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Millions of people worldwide live with a form of dementia, the most common of which is Alzheimer’s disease. Currently, there is no way to halt its progress, but clinical trials of new drugs are underway. What approach will serve specialists best?
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A new review of clinical trials advises on the best way forward.

According to the World Health Organization (WHO), approximately 50 million people around the world live with dementia, and approximately 60–70 percent have Alzheimer’s disease.

The greatest risk factor for Alzheimer’s disease is aging, and people ages 65 or older are the most vulnerable.

Current treatments for this condition address its symptoms, such as memory loss and behavioral changes. However, more and more research aims to find a therapy that will tackle the biological changes that characterize Alzheimer’s disease.

But are researchers on the right track with their investigations, and what would be the best treatment approach? A new comprehensive review published in the journal Neurology, and available online, addresses these questions.


Most trials target brain pathologies

In the review, specialists from the Alzheimer’s Drug Discovery Foundation in New York, NY analyze current clinical trials for dementia drugs and advise about the best approach going forward.

„Alzheimer’s is a complex disease with many different factors that contribute to its onset and progression,” explains Dr. Howard Fillit, the review’s senior author.

„Decades of research have revealed common processes that are relevant to understanding why the aging brain is vulnerable to Alzheimer’s disease. New therapeutics for Alzheimer’s disease will come from this understanding of the effects of aging on the brain.”

Dr. Howard Fillit

Because current therapies for Alzheimer’s focus on symptom management, but not on stopping the condition in its tracks, recent research has looked into attacking the Alzheimer’s mechanism, particularly in the brain.

One key characteristic of this condition is the buildup of toxic proteins, such as beta-amyloid and tau, which form plaques that interfere with communication between brain cells.

Thus, as the new review points out, many studies have focused on developing drugs that would effectively target beta-amyloid and tau.

In fact, such experimental drugs dominate the landscape of phase III clinical trials for Alzheimer’s treatments, with 52 percent of them testing drugs that interact with the two proteins.

Still, as Dr. Fillit notes, „It is currently not known if these classic pathologies (amyloid and tau) represent valid drug targets and if these targets alone are sufficient to treat Alzheimer’s disease.”

The reviewers observe that therapies targeting beta-amyloid and tau proteins have not, so far, been able to significantly slow down the development of Alzheimer’s, but that the trials have offered more important clues about the condition’s mechanisms.


Combination therapy most likely to succeed

Although most trials have focused on drugs that target changes in the brain, the review’s authors note that a few trials in earlier phases (phases I or II) have been looking into other strategies, particularly ones that target aging processes that may exacerbate Alzheimer’s.

„Targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases, such as Alzheimer’s,” Dr. Fillit says.

These processes include:

  • low-grade, chronic inflammation, which is associated with thinning layers of the cerebral cortex and poor blood flow to the brain — both of which can impact cognitive function
  • metabolic dysfunctions that can lead to cellular damage in the brain
  • vascular dysfunction, which can be associated with cognitive problems because it can mean that the brain does not receive enough blood, and thus may lack oxygen
  • changes in gene regulation that may contribute to Alzheimer’s mechanisms
  • a loss of synapses, the connecting points between neurons, which allow information to flow between brain cells

Dr. Fillit believes that „Our success in fighting Alzheimer’s disease will likely come from combination therapy — finding drugs that have positive effects on the malfunctions that happen as people age.”

By developing a series of drugs that each targets one of these key processes, specialists will see more success in halting the progress of Alzheimer’s, the authors argue.

„Combination therapies are the standard of care for other major diseases of aging, such as heart disease, cancer, and hypertension, and will likely be necessary in treating Alzheimer’s disease and other dementias,” adds Dr. Fillit.


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