Addressing Alzheimer’s

Developer of Aricept, the number one standard of care treatment for Alzheimer’s Disease for over 25 years, AmyriAD CEO Sharon L Rogers brings more than 30 years of leadership and service to the science and strategy of drug development. From championing start-ups to directing global large-cap companies, Rogers’ dynamic verve for improving the lives of Alzheimer’s patients has been consistent throughout her career. But why has so little progress been made in Alzheimer’s treatment options? After making her debut on The Medicine Maker Power List 2023, we spoke to Rogers to find out why.

Is enough being done in Alzheimer’s and dementia research?
 

Whilst Aricept is a great accomplishment, it is also a reminder that we have not done enough to move the needle in patient management. There’s been a longstanding effort toward disease modification in Alzheimer’s, which has come about from research into pathological proteins, such as amyloid plaques and tau tangles. The conventional wisdom had been that if we could get rid of these proteins, we could cure the disease, but it’s not that easy! Amyloid plaques and tangles are certainly a part of the problem, but even after we remove much of this protein accumulation, there remains significant evidence of dysfunction. When intervention is early, some of these drugs have effectively delayed disease progression. However, no drugs have been shown to halt or reverse the disease. In later stages of Alzheimer’s, these drugs have demonstrated no measurable benefit – it appears too much damage is already done. 

What else are we learning? 
 

In the case of Alzheimer’s, we now understand that the problem does not just lie with beta amyloid or tau; there are also issues with glucose utilization, oxidative phosphorylation, inflammation, and an important process known as autophagy, which degrades old proteins that can no longer serve their function. As we age, autophagy becomes less efficient and we start collecting denatured, dysfunctional proteins. This accumulation has two negative effects. First, deposits of ineffective proteins can impair normal cell activities; and second, it sends a negative feedback signal inhibiting transcription, which is the first step of gene expression and synthesis of new functional proteins. 

From a research perspective, I find this balancing act both elegant and exciting. In all neurodegenerative disease, there appears to be decreased autophagy within the brain. What we don’t know is how much of a deficiency will result in measurable neurologic dysfunction. Individual resilience varies greatly. For some people, it appears to be a more troublesome process than others. However, if we can enhance autophagy, not only will we mitigate accumulation of dysfunctional proteins, but that removal will signal back to the beginning of gene expression. Transcription will turn on again and new proteins will be created, which is anticipated to keep our neurons healthy and functional. 

Molecular pathways that enhance the autophagy process are fertile territory for new drug development. 

What will the treatment landscape look like? 
 

Combination therapies will be the key to the future. If you look at any chronic disease – whether it’s diabetes, high blood pressure, or Parkinson’s – patients are receiving poly-drug therapies. We layer on therapies with differing mechanisms of action knowing that each one is likely to produce a benefit of some size, always with the goal of more effective disease management.

Alzheimer’s research focused intensely on disease modification because everyone hoped to develop a cure. What we learned was that Alzheimer’s is much more complex than initially believed. It is now sinking in that a cure is unlikely to happen in the near future. So what to do for now? We need to look at different ways to enhance cognitive function and slow down the decline. I do truly believe that it will be possible to have people remain functional for more than a decade longer than they are in our current world – and that will be great for them, their families, and their caregivers. Everyone can benefit if we acknowledge the complexity and address it appropriately.