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The Accelerating Medicines Partnership ® is a public–private partnership among NIH, FDA, biopharmaceutical and life science companies, and nonprofit organizations. The goal is to transform the current model for developing new diagnostics and treatments by jointly identifying and validating promising biological targets for therapeutics.
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Several disease areas, including Alzheimer’s and Parkinson’s, are the focus of this partnership. The Accelerating Medicines Partnership® for Alzheimer’s Disease (AMP® AD) program has enabled participating research teams to identify unique candidate targets, including genes and proteins. These findings are shared with the broader research community to transform the speed at which new drug candidates can be identified.
Recent examples of AMP AD research findings include:
- Discovering the importance of the ATP6VA1 gene: In 2020, the ATP6VA1 gene was identified as a master regulator gene of a neuronal network in Alzheimer’s. With this gene, the AMP AD research team was able to improve neuronal function in lab tests with cells and flies. These findings pave the way for new drug discovery efforts targeting ATP6VA1.
- Identifying the role of the VGF gene and protein: Another AMP AD study identified the VGF gene and protein as having a key role in protecting the brain against Alzheimer’s. This discovery provides a new target for researchers seeking to develop drugs to treat or prevent Alzheimer’s.
- Differentiating types of microglia cells in the brain: Microglia in the brain act like trash collectors to help keep the brain healthy, and several teams are studying these cells for their potential as future treatment targets. In 2020, AMP AD researchers identified types of microglia associated with Alzheimer’s . One type of microglia was less abundant in the brains of people with Alzheimer’s than in control brains. The next step is to design larger, more specific studies of the role of microglia types in Alzheimer’s disease.
- Describing the trajectory of the disease process: An AMP AD team used computational approaches to make predictions about the sequence of molecular changes leading to Alzheimer’s. By better understanding the sequence of changes, researchers can identify people as being in the early stages of Alzheimer’s or farther along.
- Finding molecular subtypes of Alzheimer’s: Another AMP AD team identified several unique disease subtypes in people diagnosed with Alzheimer’s dementia . Knowing subtypes can be useful both for developing targeted treatments and having diagnostic tests for selecting patients for those treatments.
- Investigating why women are more likely to develop Alzheimer’s: A research team analyzed the changes in the levels of 180 metabolites in blood from more than 1,500 people who took part in the NIA-supported Alzheimer’s Disease Neuroimaging Initiative . The researchers reported women who carry the APOE4 gene were more likely than men to have certain metabolite changes related to known Alzheimer’s biomarkers. By identifying specific pathways that go awry within specific subgroups, researchers can develop targeted treatments.
Science Spotlight: HTT gene a rare cause of FTD and ALS
In 2020, NIH researchers and their international collaborators were surprised to find that a mutation in the HTT gene — which causes the rare and lethal Huntington’s brain disease — also causes frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in about 12 of every 100 people with FTD or ALS symptoms. However, these people do not have symptoms of Huntington’s disease.
The discovery might translate into a new way of diagnosing and treating some individuals with FTD or ALS. In fact, clinical trials of gene therapy targeting the mutated HTT gene are already in progress with those who have Huntington’s.
The investigational gene therapy may also help people with FTD or ALS who have the HTT gene mutation.
New NIH funding opportunities for researchers
NIH continues to offer the research community new funding opportunities for research projects designed to discover new biological mechanisms underlying Alzheimer’s and related dementias:
- To spur research on how TDP-43 protein is involved in several kinds of dementia, NIH recently launched the Mechanistic Basis of TDP-43-Dependent Pathobiology in Common Dementias
- Through its Molecular Mechanisms of Blood-Brain Barrier Function and Dysfunction in Alzheimer’s and related dementias initiative, NIH launched four large projects to support studies addressing how damage occurs to the blood–brain barrier and how it may contribute to cognitive impairment and dementia. The blood–brain barrier is a protective layer of cells between blood vessels and brain cells. This layer helps to control the flow of blood, oxygen, and nutrients into the brain, and block other substances.
- Through the Center Without Walls for Molecular Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD) program , NIH invited new applications for interdisciplinary team science support. Awarded projects aim to explore the molecular mechanisms underlying neurodegeneration in FTD in ways not possible through standard single-project approaches. The center will have a special focus on understanding mechanisms related to several known pathologies that occur in the brains of individuals with FTD, such as tau and TDP-43. A better understanding of FTD’s underlying molecular mechanisms has the potential to enhance therapy development.
- To increase research on why certain brain regions are more vulnerable to abnormal proteins and damage, NIH launched Mechanisms of Selective Vulnerability in LBD and FTD .
- To encourage research on how abnormal proteins spread in the brain, NIH invited researchers to develop projects for Mechanisms of Pathological Spread of Abnormal Proteins in LBD and FTD .
Science Spotlight: Genetic study of Lewy body dementia supports ties to Alzheimer’s and Parkinson’s
Five genes may play a critical role in determining whether a person will develop Lewy body dementia, according to a recent study led by NIH researchers. The research team also tied Lewy body dementia to Parkinson’s and noted that people who have Lewy body dementia may share similar genetic profiles with those who have Alzheimer’s.
The researchers identified the five genes by comparing the genes of nearly 3,000 people with Lewy body dementia with genes of about 5,000 healthy, age-matched research participants. Three genes, called SNCA, APOE, and GBA, had been implicated in Lewy body dementia in previous studies. But this study was the first to implicate the other two genes, called BIN1 and TMEM175, in Lewy body dementia. These two genes had previously been implicated in Alzheimer’s and Parkinson’s.
The findings, which suggest that Lewy body dementia is caused by a spectrum of problems that can be seen in both Parkinson’s and Alzheimer’s, may help researchers develop treatments for these diseases.
Research on psychological changes
To better understand how psychological symptoms of Alzheimer’s and related dementias differ from changes associated with normal cognitive aging, NIA has invested in a range of approaches to measure early psychological changes in the disease trajectory, as well as the behavioral and psychological symptoms of dementia. Scientists are exploring changes in affective, cognitive, social, and motivational processes in individuals with mild cognitive impairment and Alzheimer’s and related dementias.
A recent study found that people with different kinds of neurodegenerative diseases experience distinct challenges in perceiving emotion . The goal is to identify biological and behavioral targets for prevention and treatment approaches that will also promote social, emotional, and cognitive well-being.
NIA recently issued funding announcements to stimulate new research on changes in decision-making and emotional function that might be affected by early disease processes:
- Integrative Studies of Neural Mechanisms and Affective Processes
- Fundamental and Translational Research on Decision Making
- Basic and Translational Research on Affective, Motivational, and Social Function
NIA also encourages research that may aid the design of interventions that support decision-making. Specific areas of interest include the development of tools to assist adults with mild cognitive impairment or dementia:
- Decision-making interventions to leverage cognitive, emotional, social, and motivational strengths
- Tools to assess their ability to make decisions
- Strategies for simplifying choices
- Ways to promote timely advance care planning , such as a power of attorney and living wills
Investing in the Future: Research Trainee Jose Sandoval
Before graduating from college, Jose Sandoval suggested to Gino Cortopassi, Ph.D., professor of molecular biosciences at UC Davis, that they apply for an NIA grant to study the effects of APOE ε4 , the most common risk factor for Alzheimer’s.
Cortopassi’s lab studies the mechanisms of aging as well as defects in mitochondria, the energy factory of the cell. His research team also tests small molecule drugs that may treat those defects. The application was successful in receiving NIA diversity supplement funding. This type of support is geared toward eligible research trainees who desire an independent career in aging and geriatrics research and who also meet NIA’s goal to enhance diversity in the biomedical workforce .
In 2020, Sandoval graduated with honors with a bachelor of science in neurobiology, physiology, and behavior from UC Davis. Now he is now testing small molecule drugs to find out how to reverse the effects of the APOE ε4 genotype on mitochondrial function, which may have implications for the treatment of Alzheimer’s.
Sandoval became aware of research opportunities early on in his undergraduate career. As the first member of his family to attend college, he found a community and sense of belonging with his participation in the UC Davis Biology Undergraduate Scholars Program and later the NIA-funded Advancing Diversity in Aging Research Program through Undergraduate Education .
“I credit these programs with much of my success because they helped reassure me, they helped motivate me, and they gave me the tools that I used to succeed in college and hopefully medical and Ph.D. programs,” said Sandoval. “I hope to care for underserved communities disproportionately affected by metabolic disease, as well as studying that in the laboratory.”