For many individuals, mild cognitive impairment often serves as the initial indicator of Alzheimer’s disease. Researchers from AgeneBio and Johns Hopkins University are currently investigating a once-daily experimental medication to treat amnestic mild cognitive impairment caused by Alzheimer’s disease. Their findings revealed that the drug slowed brain atrophy progression in those with mild cognitive impairment due to Alzheimer’s disease, specifically in individuals who do not carry the APoE-4 genetic variant.
Previous studies indicate that mild cognitive impairment is frequently the first symptom of Alzheimer’s disease for many people.
Approximately one-third of individuals with mild cognitive impairment due to Alzheimer’s disease progress to dementia within five years.
“Our research has demonstrated that patients with mild cognitive impairment exhibit amyloid and tau pathology, along with hyperactivity in the hippocampus, a brain region crucial for memory creation and retrieval,” explained Michela Gallagher, PhD, CEO and founder of AgeneBio, and Krieger Eisenhower Professor of Psychological and Brain Sciences at Johns Hopkins University.
“This hyperactivity contributes to the memory impairment these patients experience and likely accelerates disease progression,” she elaborated.
Gallagher is the senior author of a new study published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, which examines the use of a once-daily experimental medication to treat amnestic mild cognitive impairment — primarily affecting memory — caused by Alzheimer’s disease.
Researchers discovered that this new drug, an extended-release form of the epilepsy medication levetiracetam, slowed brain atrophy progression in individuals with mild cognitive impairment due to Alzheimer’s disease who are non-carriers of the APoE-4 allele, a genetic variant associated with increased Alzheimer’s disease risk.
‘Once-a-Day Tablet’ for Seizures May Help Treat Alzheimer’s
This study represents the phase 2b portion of the HOPE4MCI clinical trial, evaluating the use of the investigational drug AGB101 to treat mild cognitive impairment in 164 individuals with Alzheimer’s disease.
“AGB101 is a once-daily tablet formulation of an anti-seizure medication that reduces brain hyperactivity to levels observed in cognitively normal older adults,” Gallagher stated.
“AGB101 was developed to treat hippocampal hyperactivity in adults, and this clinical trial focused on testing its efficacy in patients with mild cognitive impairment, including both carriers and non-carriers of the ApoE-4 allele,” explained Arnold Bakker, PhD, associate professor of psychiatry and behavioral sciences, Biomarker Core Leader of the Johns Hopkins Alzheimer’s Disease Research Center at Johns Hopkins University, and lead author of this study.
40% Reduction in Cognitive Impairment in Non-ApoE-4 Carriers
Bakker reported that study participants with mild cognitive impairment who were non-carriers of ApoE-4 and treated with AGB101 showed a 40% reduction in progression on the Clinical Dementia Rating scale over 18 months compared to participants treated with a placebo.
“This indicates a significant retention of cognitive and daily functioning for patients over this period,” he added.
“Slowing progression in the early stages of mild cognitive impairment allows individuals to maintain independent living longer and delays the onset of dementia, potentially reducing the need for nursing home care,” Gallagher noted.
Seizure Drug Reduces Atrophy in Brain Region Linked to Memory
Additionally, scientists found that AGB101 significantly reduced atrophy of the entorhinal cortex, the main connection to the hippocampus, in individuals not carrying the ApoE-4 allele. This brain region plays a crucial role in memory and time perception.
“The entorhinal cortex, adjacent to the hippocampus, is where Alzheimer’s disease pathology accumulates early and shows consistent and significant atrophy as the disease progresses. Slowing atrophy in this region generally indicates slowing disease progression,” Bakker explained.
“Our findings showed that AGB101 treatment not only provided clinical-cognitive benefits but also slowed tissue loss in this brain region, demonstrating evidence of slowing disease progression,” he added.
“This study revealed that in patients with mild cognitive impairment who are non-carriers of ApoE4, AGB101 matched the efficacy of FDA-approved biologics in clinical-cognitive progression in prodromal Alzheimer’s disease and surpassed any currently published data for Alzheimer’s disease therapeutics by significantly reducing atrophy of the entorhinal cortex, a key marker of disease progression in mild cognitive impairment due to Alzheimer’s disease,” Gallagher stated.
“Although additional studies are needed, its substantial potential effect in ApoE-4 non-carriers, combined with limited side effects in this population, holds significant promise for this approach in mild cognitive impairment due to Alzheimer’s disease,” she concluded.
‘Encouraging’ Alzheimer’s Research Using Repurposed Drug
MNT also spoke with Scott Kaiser, MD, a board-certified geriatrician and Director of Geriatric Cognitive Health for the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, CA, who found the study encouraging and promising.
“Global dementia cases are projected to triple by 2050 to over 150 million people, necessitating large-scale strategies to prevent and treat Alzheimer’s disease, cognitive impairment, and dementia,” Kaiser explained.
“What’s particularly promising about this study is the potential for multiple treatments addressing various underlying mechanisms. For instance, we have FDA-approved treatments targeting amyloid plaques, and now a potential treatment targeting a different mechanism,” he noted.
“You could envision a future where Alzheimer’s disease is managed like a chronic condition such as diabetes or hypertension, with a wide array of treatments addressing different mechanisms for an overall effective treatment,” he added.
Kaiser highlighted the significance of repurposing an existing drug, albeit at a lower dose.
“The authors noted that preclinical research was foundational in identifying this as a potential treatment target,” he continued.
“It’s crucial to invest in research for new drugs and therapies, but equally important to invest in preclinical research to better understand the disease’s biological foundations, which can help identify additional and more robust treatment targets,” he emphasized.
– Scott Kaiser, MD
