Identify/understand all Alzheimer's-related genes

by Cure Alzheimer's Fund
Vetted

New evidence—funded by Cure Alzheimer’s Fund (CAF) and others—has emerged suggesting a strong connection between air pollution and Alzheimer’s disease. “These findings underscore the complexity of this disease,” says CAF President and CEO Tim Armour, “and emphasize the need for a comprehensive approach to stop it.” 

While Alzheimer’s researchers have theorized for a more than a generation that environment and lifestyle play a significant role in the development of Alzheimer’s, only now are they learning about pollution’s important role. “In the last five years,” said University of Southern California gerontologist Caleb Finch, Ph.D., “it’s become very clear to me and others that air pollution is a likely risk factor in Alzheimer’s, as well as in other changes in brain aging that slow our cognitive processes. This is a very large issue that we face globally.”

Thankfully, it’s also an issue researchers are beginning to address seriously. “There are now more than ten labs working on this around the world,” says Finch. “Five years ago, there were just a few. The topic is catching up to the recognition that it merits.” 

Finch is helping to lead the way. A widely acclaimed biomedical gerontologist who specializes in environmental effects on brain aging, he has received numerous scientific awards and has authored 500 research studies, as well as several major books on aging. In 1984, Finch was the founding director of the University of Southern California’s Alzheimer Disease Research Center, funded by the National Institute on Aging. He joined Cure Alzheimer’s Fund’s Scientific Advisory Board in 2014.

Finch’s recent attention to pollution was stimulated by emerging epidemiological studies from USC and elsewhere showing the following:

  • A strong association between urban pollution and shorter life expectancy: about 1.5 years shorter in the U.S. and five years shorter in China. 
  • A direct correlation between urban pollution and a dangerous thickening of
    the walls of the carotid artery, limiting blood flow to the brain. 
  • A strong connection between air pollution and inflammation in parts of the brain affected by Alzheimer’s disease.
  • A direct correlation between urban pollution and decreases in verbal learning, logical reasoning and memory, and executive function in middle-aged and older adults, both in the Los Angeles area and across the U.S. 

 

From all of this, Finch concludes, “It looks to me that air pollution contributes to at least five percent of Alzheimer’s, and it may be much more.”

His own research on pollution’s effect on aging has been spurred in two ways by a 2014 CAF research grant to examine the effect of nano-sized particulate matter (derived mostly from automobile traffic in urban environments) on the creation of Abeta in mice. Small particle air pollution is particularly worrisome, because that is the material that finds its way into the bloodstream. “We’re not worried about the particles larger than 2.5 microns, such as fireplace smoke,” Finch explains. “Those are trapped in the upper airways. The ones that we’re really concerned about are invisible to the human eye — smaller than 2.5 microns. They penetrate deeply into the lung, and they reach the brain.”

That 2014 CAF-funded project, says Finch, developed in conjunction with his USC associate Mafalda Cacciottolo, later led to a substantial grant from the National Institutes of Health. Together, their research established strong evidence that urban pollution is contributing to a toxic increase in Abeta, which in turn leads to the development of Alzheimer’s. 

“This sort of leveraging of small, privately funded projects into much larger, public-funded research is central to the Cure Alzheimer’s Fund mission,” says Armour. 

While the news about air pollution’s neurotoxicity is stunning and worrisome, there is some reassuring news. These  nanoparticles though abundant around the world, are on the decline in some nations. The U.S., for example, has seen a 35 percent decrease in the concentration of small airborne particles from 2000 to 2014. “Fifteen years ago, the bulk of the country was over the EPA safety standard,” Finch says. “Now, more than half of the country is under the safety standard. So we’re making progress.”

“This is a key piece of the puzzle,” says CAF Research Consortium Chair Rudy Tanzi, Ph.D. “Alzheimer’s emerges more than a decade before symptoms begin, with the over-accumulation of Abeta in the brain. As we aggressively move toward therapies to control that process, we need to expand our understanding of the contributing factors.”

In just its first year of operation, Cure Alzheimer’s Fund’s ambitious new Genes to Therapies™ (G2T) research program has bloomed far beyond expectations. “We’re firing on all cylinders now,” says Research Consortium Chair Dr. Rudy Tanzi. “It’s exactly where we need to be headed to stop this disease.”

In 2015, Cure Alzheimer’s Fund authorized nearly $6.8 million for 22 gene variant investigations, along with the initiation of 21 transgenic mouse models. That accounts for more than half of its total research funding this year—and is far more than all of its research funding in 2014.

G2T is the next phase of Cure Alzheimer’s Fund’s long-term plan for attacking Alzheimer’s disease from every possible angle. The key to defeating Alzheimer’s, Tanzi proposed 11 years ago, is first to identify, and then closely examine, the relevant genetic variants impacting disease risk. The identification phase was accomplished through two methods—Genome-Wide Association Studies (GWAS) and Whole Genome Sequencing (WGS)—which together located nearly 100 gene variants that impact Alzheimer’s risk.

By 2014, the Research Consortium and the Cure Alzheimer’s board recognized that we were ready for the next phase: G2T, where researchers now would investigate the precise function of each gene, the consequence of each variant and precisely how to intervene to arrest the disease process. Tanzi explains that G2T establishes a highly efficient research plan. “We’re not just studying genes at random anymore,” he says. “We know to a certainty that these particular genes impact Alzheimer’s. Now we can use our new mouse models to find the ones that are druggable. If we can find a switch that turns on a deleterious gene mutation, we want to turn that switch off.”

Prioritizing these variants and recruiting the appropriate research talent to examine each one requires vision and coordination. To guide this process, Cure Alzheimer’s Fund formed the G2T Steering Committee of leading Alzheimer’s researchers David Holtzman, M.D. (Washington University, St. Louis), Sangram Sisodia, Ph.D. (University of Chicago), Rudy Tanzi, Ph.D. (Massachusetts General Hospital/Harvard University), Robert Vassar, Ph.D. (Northwestern University), and Steven Wagner, Ph.D. (University of California, San Diego). That group then set the priorities for gene investigations and implemented the time-saving idea of developing appropriate mouse models even before recruiting the appropriate researchers. Early G2T researchers include G2T Steering Committee members, as well as Berislav Zlokovic, M.D., Ph.D. (University of Southern California), and Li-Huei Tsai, Ph.D. (MIT).

Each gene to be studied may have several different mutations, each requiring its own strain of mice to study how that mutation affects Alzheimer’s pathology. Originally, the first year of G2T was expected to involve just three to five new animal models and cost a few hundred thousand dollars. But the Research Consortium’s strong support for the project quickly expanded it to 21 separate mouse models in 2015.

“This rapid expansion is a testament to both our researchers and our contributors,” says Cure Alzheimer’s Fund Chairman Jeffrey Morby. “The participating researchers have accelerated their work to a point where we can now take advantage of new techniques and breakthroughs. Meanwhile, our generous contributors have stepped up with dramatically larger donations, which has enabled us to fund more promising projects than ever before. It’s a remarkable confluence.”

The G2T Steering Committee recruited Wilma Wasco, Ph.D. (Massachusetts General Hospital), a geneticist and longtime colleague of Tanzi and other members of the Steering Committee, to manage the Genes to Therapies research core. Her expertise in Alzheimer’s genetics-driven research and her science management experience make her an ideal fit. “This is an immensely difficult job with a mind-numbing amount of important details and many different strong personalities,” explains Sisodia, a member of the Research Consortium and G2T Steering Committee. Tanzi concurs: “Wilma understands the science inside and out, and she also knows how to make the trains run on time. She’s perfect.”

This is the first time a genes-to-therapies program of this scale has been attempted, and it already has drawn the attention of the National Institutes of Health (NIH). In fact, the NIH has indicated interest in modeling a mouse program of its own on Cure Alzheimer’s G2T template. “That’s an incredible compliment,” says Cure Alzheimer’s CEO Tim Armour. “We’re humbled. It’s yet another way we continue to collaborate with NIH and take advantage of the scale they bring to the research effort.” 

Dr. Wasco also remarks how the G2T program dovetails very nicely with the recent “Alzheimer’s in a Dish” technology developed by Tanzi and Doo Yeon Kim, Ph.D. “They’re really complimentary,” says Wasco. “Alzheimer’s in a Dish is a great model and it will make things much faster for studying drugs. It’s a way to quickly find therapies. But eventually, any drug that you find has to be tested in animals for safety purposes and overall understanding of what’s going on.” 

No treatment will emerge quickly, Wasco cautions. “It takes a lot of patience to be in science,” she says. “As therapies become available, we’ll be able to test them. G2T projects funded in 2015 are already producing new insights into the function of variants we know impact Alzheimer’s risk, and that is a necessary step toward targeting their operation
with a treatment someday.”

“We have very high hopes for this project and are immensely proud of its ambitious scope,” says Morby. “We’re pressing forward with all the energy possible.
Full steam ahead!”

In 2015, Cure Alzheimer’s Fund added new members to its Research Consortium and Scientific Advisory Boards, bringing substantially more depth to our research efforts while also maintaining our standards for funding research of the highest quality with the greatest potential impact on understanding and treating AD. Research funding went from $5.4 million in 2014 to $10 million, a nearly 90% increase.

As last year came to an end, we had a new paper accepted describing yet three new AD 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 now 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 AD. Our growing database of detailed genomic data on AD continues to be the most comprehensive, largest, and of 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 research community.

The Genes to Therapies (G2T) initiative begun in 2014 accelerated in 2015.  The top Alzheimer’s disease genes, including the previously established four and a dozen new ones identified in Whole Genome Sequencing funded by Cure Alzheimer’s, are being studied for their mechanisms of action and as potential targets for therapies. The primary purpose of G2T is to translate our unprecedented database of novel genetic results into a deeper understanding of the causes of AD as well as novel drug discovery and development for treating and preventing AD.  Projects and scientists include Rudy Tanzi and the foundational genome project as well as CD33, APOE, ADAM10 and ATXN1; Li-Huei Tsai on ABCA7; Marc Diamond on MAPT; David Holtzman and Marco Colonna on TREM2; and nearly 20 others.

In addition to studying the above AD genes in various mouse and cell models, Cure Alzheimer’s Fund is also building on the success of the Alzheimer’s in a Dish technological breakthrough it funded to develop even more robust neuronal cell models for rapid drug screening. The 3-D Drug Discovery (3DDS) project with collaborators around the country is screening all existing approved drugs (~1200) and many clinically safe, but not yet approved investigational drugs to assess which can be can be repurposed to stop beta-amyloid deposition, tangle formation, and neuronal cell death in 3D cultures. The effort has already found several that appear to block tangle formation. In other studies, we are screening for drugs that will stop neuro-inflammation in AD using the AD genes involved in innate immunity in the brain, e.g., CD33. We are also developing novel 3-D systems to address innate immunity and the blood brain barrier (BBB) in AD.

Cure Alzheimer’s Fund has also supported many projects working on drug discovery and development efforts, understanding the role of neuroinflammation and innate immunity, and the role of the microbiome in mediating Alzheimer’s risk.  Two such compounds are entering clinical trials, one of which has proven to be so compelling that it received an NIH Breakthrough grant.  A number of projects are also examining ways to diagnose Alzheimer’s disease earlier and with more accurate biomarkers that track cognitive decline.  

Modern science is, by necessity, built on specialization. A century ago, one man—Dr. Alois Alzheimer—knew everything there was to know about Alzheimer’s disease. Today, thousands of Alzheimer’s researchers specialize in neuroimaging, signaling, inflammation, stem cells, genetics and so on. It takes a village to cure this disease. 

Dr. David M. Holtzman, Andrew B. and Gretchen P. Jones professor and chairman of neurology at Washington University in St. Louis, is one of the rare researchers who stands above this hyper-specialization. For more than 20 years, Holtzman has been a leader in Alzheimer’s research in large part because of his breadth. While diving deeply into topics such as the neurobiology of the apoE protein and the molecular structure and metabolism of Abeta, he has labored to constantly stay connected to the many different pieces of the puzzle.

Holtzman, who is also the Paul Hagemann professor of neurology and developmental biology, the associate director of the Alzheimer’s Disease Research Center and the scientific director of the Hope Center for Neurological Disorders, was this year awarded Washington University’s Carl and Gerty Cori Faculty Achievement Award for “embody[ing] the ideals of individual and collaborative excellence.” He is also a practicing neurologist who has found that seeing patients has led to a wider understanding of the disease. “I’ve always made sure that if I’m going to study something, it should be directly relevant to what’s going on in human beings,” he says. “That has led directly to some of our unique findings.”

With his then post-doctoral fellow at the time, Randy Bateman, for example, Holtzman co-developed a technique to determine in a human being the synthesis and clearance rates of proteins in the brain. Holtzman also was involved in creating a biobank of CSF and plasma that he and such colleagues as Anne Fagan and John Morris utilized to carry out a series of fluid biomarker studies to demonstrate that measurements of certain proteins could be utilized to diagnose preclinical Alzheimer’s disease as well as to predict who will convert from cognitively normal to impaired.

“Initially, this biobank was for my own research on apoE,” he says, “but it burgeoned into a huge biomarker program.” Holtzman joined Cure Alzheimer’s Fund’s Research Consortium in 2008 at the invitation of Consortium Chair Rudy Tanzi. His first CAF-funded study explored the relationship between synaptic activity and Abeta “plaques.” Subsequently, Holtzman developed a new method to measure tau levels in the extracellular space of the brain in order to understand more about the connection between amyloid plaques and the tau “tangles” in Alzheimer’s. Holtzman also has explored the role of certain vascular factors present in the disease such as “amyloid angiopathy,” in which amyloid deposits form in the walls of blood vessels in the brain; and contributed greatly to our understanding of how anti-amyloid antibodies affect Alzheimer’s pathology and how Abeta potentially can be cleared from the brain of Alzheimer’s patients.

Holtzman also has played a vital role on the policy stage. For the past four years, he has served on the National Advisory Neurological Disorders and Stroke Council at the National Institutes of Health (NIH). “People look to David as a leader,” says Tanzi. “He’s a careful thinker, and he can bring many different strands together to make an important new observation or ask just the right question.”

Some of Holtzman’s latest work focuses on how sleep influences Abeta metabolism. “We found that, in the brains of animals and humans, Abeta is regulated by neuronal activity,” he says. “The levels of Abeta fluctuated during the day and night. During wakefulness, the levels of protein were higher than when sleeping, and if an animal was sleep-deprived, it caused a much earlier onset of Abeta deposition in the brain. This suggests that if you optimize non-REM (deep) sleep, it might delay the onset of Alzheimer’s disease. But once you get the pathology, it further disrupts your sleep.”

Holtzman has found Cure Alzheimer’s Fund energizing. “Certain institutions have a special collaborative spirit,” he says. “But at Cure Alzheimer’s Fund, we’ve gotten to know each other so well that we trust one another and share information all the time across many institutions. That stimulates what each of us is doing.”

“The feeling is mutual,” says Cure Alzheimer’s CEO Tim Armour. “We’re very fortunate to have such a deep and invigorating relationship with David.

Three recent discoveries by University of Southern California neuroscientist Berislav Zlokovic, M.D., Ph.D., have clarified one of the least-understood elements of Alzheimer’s disease: how the blood-brain barrier becomes compromised and contributes to the disease process.

In healthy individuals, the blood-brain barrier (BBB) is a fine mesh filter that transports only select molecules from the body’s main circulatory system into the brain in a highly controlled manner, protecting the more delicate brain from a variety of dangers, and transports certain molecules back out of the brain as well. Changes to the structural components of the BBB have been known to be a normal consequence of aging for decades, but it also has been known for many years that the BBBs of Alzheimer’s patients allow more harmful particles to cross into the brain than the BBBs of those without the disease do.

Precisely when and how, though, does the BBB become compromised, and does it happen as a prelude to Alzheimer’s or as a cause of it? These are essential questions. Alzheimer’s unfolds as a complex cascade of molecular events—one event leads to another, which leads to another, and so on. The effort to stop it rests on understanding all of the key cascade events in the correct sequence—a monumental challenge requiring a coordinated
team effort. 

The discoveries by Zlokovic—director of the Zilkha Neurogenetic Institute and professor and chair of the Department of Physiology and Biophysics at the University of Southern California, Keck School of Medicine, Los Angeles, and a member of the Cure Alzheimer’s Fund Research Consortium since 2011—bring us one step closer:

  • In January, Zlokovic’s team was able to use high-resolution imaging of the living brain to show, irrefutably, that the BBB becomes leaky with age, starting in the area of the hippocampus—the area responsible for memory and learning that is affected very early in Alzheimer’s disease. This leakiness begins long before there are any cognitive symptoms. The discovery, published in the journal Neuron, suggests that specialized brain scans might, in the near future, help doctors routinely spot very early, presymptomatic warning signs of dementia. It also identified early injury to brain vascular cells called pericytes, a type of mural cell that surrounds brain capillaries and acts as a “gatekeeper” of the blood-brain barrier. 
  • In March, Zlokovic’s team discovered that deficiency of a key BBB protein called GLUT1, which helps move glucose, a major energy substrate for the healthy brain, across the BBB, is directly connected to a compromised barrier. It also suggested that the gene regulating this protein could be an excellent drug target. The discovery was published in the journal Nature Neuroscience
  • In May, Zlokovic discovered the mechanism of action for an Alzheimer’s-implicated gene encoding protein known as PICALM. The PICALM-Alzheimer’s connection had been studied previously by Cure Alzheimer’s Research Consortium Chair Rudy Tanzi, Ph.D., and Zlokovic in a Cure Alzheimer’s Fund-supported study. Zlokovic, publishing his research in Nature Neuroscience, showed that PICALM is crucial for clearing Abeta across the BBB. PICALM variants associated with increased risk for Alzheimer’s lead to diminished expression of PICALM and faulty clearance of Abeta from the brain, leading to its accumulation both in the human brain and animal models of the disease. This suggests that, while Abeta is crucial in the subsequent cascade that leads to Alzheimer’s disease, the compromise of the BBB may happen earlier in the process, and may contribute directly to the destructive excess of Abeta in the brain.

“The brain cannot function in the presence of blood-brain barrier breakdown,” said Zlokovic. “Now we know that not only is Abeta important in Alzheimer’s, but also that this barrier, which is regulating transfer of molecules between the brain and blood, and vice versa blood and brain, can become leaky and dysfunctional and lead to subsequent problems likely contributing to onset and progression of dementia.”

Jeffrey Morby, chairman of Cure Alzheimer’s Fund, added, “We created our Research Consortium in order to spur innovation through the speedy sharing of vital data between top researchers. Dr. Zlokovic’s latest advance with PICALM is a perfect example of what we’ve been able to do, and it brings us that much closer to a cure.”

 

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Organization Information

Cure Alzheimer's Fund

Location: Wellesley Hills, Ma - USA
Website: http:/​/​www.curealz.org
Project Leader:
Laurel Lyle
Wellesley Hills, MA United States

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