There is new hope for people living with the early onset of Alzheimer’s disease. New drugs are now available that remove beta-amyloid, which happens to be a protein that builds up into plaques in the brain.
These plaques are believed to contribute to the cognitive and functional decline that happens in Alzheimer’s.
Two such amyloid-fighting drugs are currently available to the public, lecanemab (Leqembi) and aducanumab (Aduhelm). Meanwhile, there are more in development, as was highlighted at the 2023 International Conference on Alzheimer’s and Parkinson’s Diseases.
Although a number of researchers are excited about the benefits of anti-amyloid therapies, a study from the March 27 Neurology journal shares that there could still be an adverse downside.
According to the study findings, anti-amyloid therapies were also causing brain volume loss, which had the potential to “compromise long-term brain health by accelerating brain atrophy.”
What is Atrophy, or Brain Shrinkage?
The National Institute on Aging shares that brain atrophy is ‘a sign that Alzheimer’s disease is progressing.’ When it comes to brain atrophy, neurons are injured and die throughout the brain, making the connections between the networks of neurons break down, causing a number of brain regions to shrink. As for the final stages of Alzheimer’s, they’re marked by a major and widespread loss of brain volume.
The authors of the study in Neurology wrote, “Our analysis calls for urgent revaluation of prior trials and renewed procedures to monitor patients in current trials and in the community.”
This research has contributed to an ongoing debate surrounding the benefits of anti-amyloid drugs. While the Alzheimer’s Association acknowledges the potential of these therapies in curbing mental decline among individuals with early Alzheimer’s, a study from 2021, published in BMJ, based on evidence from 14 trials involving amyloid-targeting drugs, concluded that strategies aimed at reducing amyloid did not substantially enhance cognitive function.
Rudolph J. Castellani, MD, a professor of pathology at Northwestern University’s Feinberg School of Medicine, who has studied amyloid plaques and Alzheimer’s disease, said, “Clinical use of anti-amyloid therapy is a precarious balancing act, between amyloid clearing and brain toxicity, and it still remains to be proven, and appears doubtful, that amyloid clearing even in the absence of toxicity will reverse the disease process.”
“The question is whether the rate of downward decline is altered,” Dr. Castellani adds.
Quantifying Brain Volume Changes Under Anti-Amyloid Therapies
The Neurology study combined data from 31 clinical trials of anti-amyloid drugs to investigate brain volume changes. The trials provided insights into alterations in hippocampus volume (associated with memory) for 8,974 patients, lateral ventricle volume for 8,062 patients (the large cavities in the brain filled with cerebrospinal fluid), and overall brain volume for 10,279 patients.
Researchers utilized MRI brain scans to gauge brain volume shifts, manifesting as either reduced brain volume or increased ventricle volume, reflecting loss of brain matter. In comparison to placebos, anti-amyloid drugs exhibited an average 16.7 percent expansion in ventricle volume and an average 9.3 percent reduction in total brain volume.
The data highlighted significant brain volume loss in lecanemba users, with a 28 percent higher decrease in brain volume over approximately 18 months compared to Alzheimer’s patients on placebos. In terms of ventricle volumes, individuals on lecanemab showed a 36 percent average increase, while those on aducanumab demonstrated a 57 percent increase, both in contrast to placebo users.
Different Expert Opinions on Brain Volume Loss Implications
Dr. Howard Fillit, Chief Scientific Officer for the Alzheimer’s Drug Discovery Foundation (ADDF), suggests that changes in brain volume may be attributed to the extent of plaque removal. He notes that the study doesn’t establish whether brain volume loss correlated with cognitive and functional symptom mitigation.
According to Dr. Fillit, “While the paper shows an association between some anti-amyloid drugs and decreased brain volume, I think it is a misrepresentation to say that the accelerated decrease in brain volume is caused by anti-amyloid drugs.” Notably, he was not involved in the study. “They speculate a lot on what caused this accelerated brain volume, but we don’t really know. These volume changes could be due to other causes,” he says.
Dr. Fillit also explains that the study lacks data on whether brain volume loss was associated with slowing the cognitive and functional symptoms of the disease. “They’re concluding that this volume loss is a terrible thing, but is this clinically important in terms of its effect on memory, cognition, etc.?” he adds.
Dr. Fillit also says that the studies on lecanemab and aducanumab have shown some cognitive benefits. A late-stage trial, which was published in The New England Journal of Medicine in January 2023, showed how lecanemab slowed cognitive decline over 18 months in those with early Alzheimer’s disease aged 50 to 90.
Moreover, a review of aducanumab published on March 9, 2022 in the International Journal of Alzheimer’s Disease claimed that an infusion of aducanumab resulted in “a modest slowing of cognitive decline among patients with mild cognitive impairment or early-onset Alzheimer’s disease dementia.”
More Exploration Needed on Anti-Amyloid Therapies
Aside from needing more studies and research on the topic, the authors also say that there is a need for clinicians to educate patients about the potential for accelerated neurodegeneration markers with these drugs, while monitoring brain volume alternations in those undergoing anti-amyloid therapies.
Dr. Castellani, not involved in the study, also stresses the necessity for additional research to ascertain whether the benefits of anti-amyloid therapy outweigh the potential risks.
He explains, “There are precious little data on such basic aspects of the anti-amyloid therapy, such as mechanisms of toxicity and mechanisms of amyloid clearance, yet it’s ‘Damn the torpedoes, full speed ahead.’”
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