The hope for future drugs
Currently, there are five FDA-approved Alzheimer's drugs that treat the symptoms of Alzheimer's — temporarily helping memory and thinking problems in about half of the people who take them. But these medications do not treat the underlying causes of Alzheimer's.
In contrast, many of the new drugs in development aim to modify the disease process itself, by impacting one or more of the many wide-ranging brain changes that Alzheimer's causes. These changes offer potential "targets" for new drugs to stop or slow the progress of the disease. Many researchers believe successful treatment will eventually involve a "cocktail" of medications aimed at several targets, similar to current state-of-the-art treatments for many cancers and AIDS.
"Despite increasing momentum in Alzheimer's research, we still have two main obstacles to overcome. First, we need volunteers for clinical trials. Volunteering to participate in a study is one of the greatest ways someone can help move Alzheimer's research forward. Second, we need a significant increase in federal research funding. Investing in research now will cost our nation far less than the cost of care for the rising number of Americans who will be affected by Alzheimer's in coming decades."
- Bill Thies, Ph.D., Chief Medical and Scientific Officer, Alzheimer's Association
Targets for future drugs
Over the last 30 years, researchers have made remarkable progress in understanding healthy brain function and what goes wrong in Alzheimer's disease. The following are examples of promising targets for next-generation drug therapies under investigation in current research studies:
 Beta-amyloid is the chief component of plaques, one hallmark Alzheimer's brain abnormality. Scientists now have a detailed understanding of how this protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretase. Researchers are developing medications aimed at virtually every point in amyloid processing. This includes blocking activity of both enzymes; preventing the beta-amyloid fragments from clumping into plaques; and even using antibodies against beta-amyloid to clear it from the brain. Several clinical trials of investigational drugs targeting beta-amyloid are included below in the key clinical trial summaries.
- Tau protein is the chief component of tangles, the other hallmark brain abnormality. Researchers are investigating strategies to keep tau molecules from collapsing and twisting into tangles, a process that destroys a vital cell transport system.
- Inflammation is another key Alzheimer's brain abnormality. Scientists have learned a great deal about molecules involved in the body's overall inflammatory response and are working to better understand specific aspects of inflammation most active in the brain. These insights may point to novel anti-inflammatory treatments for Alzheimer's disease.
- Insulin resistance and the way brain cells process insulin may be linked to Alzheimer's disease. Researchers are exploring the role of insulin in the brain and closely related questions of how brain cells use sugar and produce energy. These investigations may reveal strategies to support cell function and stave off Alzheimer-related changes.
Gauging treatment impact with brain imaging and biomarkers
In addition to investigating experimental drugs, many clinical trials in progress include various brain imaging studies and testing of blood or spinal fluid. Researchers hope these techniques will one day provide methods to diagnose Alzheimer's disease in its earliest, most treatable stages — possibly even before symptoms appear. Biomarkers may also eventually offer better methods to monitor response to treatment.
Learning from families with rare Alzheimer-causing genetic changes
Another new approach to testing experimental drugs to be given before symptoms appear focuses on individuals with rare genetic mutations that guarantee they'll eventually develop Alzheimer's disease. All of these currently known mutations affect beta-amyloid processing or production.
One project is the Alzheimer's Prevention Initiative (API), an international public-private consortium established to conduct research in an extended family in Antioquia, Colombia, in South America. At 5,000 members, this family is the world's largest in which a gene for familial (inherited) Alzheimer's has been identified. Familial Alzheimer's disease is also known as autosomal-dominant Alzheimer's disease (ADAD).
API's first clinical studies will test therapies targeting beta-amyloid in family members who are known to carry the Alzheimer's-causing gene but who have not yet experienced symptoms. Delaying or preventing the appearance of Alzheimer's in these family members could offer compelling evidence for the promise of beta-amyloid as a therapeutic target.
Catalyst to progress
Kenneth S. Kosik, MD, recipient of a 1991 Alzheimer's Association Zenith Fellows Award, played a pivotal role in the early 1990s documenting that the Colombian family's symptoms are due to Alzheimer's disease. He also helped raise awareness of the family's existence among the international research community. To identify the specific gene involved, he enlisted the help of Alison M. Goate, PhD, now a member of the Alzheimer's Association Medical and Scientific Advisory Council. Dr. Goate and her team pinpointed a previously unknown mutation in the presenilin-1 gene on chromosome 14 as the Alzheimer's-causing change affecting this family
API collaborators include the Dominantly Inherited Alzheimer Network (DIAN) study, an international initiative funded by the National Institute on Aging (NIA). DIAN will track participants from families in whom an Alzheimer's-causing mutation has been identified. The goal is to detect physical or mental changes that might distinguish those who inherit a mutation from those who do not. One strategy will involve monitoring brain beta-amyloid levels with PET scans and Pittsburgh compound B (PIB), the first proof-of-concept beta-amyloid detection compound. PIB was developed in part with Alzheimer's Association funding.
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Recent treatment trials
Below is a list of recent treatment trials, in alphabetic order by the generic name of the drug being tested. Every clinical trial, even those in which a treatment doesn't work as hoped, contributes valuable knowledge that will ultimately help researchers discover new treatments.
ACC-001
Phase: 2
Status: Active, recruiting
Mechanism: A "vaccine" that stimulates the body to produce its own antibodies against beta-amyloid. The mechanism is similar to AN-1792, the first Alzheimer's vaccine to reach clinical trials (see next summary), but ACC-001 is a different formulation.
AN-1792
Phase: 2
Status: Discontinued after about 6 percent of participants developed brain inflammation.
Mechanism: The first "Alzheimer's vaccine" targeting beta-amyloid. AN-1792 contained a form of beta-amyloid intended to mobilize a recipient's own immune system against the protein fragment.
Lessons learned: AN-1792 trials ended before investigators could obtain definitive evidence on its effectiveness as an Alzheimer's treatment. Preliminary data still provided some encouraging signals, and proved that an "Alzheimer's vaccine" could have a profound effect on the brain. Many study participants granted permission for their brains to be autopsied. Researchers continue to learn about AN-1792's impact on the brain as they gather more autopsy results.
bapineuzumab (AAB-001)
Phase: 3
Status: A number of bapineuzumab trials are active and currently recruiting
Mechanism: A monoclonal (laboratory-produced) antibody targeting beta-amyloid. A monoclonal antibody does not mobilize a recipient's own immune system.
Lessons learned: Phase 2 results suggested that bapineuzumab might have a stronger effect in recipients who do not have the Alzheimer's APOe4 risk gene. As a result, several of the active trials are recruiting specific groups of participants with and without APOe4. Positron emission tomography (PET) imaging with Pittsburgh compound B (PIB) indicated that bapineuzumab reduced brain beta-amyloid levels. While these data support the theory that beta-amyloid is active in the brain of those with Alzheimer's, they do not yet tell us whether reducing beta-amyloid levels is an effective treatment.
davunetide (AL-108)
Phase: 2
Status: Completed, Phase 3 planned
Mechanism: Davunetide is in development for Alzheimer's disease and other neurodegenerative disorders involving tau protein abnormalities, including schizophrenia and frontotemporal dementia. In a Phase 2 study enrolling participants with Alzheimer's disease and mild cognitive impairment (MCI), those receiving davunetide scored better on certain memory tests than those who received the placebo.
dimebon (latrepirdine, Dimebolin)
Phase: 3
Status: Trials completed, results negative. Participants receiving dimebon did not have better outcomes than those receiving the placebo (inactive treatment) in studies evaluating the drug as either a standalone treatment or as an add-on to ongoing therapy with the FDA-approved Alzheimer's drug donepezil.
Mechanism: Dimebon showed preliminary evidence of working in several different ways, including supporting communication among nerve cells by functioning as both a cholinesterase inhibitor and an NMDA receptor blocker. Early data also showed the drug might support cell energy production.
Lessons learned: A preliminary study conducted in Russia indicated that dimebon might be effective for Alzheimer's symptoms affecting both thinking and behavior. Although phase III studies were unable to confirm those results, the mechanisms through which dimebon was thought to work remain viable areas of research.
docosahexanenoic acid (DHA)
Phase: Two Phase 3 trials — one enrolling adults who had normal age-related memory problems but did not have Alzheimer's disease or mild cognitive impairment (MCI), and a second study enrolling participants with Alzheimer's disease.
Status: Completed. In the study of normal age-related memory trouble, participants who took DHA had greater score improvement on a test of visual memory and learning. In the Alzheimer's study, those who took DHA had no greater benefit overall than those who received the placebo (inactive, look-alike treatment). Participants without the APOe4 Alzheimer's risk gene may have benefited more than those who have the risk gene.
Mechanism: DHA, an omega-3 fatty acid, is one of the chief substances in the membranes surrounding nerve cells. It affects nerve cell function in several ways.
Lessons learned: The fact that DHA may have helped improve memory in healthy older adults but not in those with Alzheimer's may highlight the difference between preventing a disease from developing and treating established disease.
intravenous immunoglobulin (abbreviated IVIG, trade name Gammagard)
Phase: 3
Status: Active, recruiting
Mechanism: IVIG is a human blood product currently approved by the FDA to treat certain immune deficiency disorders. IVIG contains many different types of antibodies, including some that may promote clearance of beta-amyloid from the brain.
Lessons learned: Early stage trials in very small numbers of participants indicated that IVIG might also help those with Alzheimer's disease.
methylene blue (Rember)
Phase: 2
Status: Completed. The results were described as positive by the principal investigator, who presented the data at AAIC but has not yet published them.
Mechanism: Methylene blue is a deep indigo compound currently used as a malaria treatment and for tissue staining. In Alzheimer's disease, it may prevent aggregation of tau protein fibers into the tangles that are one hallmark of the disease.
PBT-2 (clioquinol)
Phase: 2
Status: Completed
Participants who received PBT2 performed better on several tests of thinking and judgment and had lower levels of beta-amyloid in their spinal fluid.
Mechanism: Acts in several ways to prevent aggregation of beta-amyloid into plaques.
resveratrol
Phase: 3
Status: Active, recruiting
Mechanism: Resveratrol is a naturally occurring substance that may protect brain cells through several mechanisms. This study is testing resveratrol in combination with glucose and malate, another substance that my help brain cells use energy more efficiently.
rosiglitazone (Avandia)
Phase: 3
Status: Completed, results negative
Mechanism: Rosiglitazone is an oral medication currently FDA-approved to treat type 2 diabetes by increasing cells' sensitivity to insulin. Several lines of evidence suggest that type 2 diabetes, insulin resistance and the body's insulin processing may be linked to Alzheimer's disease. Small early-stage clinical studies suggested that rosiglitazone might benefit people with Alzheimer's disease who do not have the APOe4 risk gene. But data from several large-scale Phase 3 studies did not show a benefit for any participants.
semagacestat (LY450139)
Phase: 3
Status: Trial discontinued after interim data analysis showed participants receiving semagacestat fared worse than those taking a placebo.
Mechanism: An inhibitor of gamma-secretase, one of the enzymes involved in producing beta-amyloid from its parent compound amyloid precursor protein (APP).
Lessons learned: Phase 2 trials studied samegacestat's effect on biomarkers. Preliminary data show that the drug lowers beta-amyloid levels in blood and cerebrospinal fluid, as reported in PubMed.
solanezumab (LY2062430)
Phase: 3
Status: Ongoing, still recruiting
Mechanism: Monoclonal (laboratory-produced) antibody to beta-amyloid. May bind to beta-amyloid and remove it from the brain before it accumulates into plaques.
tarenflurbil (Flurizan)
Phase: 3
Status: Completed, results negative
Mechanism: Changes the behavior of gamma-secretase, one of the enzymes involved in producing beta-amyloid from its parent molecule, APP. Flurizan failed to improve either memory and thinking or ability to perform daily activities.
tramiprosate (Alzhemed)
Phase: 3
Status: Completed, results negative
Mechanism: Tramiprosate is a modified form of taurine, one of the amino acids that are the chemical building blocks of proteins. It may prevent aggregation of beta-amyloid into plaques. Analysis of the Phase 3 trial data was initially inconclusive for a variety of reasons. Investigators tried to work with the FDA to obtain clearer results, but the developer decided to abandon development of Alzhemed as a prescription drug and market it as a "medical food." See the statement of the Alzheimer's Association Medical and Scientific Advisory Council on medical foods.
Participate in a clinical trial
If you are interested in participating in a current clinical trial, use Alzheimer's Association TrialMatch, a free individualized service that matches volunteers with trials based on certain criteria, such as stage of disease, current treatments and location. A lack of volunteers for Alzheimer's clinical trials is one of the greatest obstacles slowing the progress of potential new treatments.
Related information
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