Treatment Horizon

A worldwide quest is under way to find new treatments to stop, slow or even prevent Alzheimer’s. Because new drugs take years to produce from concept to market—and because drugs that seem promising in early-stage studies may not work as hoped in large-scale trials—it is critical that Alzheimer’s and related dementias research continue to accelerate. To ensure that the effort to find better treatments receives the focus it deserves, the Alzheimer’s Association funds researchers looking at new treatment strategies and advocates for more federal funding of Alzheimer’s research.

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.

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 beta-secretase enzyme; preventing the beta-amyloid fragments from clumping into plaques; and even using antibodies against beta-amyloid to clear it from the brain.

Current drug in research that targets beta-amyloid: Solanezumab
Solanezumab is a monoclonal antibody designed to lower the level of beta-amyloid in the brain. These antibodies bind to beta-amyloid, preventing the formation of plaques; solanezumab may also help carry excess beta-amyloid away from the brain. Several studies of this drug are under way with the goal determining if solanezumab improves participants’ cognition (thinking and memory) and functioning. Some participants will undergo a brain scan called positron emission tomography (PET) to determine levels of beta-amyloid in the brain. (Drug is still in research; not available to the public.)

Beta-secretase (BACE) is one of the enzymes that clips APP and makes it possible for beta-amyloid to form. Therapies that interrupt this process may reduce the amount of beta-amyloid in the brain and ultimately intervene in the development of Alzheimer’s disease.

Current drug in research that targets beta-secretase: MK-8931
MK-8931 is a BACE inhibitor — it inhibits the ability of the beta-secretase enzyme to make beta-amyloid. At the Alzheimer’s Association International Conference® 2013 (AAIC®), researchers reported that the drug significantly lowered beta-amyloid levels in people with mild-to-moderate Alzheimer’s. MK-8931 is being tested in two phase 3 clinical trials. (Drug is still in research; not available to the public.)

Tau protein is the chief component of tangles, the other hallmark brain abnormality of Alzheimer’s. Tau protein helps maintain the structure of a neuron, including tiny tube-like structures called microtubules that deliver nutrients throughout the neuron. Researchers are investigating mechanisms to prevent tau protein from collapsing and twisting into tangles, a process that destroys microtubules and, ultimately, the neuron itself.

Current drug in research that targets tau protein: AADvac1
AADvac1 is a vaccine that stimulates the body’s immune system to attack an abnormal form of tau protein that destabilizes the structure of neurons. If successful, it has the potential to help stop the progression of Alzheimer’s disease. At AAIC 2015, researchers reported that AADvac1 was safe and well tolerated by participants in a phase 1 clinical trial. (Drug is still in research; not available to the public.)

Inflammation is another key Alzheimer’s brain abnormality. Both beta-amyloid plaques and tau tangles cause an immune response in the brain. Microglia are cells that act as the first form of immune defense in the brain. While microglia help clear beta-amyloid in the brain, they may become overactive in the presence of beta-amyloid and produce compounds that damage nearby cells.

Current drug in research that targets inflammation: CSP-1103
CSP-1103 is a microglial modulator that aims to reduce inflammation in the brain. At AAIC 2013, researchers presented the results of a 90-week trial in which people who had mild cognitive impairment (MCI) were given CSP-1103. Preliminary studies showed that CSP-1103 prevented beta-amyloid from being deposited on neurons and forming plaques. It also reduced problems with thinking and memory (cognition). The cognitive tests of people who had participated for at least 64 weeks showed statistically significant improvements in participants’ cognitive abilities. (Drug is still in research; not available to the public.)

Insulin resistance in the brain is another common feature of Alzheimer’s disease. For reasons researchers do not completely understand, the brain becomes resistant to the normal effects of insulin, including the conversion of glucose to energy that brain cells can use to fuel cell functioning. Some research suggests that beta-amyloid decreases the body’s ability to use insulin. Other research has found reduced levels of insulin in the brain.

Current drug in research that targets insulin resistance: Intranasal insulin
Intranasal insulin is a therapy being tested in multiple studies for its effects on memory, thinking and daily functioning in people with MCI and mild-to-moderate Alzheimer’s disease. There is growing evidence that insulin plays an important role in keeping the brain healthy. Intranasal administration of insulin may help by increasing insulin signaling in the brain. (Drug is still in research; not available to the public.)

Alzheimer’s prevention trials 

The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Trial
The A4 trial is studying the effectiveness of solanezumab, a drug targeting beta-amyloid, in 1,150 symptom-free volunteers whose PET scans show abnormally high levels of beta-amyloid in the brain. High levels of beta-amyloid in the brain increase the risk for developing Alzheimer’s disease. Researchers hope that early intervention in individuals at increased risk of developing Alzheimer’s will prevent the cognitive decline of this devastating and ultimately fatal disease.

The TOMMORROW Trial includes 3,500 asymptomatic individuals, some of whom have the Alzheimer’s risk gene apolipoprotein E e4 (APOE-e4) or the TOMM40 risk gene. The trial will explore whether the anti-diabetes drug pioglitazone can prevent mild cognitive impairment due to Alzheimer’s disease. Studies suggest that pioglitazone may decrease inflammation and beta-amyloid levels in the brain, improve blood flow to the brain and increase the brain’s ability to use glucose to fuel nerve cells.

Dominantly Inherited Alzheimer Network Trial Unit (DIAN TU)
Mutations on three genes are known to cause a rare form of Alzheimer’s disease that accounts for less than 1 percent of cases. When a person has one of these mutations, he or she has a 95 percent to 100 percent chance of developing Alzheimer’s. DIAN TU tracks changes in the brains of people with those rare Alzheimer’s gene mutations who have not yet developed the disease. In addition, researchers are studying two drug candidates (gantenerumab and solanezumab) that may slow or stop brain changes and prevent symptoms like memory loss from occurring.

The Alzheimer’s Prevention Initiative (API)
Like DIAN TU, API tests therapies in people who have a gene mutation that causes Alzheimer’s, but have not yet developed symptoms. Drugs that delay or prevent symptoms in people with genetic mutations for Alzheimer’s may potentially delay or prevent symptoms in people with the brain changes of Alzheimer’s who do not have these genetic mutations. The API trial is studying the effects of crenezumab, an immune-based therapy. Crenezumab delivers antibodies against beta-amyloid in an effort to reduce the negative cognitive effects of excess beta-amyloid.