Apolipoprotein E4 (ApoE4) status is the primary and biomedically most important risk factor for Alzheimer’s disease (AD). We have found a novel mechanism by which ApoE4 weakens synaptic strength in neurons, which led us to identify a promising novel endosomal drug target. This proposal aims to establish the necessary mechanistic and infrastructural baseline to screen for modifiers of endosomal function and for discovering novel potential methods to target the endosome in vitro and in vivo. This is necessary for the evolution of a conceptually novel and therapeutically effective preventive approach to AD, at least for the majority of patients carrying the ApoE4 allele.
See what research we fund.
BrightFocus drives innovative research worldwide on Alzheimer’s, macular degeneration, and glaucoma.
Search our grant awards to learn more.
- Joachim Herz, MDThe University of Texas Southwestern Medical Center (Dallas, TX)ID:A2016396SJuly 1, 2016 to June 30, 2019Alzheimer'sStandard$300,000
Depressive Symptoms, Proteins Aβ and Tau, and Neuronal Network Activity in Prodromal and Early Alzheimer’s DiseaseJennifer R. Gatchel, MD, PhDMcLean Hospital/Massachusetts General Hospital (Belmont, MA)
In Alzheimer’s disease (AD), changes occur not only in a person’s memory and thinking, but also in their mood and behavior. Symptoms such as depression, apathy and withdrawal are common and distressing to patients and their families, and can be just as debilitating, if not more so, than changes in memory and thinking. These psychiatric and behavioral symptoms may occur very early in the disease process, in the “pre-Alzheimer’s” disease stage, when a person may have the AD proteins, amyloid beta (Aβ) and tau, in their brains, but before they have developed overt signs of the disease. There is currently not a clear understanding of why and how these debilitating psychiatric and behavioral symptoms occur, and there are few effective treatments. In this project we will be visualizing Aβ in the brains of older adults, and now, due to an exciting new technology developed in our group, for the first time we also will be able to visualize tau protein in the brains of living older adults. This project will be vital by 1) allowing us to see how mild psychiatric and behavioral symptoms relate to build up of Aβ, tau, and brain pathway changes in normal older adults and those in the pre-Alzheimer’s and early AD stages; and 2) providing important information about patterns of psychiatric and behavioral symptoms that may help us to identify those older adults most at risk. The results will pave the way for developing more effective treatments and prevention strategies for AD.ID:A2016434FMentors:Reisa A. Sperling, MD; Gad A. Marshall, MD; Diego A. Pizzagalli, PhD; Brent P. Forester, MDJuly 1, 2016 to June 30, 2018Alzheimer'sPostdoctoral Fellowship$100,000
This grant is made possible by a bequest from the Howlett Revocable Trust.
- Qiaoqiao Shi, PhDBrigham and Women's Hospital (Boston, MA)
Complement component 3 (C3) is an immune molecule that helps to refine the visual system during brain development by removing weak synapses, or connections between nerves. C3 is up-regulated in Alzheimer’s disease (AD) and therefore may contribute to the synapse loss that underlies cognitive decline. We recently reported that aged mice lacking C3 throughout life have preserved synapses and better memory than normal-aged mice. To further understand when and where C3 plays a role in AD, we have generated two novel mouse models in which C3 gene expression can be shut off at any age by injection of a chemical, or deleted in specific immune cells (only) throughout life. Further characterization of these mice will better define the role of C3 in the aging brain and AD and may direct us to new therapies.ID:A2016425FMentors:Cynthia Lemere, PhDJuly 1, 2016 to June 30, 2018Alzheimer'sPostdoctoral Fellowship$100,000
This grant is made possible in part by a bequest from the Estate of Frederick J. Pelda.
- Stephen Martin, PhDUniversity of Texas at Austin (Austin, TX)
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting the elderly, but all approved medications for AD only temporarily address the symptoms, not the progression, of AD. Because there is an urgent, unmet need for drugs to treat both the symptoms and the disease, the proposed program will explore a novel strategy to treat AD by targeting a biological pathway different from those of all existing drugs and all but one known clinical candidate. If successful, a compound will be identified that holds promise for those suffering from AD, thus representing a new way to treat this devastating disease.ID:A2016443SJuly 1, 2016 to June 30, 2018Alzheimer'sStandard$185,020
This grant is made possible in part by a bequest from the Trust of Francis C. Dykeman and in honor of Marie E. Dykeman.
- Ana Pereira, MDThe Rockefeller University (New York, NY)
Glutamate is a chemical that allows neurons to communicate; a critically important feature for memory. Glutamate needs to be at the correct place and time to allow efficient neuronal communication and to avoid toxicity. Glutamate levels are regulated by the glutamate transporter 1 (GLT-1), which is a protein that plays the important role of regulating concentrations of glutamate in the brain’s extracellular space by transporting it, along with other ions, across cellular membranes. This proposal investigates the mechanisms through which GLT-1 becomes dysregulated using several techniques. These experiments may allow development of novel medications that can bring GLT-1’s function closer to normal levels and significantly benefit Alzheimer’s patients.ID:A2016478SJuly 1, 2016 to June 30, 2019Alzheimer'sStandard$300,000
This grant is made possible in part by support from the Ping Y. Tai Foundation.
- Laura Wisse, PhDUniversity of Pennsylvania (Philadelphia, PA)
Drug trials are increasingly being started in an early stage of Alzheimer’s disease (AD), before memory problems start. This is an attempt to intervene before brain damage becomes too severe. To test how well such treatments are working, we need a good measure that can track various treatment effects in the brain. A good candidate for assessment is the brain region known as the medial temporal lobe (MTL), because it is affected in an early stage of AD. However, a fact that complicates using the MTL as a marker is that this brain region is also affected in normal aging. To separate the effects of preclinical AD from normal aging, we plan to investigate the MTL with an extremely precise, high resolution magnetic resonance imaging scanner. This will allow us to investigate smaller regions within this brain region which has an advantage over cruder measurements and methodologies in that it is expected to show differential effects of aging and preclinical AD.ID:A2016432FMentors:David Wolk, MD, PhD; Paul Yushkevich, PhDJuly 1, 2016 to June 30, 2018Alzheimer'sPostdoctoral Fellowship$100,000
This grant is made possible in part by a bequest from the Trust of Elenore Lundeen.
- Huda Zoghbi, MDBaylor College of Medicine (Houston, TX)
Alzheimer disease (AD) is characterized by the deposition of amyloid plaques and the accumulation of neurofibrillary tangles (eg, tau tangles), These AD pathologies are the, products of amyloid precursor protein (APP) processing and tau hyperphosphorylation, respectively. Several studies demonstrate that reduction of APP is therapeutically beneficial in AD mouse models. This evidence prompted us to hypothesize that modest reduction in the levels of APP proteins would delay the onset and retard progression of AD. We plan to identify new therapeutic targets using an unbiased, high-throughput screen that employs two different assay systems in parallel (human neuronal cell lines and fruit flies expressing human APP).Our goal is to identify those proteins whose reduction results in lower levels of APP, and whether this reduction rescues neuronal degeneration in flies.ID:A2016151SCo-principal Investigators:Juan Botas, PhDJuly 1, 2016 to June 30, 2019Alzheimer'sStandard$299,732
- Emilie Reas, PhDUniversity of California, San Diego (La Jolla, CA)
As age-related cognitive impairment and dementia become increasingly common health concerns for our aging population, it's important to develop tools to accurately detect and distinguish these other aspects of aging from the earliest signs of Alzheimer's disease (AD). Although imaging methods, such as magnetic resonance imaging (MRI), have shown promise at measuring changes in brain structure associated with cognitive impairment and dementia, these approaches are relatively insensitive to the earliest disease stages, when treatments will likely be most effective. A new brain imaging technique, restriction spectrum imaging (RSI), has shown promise at revealing smaller-scale features of brain structure than standard techniques. This project will test whether new RSI-based measures can identify small-scale pathways thought to be affected by AD; accurately predict which individuals will decline cognitively; and correlate with other known markers of AD.ID:A2016241FMentors:Linda K. McEvoy, PhDJuly 1, 2016 to June 30, 2018Alzheimer'sPostdoctoral Fellowship$100,000
- Paul Seidler, PhDUniversity of California, Los Angeles (Los Angeles, CA)
This project will expand our understanding of Alzheimer’s disease by delineating the structural assemblies that are available to tau, another amyloid protein that, along with amyloid beta, is associated with AD. Toxic forms of the protein will be identified and used as a template enabling the design of peptide agents that block the assembly of these structures. Natural variations in tau that protect against the formation of toxic assemblies will be studied to uncover new possibilities for therapeutic intervention, and to gain insights into the mechanisms by which amyloid fibers form, propagate, and exert toxicity.ID:A2016588FMentors:David Eisenberg, PhDJuly 1, 2016 to June 30, 2018Alzheimer'sPostdoctoral Fellowship$94,536
- Tara Tracy, PhDThe J. David Gladstone Institutes (San Francisco, CA)
Alzheimer’s disease (AD) afflicts many elderly people in our society; however, there are few treatment options available and no known cure for this devastating disease. The structures by which neurons communicate with each other in the brain, called synapses, are especially vulnerable to toxicity in AD. My research will advance our understanding of how the loss of a kidney and brain-expressed (KIBRA) protein at synapses contributes to cognitive decline in AD.ID:A2016360FMentors:Li Gan, PhDJuly 1, 2016 to June 30, 2018Alzheimer'sPostdoctoral Fellowship$100,000