With the size of the global aged population increasing, the incidence of Alzheimer disease (AD), the most common type of dementia, is also on the rise.

Positive strides have been made in recent years. Two FDA-approved medications (donepezil and rivastigmine) may slightly slow down progression of symptoms in individuals with mild AD; however, their long-term effects on behavior, thinking, and independent living are unknown.

Woloshin S, Kesselheim AS. What to know About the Alzheimer drug aducanumab (Aduhelm). JAMA Intern Med. 2022;182(8):892.

 

 

AD costs and prevalence

The Alzheimer’s Association reports that in the US alone, there are an estimated 6.5 million individuals with AD; this number is projected to increase to 12.7 million by the year 2050. According to Alzheimer’s Disease International, the global prevalence of AD is expected to more than triple from 50 million as of 2020 to approximately 152 million by 2050.

A tremendous cost burden is associated with AD; the cost of caring for patients with AD and related dementias was $355 billion in 2021. Also the emotional and mental toll on caretakers, specifically family member caretakers who care for their loved ones with AD, is significant.

 

Aducanumab approved

In 2021, the FDA approved aducanumab (Aduhelm) for the treatment of mild symptoms of AD patients, such as individuals who are still independent in basic daily functioning. It was (controversially) approved using the accelerated approval pathway, and was the first novel therapeutic to be approved for AD since 2003.

Cavazzoni P. FDA’s decision to approve new treatment for Alzheimer's disease. FDA. Updated June 7, 2021.

 

Aducanumab is the first AD treatment that targets the amyloid beta plaques that form in the brains of AD patients and are a hallmark of the disease. It is a monoclonal IG1 antibody that binds to the amyloid beta protein at amino acids 3–7. Research showed that aducanumab led to a decrease in these plaques in patients with AD.

Not everyone with plaques has or will get AD, and other plaque-reducing medications have not shown meaningful patient benefit. Aducanumab was approved on the basis that Biogen conducts further, post-approval clinical studies to ensure that the drug provides clinical benefit.

In addition to aducanumab, there are two additional monoclonal antibodies, lecanemab and donanemab, that have shown promising results in clinical trials. Another monoclonal antibody, solanezumab, didn’t offer patients with mild or moderate AD any benefit and as a result, these phase 3 trials were terminated.

A phase 2/3 clinical trial is testing solanezumab in individuals who have a genetic mutation that may put them at risk for developing AD. Solanezumab and gantenerumab (an additional AD investigational therapy) will both be tested against placebo to see if they can reduce patients’ rate of decline.

Solanezumab. Alzheimer’s News Today.

 

 

Exploring additional mechanisms of action

AD research has shown that beta-amyloids are synthesized in a two-step process that’s carried out by different enzymes.

What new Alzheimer’s treatments are on the horizon? Mayo Clinic. June 30, 2021.

Beta- and gamma-secretase inhibitors aim to inhibit the activity of these enzymes. Enthusiasm has decreased for beta-secretase inhibitors, however, as these drugs didn’t slow down AD progression and were associated with significant side effects.

 

Researchers are looking into different ways to stop the tau protein from forming these microscopic fibers. Tau vaccines and aggregation inhibitors are currently being investigated in clinical trials.

 

What’s in the pipeline?

According to a 2022 review article published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions, there were 143 therapeutic agents in the developmental pipeline for AD as of January 25, 2022.

Cummings J, Lee G, Nahed P, et al. Alzheimer’s disease drug development pipeline: 2022. A&D Transl Res & Clin Interv. 2022;8(1).

More specifically, there were 31 treatments for AD in 47 phase 3 trials, with most of the investigated agents being disease-modifying therapies.