2015 was another great year for the research funded by Cure Alzheimer’s Fund (CAF). I am very pleased to report that we capitalized on our previous momentum and made immense progress.
During the year, we added many new esteemed colleagues to our Research Consortium and our Scientific Advisory Board, as well as collaborators and grantees. These additions to our already significant group of accomplished scientists has the impact of substantially expanding our research efforts while maintaining our standards for only funding research of the highest quality and with the greatest potential impact on understanding and treating Alzheimer’s disease (AD).
For 2015, we increased our funded research to over $10 million, double the amount from 2014 of just over $5 million. I am confident in stating that Cure Alzheimer’s Fund is operating at an entirely new level of research excellence, which is unparalleled in the field of Alzheimer’s disease research.
Most of our projects remain focused on the Genes to Therapies™ (G2T) initiative, which is now in high gear. G2T involves taking the top Alzheimer’s disease genes, including the previously established (4) as well as a dozen of our new ones, and using them to create new disease models to study AD. The primary purpose of G2T is to translate our unprecedented database of novel genetic results into a deeper understanding of the causes of Alzheimer’s disease as well as novel drug discovery and development for treating and preventing the disease.
In addition to studying the above Alzheimer’s disease genes in various mouse and cell models, we are incorporating the new disease gene-derived data into our 3D stem cell-derived neuronal cell cultures (Alzheimer’s in a Dish). We have also used Alzheimer’s in a Dish to initiate the 3D Drug Screening (3DDS) project with several collaborators. Our approach is to use 3DDS to screen all existing approved drugs (~1200) and many clinically safe, but not yet approved, investigational drugs. The objective is to evaluate which drugs can be repurposed to stop beta-amyloid deposition, tangle formation and neuronal cell death in 3D cultures. The studies have already resulted in the identification of several drugs that appear to block tangle formation. In other studies, we are screening for drugs that will stop neuroinflammation using the AD genes involved in innate immunity in the brain, such as CD33. And, we are developing novel 3D systems to address innate immunity and the blood-brain barrier (BBB) in Alzheimer’s disease.
In addition to screening for new drugs, there are other projects in development that will take drugs funded by Cure Alzheimer’s Fund into clinical trials in patients with Alzheimer’s disease. Most notably, these include the gamma secretase modulators (GSM), aimed at lowering Abeta levels, and the Amylyx compounds, aimed at protecting neurons from neuroinflammation. This research effort is currently being conducted and will continue through 2016.
The Cure Alzheimer’s Fund portfolio of projects aimed at diagnosis and detection of Alzheimer’s disease has been steadily increasing, especially pre-symptomatically for the purposes of early prediction, early detection and early intervention.
An area of great growth is in the study of the role of neuroinflammation and innate immunity in the pathological pathways of Alzheimer’s disease. In addition to the G2T projects focusing on several new AD genes involved in these pathways, such as CD33 and TREM2, we are also investigating how microglial cells and astrocytes contribute to the death of nerve cells in AD.
Cure Alzheimer’s Fund was one of the first foundations to appreciate the key role played by innate immunity in Alzheimer’s disease, when we discovered in 2008 that CD33 is an AD gene. Today, entire AD research programs around the world are focused on CD33 and its counterpart gene, TREM2, first discovered by the recipient of a grant from Cure Alzheimer’s Fund.
As an extension of studies of innate immunity in the brain and its role in AD, our research has been advancing our ongoing studies of the role of microbial organisms, such as bacteria, viruses and fungus (yeast) in Alzheimer’s disease pathology. The ongoing work has resulted in a very exciting new paper, now in press. This paper is poised to rock the very foundation of our current models of the etiology and pathogenesis of Alzheimer’s disease. We have now shown in several different animal models and cell culture models (mice, fruit flies, dirt worms and neurons) that beta-amyloid is clearly an anti-microbial substance produced in the brain to protect against infection, including yeast (candida), herpes simplex virus 1 and various bacteria.
Our research has demonstrated that by infecting the brain of a very young (one-month-old) AD mouse model, in which no plaque would normally be present until 6-8 months of age, abundant amyloid deposition could be seeded in the brain, virtually overnight. Moreover, each amyloid plaque that formed overnight was observed to contain at its center a single bacterium. The resulting theory is that, in the brain, just a single bacterium that gains entry across the blood-brain barrier can lead to a senile plaque. As revealed with Alzheimer’s in a Dish, amyloid deposition can then trigger tangles to form in neighboring nerve cells, leading to cell death. In view of these results, we are now actively investigating our hypothesis that as we age, low-grade and clinically non-symptomatic infections of the brain from viruses, bacteria and yeast, trigger beta-amyloid deposition in the brain as a protective mechanism. Beta-amyloid then leads to tangle formation, followed by cell death, inflammation and, ultimately, dementia. If this hypothesis is borne out, we can envision potentially stopping the pathological process of Alzheimer’s disease at its earliest pre-symptomatic stage, by therapeutically targeting specific microbial infections in the brain.
The other role of microbes in Alzheimer’s disease involves beneficial microbes that make up our “microbiome.” The microbiome is the total collection of the several thousand species of bacteria that live in our gut, on our skin and in body cavities. In particular, the gut microbiome is directly connected to the brain and has been shown to affect mood and neuroinflammation in the brain. Two projects have now been funded by Cure Alzheimer’s Fund to explore the role of the gut microbiome in Alzheimer’s disease. The goal of these studies is to determine how we might treat and prevent AD, and otherwise enhance brain health, by managing the gut microbiome.
As 2015 came to a close, we had a new paper accepted describing (3) new Alzheimer’s disease genes, all of which offer new targets for drug discovery, including one involved in cholesterol metabolism and two others that appear to be involved in tangle formation. We have also finalized our whole genome sequencing data to arrive at roughly 350 different gene mutations and variants in about 50 genes that directly affect risk and/or age-at-onset for Alzheimer’s disease. Our growing database of detailed genomic data on AD continues to be the most comprehensive and highest quality, worldwide. We are currently preparing the publication of our unprecedented whole genome sequencing data and plan to make all of it available to the entire research community.
In summary, this has been a landmark year for Cure Alzheimer’s Fund. Not only are we supporting some of the most exciting and state-of-the-art research in the field of Alzheimer’s disease, we have also dramatically expanded our team of investigators. We now have the breadth, depth and focus in our research portfolio to move forward with true momentum.
2015 was a very exciting year, and 2016 is even more so. Our work is only possible because of the generosity of all of those who have donated to and supported Cure Alzheimer’s Fund. Thank you to my colleagues, to the Board and staff of Cure Alzheimer’s Fund. We are all enthusiastic about our progress and know that our work continues. We will not stop until we have discovered a way to end Alzheimer’s disease.
Rudolph E. Tanzi, Ph.D.
Joseph P. And Rose F. Kennedy Professor of Neurology
Harvard Medical School
Vice Chair, Neurology
Director, Genetics and Aging Research Unit
Massachusetts General Hospital