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Due in part to substantial increases in funding, the pipeline of potential treatments for Alzheimer’s disease and related dementias is more robust and diverse than ever. NIH is currently conducting and supporting research into all aspects of drug development: basic research to drug discovery, preclinical studies, and early- to late-stage clinical trials. The goal is new treatment options that will prevent, slow, or reverse the development of dementia.
What happens to the brain in Alzheimer’s disease?
The healthy human brain contains tens of billions of neurons, specialized cells that transmit messages between different parts of the brain and between the brain and other parts of the body, such as muscles and organs. In Alzheimer’s, toxic changes can disrupt communication among neurons. Researchers believe this process involves abnormal forms of certain proteins.
In people with Alzheimer’s, abnormal levels of the beta-amyloid protein clump together to form plaques that slowly build up between neurons. Abnormal forms of the tau protein accumulate in neurons, eventually forming tangles inside the neurons.
Ultimately, beta-amyloid plaques and tau tangles spread throughout the brain and prevent neurons from functioning properly. As many neurons stop functioning, they lose connections with other neurons and may die. Researchers are working to discover how other factors, such as inflammation, the brain’s blood supply, and brain changes caused by proteins other than beta-amyloid and tau (including alpha-synuclein and TDP-43, which are discussed later in this report) may also contribute to Alzheimer’s and related dementias.
Discovering new dementia drugs
Through its Alzheimer’s Disease Drug Development Program, NIA supports research aimed at discovering new drug candidates that target various biological processes involved in Alzheimer’s and related dementias. Since its inception in 2006, this initiative has supported 47 drug development projects and resulted in 12 new, disease-modifying dementia drug candidates that have advanced to testing in human trials.
- It is understood that brain inflammation increases the risk of Alzheimer’s and related dementias. One cause of this inflammation is deposits of fibrin, a protein which helps to form blood clots. NIA is funding a study focused on developing an antibody against fibrin as a potential treatment for Alzheimer’s.
- Mebendazole, used to treat parasitic infections in humans, has been shown to reduce the buildup of tau tangles in most research models of Alzheimer’s. NIA is funding a study aimed at changing the chemical structure of mebendazole and transforming it into a new drug candidate that can reduce tau pathology and improve the memory deficits in people living with Alzheimer’s.
- A protein called TDP-43 accumulates in the brain of older adults with dementia. Initial research identified small molecules that bind to TDP-43 and prevent its accumulation. NIA-funded drug development studies will optimize these small molecules into a drug candidate for the treatment of Alzheimer’s and related dementias. NIA advances efforts to repurpose existing drugs for other conditions to treat dementias.
The NIA-funded Alzheimer’s Clinical Trials Consortium (ACTC) is a clinical trials infrastructure designed to accelerate studies for therapies in Alzheimer’s and related dementias.
- CT1812 removes toxic beta-amyloid clumps from the critical signaling connections between brain cells, with the goal to prevent cell damage. NIA-funded grants supported data collection to confirm the safety of CT1812. With additional support from a five-year NIA grant, CT1812 is now being tested in a Phase 2 trial in collaboration with the ACTC.
New treatment strategy targeting protein malfunction tested in clinical trials
Molecules called chaperones help proteins form correctly inside cells. In Alzheimer’s, chaperones stop working normally, causing proteins in the cell to take on the wrong shape and interact with each other in ways that can cause disease. Through NIA-funded research, the PU-AD molecule was developed to target the malfunctioning chaperones . A Phase 1 clinical trial showed that PU-AD is safe in healthy volunteers, and future clinical trials will assess whether this drug is an effective treatment for Alzheimer’s.
Anti-amyloid medicines for dementia treatment and prevention
In Alzheimer’s disease, beta-amyloid clumps together to form plaques in the brain. One possible strategy to treat or prevent Alzheimer’s is to reduce these plaques with monoclonal antibodies (antibodies made in the laboratory) that bind to beta-amyloid.
- Aducanumab and similar antibody drugs may slightly improve brain function by reducing plaques in the brain, according to an analysis by NIA scientists. But the drugs also raise the risk of certain brain abnormalities. Aducanumab received U.S. Food and Drug Administration (FDA) accelerated approval in 2021, based on the effect of treatment on biomarkers, such as brain imaging. Although NIH did not directly fund the development of aducanumab, the agency did support critical foundational research leading to the discovery of antibody drugs.
- A recent NIA-funded study showed that treatment with either gantenerumab or solanezumab (other anti-amyloid antibodies) did not slow cognitive decline in people who have a rare, early-onset form of Alzheimer’s called dominantly inherited Alzheimer’s disease. However, gantenerumab reduced certain biomarkers of the disease, such as brain cell damage and tau levels, indicating that higher doses and longer treatment times may be effective.
- A 2022 NIA-funded study found that the anti-amyloid antibody crenezumab did not prevent or slow cognitive impairment in people with autosomal dominant Alzheimer’s disease (ADAD).
- People living with Down syndrome have a high risk of developing Alzheimer’s. They are born with an extra copy of a key gene that produces amyloid, leading to a buildup of beta-amyloid clumps in the brain. Researchers have developed a vaccine called ACI-24 that causes the body to make antibodies against these clumps, in the hope of preventing harmful plaques from forming. An NIA-funded Phase 1 clinical trial found that the ACI-24 vaccine was safe and well-tolerated in adults with Down syndrome and was effective at inducing the production of anti-beta-amyloid antibodies . The vaccine will be tested in Phase 2 trials to validate these results in a larger group of participants.
- Based on lessons learned from previous work, NIH-funded research has resulted in a DNA-based vaccine, called AV 1959D , which triggers an immune response against beta-amyloid. Studies in animal models have shown that AV-1959D is safe and effective at preventing beta-amyloid accumulation and brain cell death. As a result of preclinical studies, NIA awarded a grant to test AV-1959D in clinical trials with individuals with early-stage mild cognitive impairment (MCI) or Alzheimer’s. The trial began in late 2022.
Repurposing existing drugs for other conditions to treat dementias
Researchers are leading studies to determine whether drugs currently used to treat other conditions can help prevent or treat Alzheimer’s. This strategy, called drug repurposing, is an alternative to traditional drug development research. In 2021 and 2022, drug repurposing studies made several important discoveries.
- NIA researchers are using an animal model to test drugs with similar structures to thalidomide (thalidomide analogs) as a way to reduce brain inflammation associated with Alzheimer’s and related dementias. Thalidomide is an FDA-approved drug that reduces inflammation and is currently used to treat some types of cancer, including multiple myeloma, and skin conditions such as leprosy. One study found that the thalidomide analog 3,6’-dithiopomalidomide (DP) reduces brain inflammation, prevents brain cell death, and improves motor and behavioral functions in mice with beta-amyloid plaques. Another study found that the thalidomide analog NAP (N-adamantyl phthalimidine) promotes recovery from severe brain injuries, which can increase the risk of developing Alzheimer’s.
- In cell culture experiments, two drugs, an FDA-approved treatment for myeloid leukemia called dasatinib and an experimental treatment for liver cancer, were able to correct distinct molecular abnormalities associated with Alzheimer’s pathogenesis . These drugs may target proteins in the brain that appear to be altered early in the course of Alzheimer’s. The study included samples from participants in the NIA-led Baltimore Longitudinal Study of Aging and the NIA-funded Religious Orders Study.
- Bumetanide, a common diuretic, may lower the risk of Alzheimer’s in people who have a genetic risk for this disease . Scientists obtained these results by analyzing data from databases of brain tissue samples and FDA-approved drugs. The researchers mapped individuals’ genetic risk for disease against the pathologies in their brains, cross-referenced with the prescription drugs they took.
- In 2021, a multicenter trial that NIA funded through its Alzheimer’s disease clinical trials program showed that two daily doses of the drug methylphenidate (commonly known by the brand name Ritalin) safely reduced apathy among adults living with Alzheimer’s . Apathy, a loss of interest or motivation, is common among people with Alzheimer’s and is associated with increased medical costs, mortality, and caregiver burden.
Clinical trial will test gene therapy for Alzheimer’s and MCI
Gene therapy is an emerging technology that treats or reverses conditions by correcting problems with DNA. Via its Alzheimer’s disease clinical trials program, NIA launched a first-in-human (Phase 1) clinical trial to test a gene therapy to increase levels of brain-derived neurotrophic factor (BDNF) . BDNF is a brain growth factor that reduces cell death and promotes connections between brain cells; previous studies have found reduced BDNF levels in people with Alzheimer’s.
The trial is enrolling people with early Alzheimer’s or MCI, which can be a precursor to dementia. This being a Phase 1 trial, the goal is to test the safety, tolerability, and preliminary efficacy of BDNF gene therapy. The researchers are hopeful that this treatment will prevent and possibly even reverse the loss of brain cells in people with dementia.