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In 1906, a German doctor, Alois Alzheimer, described a patient, “Auguste D,” who suffered memory loss, abnormal behavior, and brain shrinkage. The neurodegenerative disease that bears his name, Alzheimer’s Disease (AD), is responsible for countless heart-breaking stories about memory loss and confused thinking. It affects an estimated 6.7 million Americans aged 65 and older, and is the fifth leading cause of death in the U.S. More than 11 million family members and other unpaid caregivers provided an estimated 18 billion hours of care to people with AD or other dementias in 2022.
AD is characterized by depositions in the brain of high amounts of two proteins, beta amyloid and tau, which are thought to play a central role in the cognitive decline. The protein depositions create tangles of nerves that interrupt the brain’s normal function. New drugs such as aducanumab, lecanemab, and donanemab target removal of beta amyloid plaques with beneficial clinical results.
Donanemab, an immunoglobulin monoclonal antibody (an antibody that attaches to one antigen), clears the brain of amyloid by binding to a specific type of beta amyloid called N3pG that then is removed by the brain’s scavenger cells. Donanemab’s specificity may provide an advantage over other AD drugs.
Among 1,736 participants (60-85 years old) with early symptomatic (mild cognitive impairment or mild dementia) AD and amyloid and tau brain deposits, monthly intravenous administration of donanemab significantly slowed clinical progression of AD at 76 weeks in the group with low/medium tau and in the group with combined low/medium and high tau. Donanemab reduced brain amyloid plaque deposits compared with the placebo group. Nearly half of the participants had no clinical progression of AD at one year.
Side effects included reactions at the injection site, amyloid related imaging abnormalities such as edema (brain swelling), effusion (fluid accumulation), microhemorrhages (small blood vessel ruptures) and hemosiderin deposits (iron from beakdown of blood) in about one third participants receiving donanemab and 15 percent receiving placebo. These side effects were usually asymptomatic and spontaneously resolved in most patients. When symptoms occurred, they were usually mild, like a headache or increase in confusion, but could be more severe, such as seizures. In some instances, these events led to death.
What do these trial results with donanemab mean for AD patients and their families?
Lecanemab has been approved by the FDA, but donanemab is awaiting approval, hopefully by the end of 2023. The trials show that donanemab results in better outcomes than previous AD medications. Donanemab slowed AD progression by up to 60 percent in patients with the earliest, symptomatic stages, and drug administration would be restricted to that population diagnosed with early AD. Nevertheless, the drug would expand treatment options to nearly 6 million Americans living with AD. Future studies are necessary to further evaluate the risks of brain swelling and bleeding and identify the best approaches to drug administration. It is possible that earlier treatment of AD will reduce these risks.
In conclusion, donanemab holds promise as a potential breakthrough in the treatment of AD. Its targeted approach to removing beta amyloid plaques and its demonstrated cognitive improvements in a clinical trial offer hope for patients and their families. While challenges and uncertainties remain, donanemab’s development indicates a significant step forward in the efforts to combat this devastating condition, offering a beacon of hope in the fight against AD.
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