Thoughts on Leqembi, and the future of Alzheimer’s drugs, from one of the discoverers of the Alzheimer’s gene

Entering a new era

The anti-amyloid immunotherapy, Leqembi, is the beginning of a new and exciting era in Alzheimer’s disease treatment but is not the final answer to treating Alzheimer’s disease. The clinical trial showed it slowed cognitive decline in patients with the mildest stage of Alzheimer’s disease. Nevertheless, we need to do much better to treat all patients and prevent this disease pre-symptomatically.

Leveraging what we’ve learned

I was one of three researchers that discovered the amyloid gene (APP) back in 1987 - the first Alzheimer’s disease gene. Since that time, our lab has never wavered from the belief that beta-amyloid causes Alzheimer’s disease. Yet, all the data, from genetics to brain imaging, indicate that amyloid causes Alzheimer’s disease in the same manner that high cholesterol causes coronary artery disease. In other words, the deposition of amyloid in the brain initiates the disease process decades before symptoms. Amyloid deposition leads to the insidious loss of neurons in the brain over a decades long period, ultimately, leading to symptoms of dementia. It would be best to nip amyloid deposition in the bud when we first learn that amyloid is accumulating in the brain. The good news is that we already have the blood test and brain imaging to determine when amyloid is first accumulating in the brain decades before there is enough neuronal loss in the brain to lead to cognitive decline. Leqembi lowers amyloid but is very expensive and requires routine MRI to assure the brain is not swelling or hemorrhaging, the two side effects of the drug. This would make it difficult to use Leqembi for widespread prevention of amyloid buildup in the millions of Americans who currently have amyloid accumulating in their brains, but do not yet have symptoms of Alzheimer’s disease.

Leqembi is a great start but not the final answer

Just as we must measure and lower cholesterol early in life to reduce risk for coronary artery disease, we must measure and lower amyloid levels in the brain early in life to reduce risk for Alzheimer’s disease. Reducing amyloid only when one is already suffering from dementia will not be enough for addressing cognitive dysfunction once the symptoms of dementia have already begun.

Treating amyloid only after symptoms of dementia arise is akin to only lowering cholesterol when advanced coronary artery disease or congestive heart failure is already present.

Thus, the key will be to use a strategy of “early detection - early intervention" to lower amyloid decades before symptoms arise to reduce risk for Alzheimer’s disease. The problem is Leqembi, is currently too expensive and unsafe for the decades of use required to prevent AD in millions of Americans who already have amyloid building up in their brains but are still decades away from possible symptoms of Alzheimer’s-related dementia. 

Hope ahead

The FDA approval of Leqembi now opens the door for future anti-amyloid drugs that are more affordable and safer than Leqembi for lowering brain amyloid both for treatment and prevention of Alzheimer’s disease. For the past 20 years, my lab has been developing safer and more affordable amyloid drugs, which are now ready for clinical trials at the McCance Center. Our anti-amyloid drugs include a gamma secretase modulator, which lowers amyloid production in the brain, and combinations of safe known drugs that can now be repurposed for clearing amyloid from the brain and reducing inflammation, hopefully in a safe and affordable manner.

In summary, while Leqembi clears amyloid very effectively, the expense and safety profile may not enable it to be a true prevention tool for the masses who need it to avoid Alzheimer’s disease later in life. The good news is Leqembi has now opened the door for the drugs such as those we are developing at the McCance Center, aimed at achieving the same goal, but, in a much safer and more affordable manner. In this way, they will someday hopefully be used for early prevention of Alzheimer’s disease, beginning decades before symptoms when the greatest clinical benefit can be achieved.