se Hoon Choi, were the first to use human stem cells to create three-dimensional cell culture organoids of AD, dubbed by the New York Times as “Alzheimer’s-in-a-Dish”. This model was the first to recapitulate all three key AD pathological hallmarks in vitro, and, most importantly, resolved a decades long debate as to whether Abeta pathology causes the formation of neurofibrillary tangles. Using this system, they were the first to definitively show that amyloid plaques directly cause neurofibrillary tangles, something that could not be shown in mouse models of early-onset familial AD gene mutations in APP and the presenilins. This 3-D cell culture model/human brain organoid system of AD has also made drug screening considerably faster and more cost-effective. Most recently, using a modified 3-D human stem cell-derived neural-glial cell AD model, Dr. Tanzi has helped develop therapies targeted against neuroinflammation in AD. These include ALZT-OP1 targeting microglial activation and neuroinflammation, and a neuroprotective drug combination, called AMX0035. AMX0035 was successful in a phase 2 clinical trial of ALS and now under consideration for approval by the FDA, while it also being tested in a phase 2 clinical trial in AD patients.
In another set of groundbreaking studies, Dr. Tanzi, working with Dr. Rob Moir, investigated whether amyloid beta may play a normal role in the brain. They demonstrated Abeta to be a potent antimicrobial peptide in the brain’s innate immune system. After showing that the beta-amyloid protein protects against various infections in different animal models ranging from C. elegans to mouse models, they made the even more striking discovery. They showed that subclinical levels of microbes can rapidly seed amyloid plaques. It has long been held that amyloid plaques require a decade or more to form in the brain. However, injecting either bacteria or virus into the hippocampus of very young AD mice, they showed that amyloid plaques formed overnight. These findings suggest that even subclinical levels of bacteria, viruses, or other microbes, entering or activated in the brain, may initially trigger plaque formation and start the amyloid cascade rolling. Dr. Tanzi is currently carrying out large-scale metagenomic sequencing of post-mortem AD brains, to catalog the microbes that may be initiating amyloid pathology. In 2018, they published back to back papers with a group at Mt. Sinai implicating Herpes viruses in triggering plaque pathology in AD. If successful, these new studies could lead to a new paradigm regarding the etiology of AD and new modes of prevention and treatment, based on targeting microbes that initiate amyloid pathology. Dr. Tanzi and Dr. Moir refer to this as the “antimicrobial protection hypothesis” of AD, and have noted that it may also be relevant to other neurodegenerative diseases, e.g. Creutzfeld-Jacob disease and Parkinson disease, given that the prion protein and alpha-synuclein have since been reported to also have antimicrobial properties.
In other studies, Dr. Tanzi and his ex-trainee, Dr. Zhongcong Xiem published several seminal papers providing the first evidence that the widely used general inhalant anesthetic, isoflurane, induces Abeta generation, apoptosis, and neurodegeneration in the mouse brain and in post-operative CSF of patients. This has gradually led to a dramatic reduction in the clinical use of isoflurane in the operating room, especially in elderly patients and Alzheimer’s patients. With ex-trainee, Dr. Lee Goldstein, Dr. Tanzi showed how head injury due to bomb blast or collision causes rapid induction of tangles and gliosis in mice. Now referred to as the “bobble head” effect, it has been postulated to be the main cause of subsequent onset of chronic traumatic encephalopathy in human subjects exposed to repeated concussion and head trauma.
Tanzi serves on dozens of editorial and scientific advisory boards, and as Chair of the Cure Alzheimer’s Fund Research Leadership Group. He has published over 550 research papers and has been issued numerous patents. He has also co-authored the books "Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease", and three international bestsellers : New York Times Best Seller, "Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health Happiness, and Spiritual Well-Being", "Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being", and "The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life". Dr. Tanzi has hosted three shows on public television: "Super Brain with Dr. Rudy Tanzi", "Super Genes with Dr. Tanzi" and "The Brain, Body, Mind Connection". Dr. Tanzi regularly appears on network television programs, including CBS Morning News, The Today Show, NBC Nightly News, CNN, MSNBC, Dr. Oz, and Nova. He has testified to Congress on both Alzheimer’s disease and brain health.
Dr. Tanzi has received numerous awards, including the two highest awards for Alzheimer's disease research: The Metropolitan Life Award and The Potamkin Prize. He was included on the list of the "Harvard 100 Most Influential Alumni", and was chosen by the Geoffrey Beene Foundation as a “Rock Star of Science”. In 2015, he was named by TIME magazine to the TIME100 Most Influential People in the World list. In 2015, Dr. Tanzi also received the Smithsonian American Ingenuity Award, the nation's highest award for invention and innovation. He also received the Silver Innovator Award, the Brain Research Foundation Award, the Ronald Reagan Award, Pew Scholar Award, Nathan Shock Award, Rustum Roy Award, and the Oneness in Humanity Award.
In 2018, Dr. Tanzi was inducted into the Rhode Island Heritage Hall of Fame, and as a native of Cranston, R.I., he was also inducted into the Cranston Hall of Fame in 2000. Dr. Tanzi was awarded an honorary doctorate from The University of Rhode Island on May 17, 2015.
Summary of Key Discoveries:
In musical pursuits, Dr. Tanzi serves as a studio keyboard player for Joe Perry and Aerosmith. He also co-wrote the song tribute to Alzheimer's patients called "Remember Me", performed by singer Chris Mann. He plays keyboards on the albums: Aerosmith: Music from Another Dimension, and Joe Perry: Sweetzerland Manifesto. He has also performed with the legendary opera star, Renee Fleming.

Books