ISLAMABAD, July 8 — For decades, the sticky clumps of protein that build up in the brains of Alzheimer’s patients have been a defining feature of the disease, first noted by Alois Alzheimer in 1906. Now, a new class of drugs is directly targeting those fragments — called amyloid beta — with the goal of clearing them before they can form plaques. Two monoclonal antibody treatments, lecanemab and donanemab, have received US regulatory approval in recent years, marking a significant shift in how doctors approach Alzheimer’s.
Both drugs work by binding to different forms of the amyloid beta protein, aiming to remove it from the brain. The underlying theory, known as the amyloid cascade hypothesis, was first proposed in 1992 by researchers John Hardy and Gerald Higgins.
It suggests that the accumulation of amyloid beta triggers a chain reaction — including tau pathology and eventual neurodegeneration. Lecanemab, which received accelerated approval from the US Food and Drug Administration in July 2023, targets soluble amyloid beta protofibrils. These are smaller, floating clumps of the protein that form before they coalesce into plaques.
The drug is designed to clear these protofibrils early in the process. Donanemab, approved in July 2024, targets a different form — pyroglutamate-modified amyloid beta, which is already deposited in the brain as plaque.
Both treatments are administered intravenously, with infusions every two to four weeks. The clinical trial data, while not a cure, has shown measurable results. In the Clarity AD trial for lecanemab, published in 2022, patients saw a mean reduction of 59 centiloids in amyloid plaque levels on PET scans over 18 months.
The TRAILBLAZER-ALZ 2 trial for donanemab, published in 2023, reported that 47% of participants had their amyloid plaque cleared to below a pre-defined threshold within 12 months. The encouraging part is that these drugs are the first to directly intervene on the biological mechanism that many researchers believe is central to Alzheimer’s. For years, the field struggled with failed trials and a lack of effective treatments.
These approvals signal that the amyloid hypothesis, while still debated by some, has produced a viable therapeutic strategy.
Side effects require careful monitoring
But these drugs are not without risk. A condition called ARIA — amyloid-related imaging abnormalities — has been observed in clinical trials. This involves swelling or small bleeds in the brain, detected on MRI scans.
In the lecanemab trials, ARIA occurred in 12.6% of patients. For donanemab, the rate was higher, at 24% of participants.
Most cases were mild to moderate, but serious events did occur, and patients need to be monitored regularly during treatment. Patients should talk to their doctors about whether these treatments are appropriate for them. The decision involves weighing the potential for slowing cognitive decline against the risk of side effects.
Early findings suggest that the drugs are most effective in people with mild cognitive impairment or early-stage Alzheimer’s, before significant brain damage has occurred. The amyloid cascade hypothesis itself has been a subject of intense research since the early 1990s.
Hardy and Higgins proposed that the abnormal accumulation of amyloid beta in the brain is the primary event that sets off a cascade of damage, including the formation of tau tangles and the death of neurons. This theory has guided drug development for decades, but it has also faced criticism, especially after many early anti-amyloid drugs failed in clinical trials. The success of lecanemab and donanemab has revived confidence in the approach.
Looking ahead in Alzheimer’s research
For Pakistani patients and their families, these developments are a reminder that Alzheimer’s research is moving forward. While these drugs are not yet widely available in Pakistan, and their cost and infrastructure requirements — including regular IV infusions and MRI monitoring — pose significant challenges, the progress is real. The hope is that as more data accumulates and manufacturing scales up, access may improve over time.
The encouraging part is that the field now has two FDA-approved drugs that directly target the underlying pathology of Alzheimer’s, not just its symptoms. Researchers continue to study how these treatments might be combined with other approaches, such as therapies targeting tau protein or inflammation, to achieve even better outcomes.
Patients should always talk to their doctor before considering any new treatment. Alzheimer’s is a complex disease, and what works for one person may not be suitable for another. The best approach remains an honest conversation with a healthcare professional who knows your individual medical history. Consult your doctor for medical advice.
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