Could Preventing the Development of Amyloid Beta Lesions in the Brain Stop Alzheimer’s?

The DIAN-TU trials and other clinical trials are investigating this approach.

 

Alzheimer’s disease is a neurodegenerative disorder that leads to memory loss, an inability to focus and other symptoms owing to the development of neurofibrillary tangles in nerve cells and/or the buildup of deposited protein called beta-amyloid plaques in the brain. According to the Alzheimer’s Association, 5.6 million Americans age 65 and older and approximately 200,000 individuals under age 65 suffer from the disease. In addition, Alzheimer's disease is the sixth leading cause of death in the United States, and, between 2000 and 2017, the number of deaths from Alzheimer’s disease more than doubled.

 

Many attempts have been made to develop drugs that target the beta-amyloid lesions in the brain of patients with Alzheimer’s, but to no avail. The latest example is Biogen’s amyloid-blocking antibody aducanumab, for which clinical trials were halted earlier in 2019.

 

A current study is taking a different approach. The DIAN-TU trials are investigating whether Alzheimer’s disease can be delayed and the symptoms lessened in people genetically predisposed to the condition by preventing the development of the deposits.


The study is both ambitious and challenging. Three other studies looking to identify positive effects by preventing amyloid plaque build-up were terminated early. These trials used BACE (β-secretase) inhibitors in high-risk patients. In the DIAN-TU trial, however, the drug under investigation has a different mechanism of action.

 

The thinking of the DIAN-TU researchers is that, in patients who are exhibiting symptoms, the beta-amyloid deposits have already caused significant and irreversible damage. They are therefore enrolling patients with several mutations (in the PSEN1, PSEN2 or APP genes) known to be associated with frequent disease onset (seven out of 10 cases).

 

People with a parent that carries one of these mutations have a 50% chance of inheriting the mutation, and nearly all carriers of the mutations develop Alzheimer's disease, according to DIAN-TU director Randall Bateman. On the flip side, this form of Alzheimer’s accounts for <1% of patients with the disease.

 

The patients are being treated with Eli Lilly's solanezumab and Roche's gantenerumab, antibodies that bind to forms of beta-amyloid and prevent them from accumulating in the brain. Both failed phase III studies for treatment of patients with symptomatic Alzheimer’s disease. The last doses should be administered in November 2019, and initial results should be reported early in 2020.

 

Two other preventive trials are also underway. The A4 trial is investigating the use of solanezumab in patients with evidence of amyloid brain pathology, while the API-ADAD trials is using Roche's crenezumab, a monoclonal antibody that recognizes multiple forms of aggregated Aβ, including oligomeric and fibrillar species and amyloid plaques with high affinity, and monomeric Aβ with low affinity, in patients with the same mutation as those enrolled in DIAN-TU.

 

If the DIAN-TU trials results are positive, the researchers hope to submit the treatment for approval by the FDA in the specific patient population investigated in the study, Ultimately, the hope is that, if this approach is effective in this specific patient population, it may also work for other Alzheimer’s patients as well.

 

The challenge will be to get people diagnosed before cognitive impairments appear –– which is extremely difficult at this point.

 

Bateman has developed a biomarker test that detects the ratio of beta-amyloid peptide 42 to peptide 40, which is known to be an indicator of the level of amyloid accumulation in the brain. Most scientists in the field do not expect DIAN-TU to be successful, but the advance of genetic and biomarker studies is seen as the key to future solutions.

Cynthia A. Challener, Ph.D.

Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.