FRAMINGHAM, Massachusetts — Alzheon has released new peer-reviewed evidence supporting the use of hippocampal volume as a surrogate marker for clinical benefit and neurodegeneration in early Alzheimer’s disease. The findings were published in the journal CNS Drugs in a comprehensive review titled “Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer’s Disease: Synthesis of Evidence from Observational and Interventional Trials,” now available online.
The publication, authored by Alzheon scientists and leading Alzheimer’s disease neuroimaging researchers, underscores the urgent need for reliable biomarkers to accelerate drug development in a field where therapeutic progress remains slow. The analysis shows that hippocampal shrinkage closely parallels memory decline and overall disease progression, and that hippocampal volume is highly responsive to disease-modifying therapies in early Alzheimer’s disease.
The review found that hippocampal atrophy consistently tracks with cognitive decline across both observational studies and interventional clinical trials, making it a reliable and sensitive measure of disease progression. Research evaluating therapies such as lecanemab, donanemab, and valiltramiprosate/ALZ-801 showed that treatments capable of slowing cognitive decline also slowed hippocampal atrophy. The authors also identified a threshold of at least 40 mm³ of hippocampal volume preservation that corresponds with meaningful cognitive improvement in patients at the mild cognitive impairment stage, reinforcing the potential value of hippocampal volume as a regulatory endpoint.
“Developing reliable non-invasive imaging-based surrogate markers is essential to accelerate Alzheimer’s drug development,” said Murali Doraiswamy, MBBS, FRCP, Professor of Psychiatry and Medicine at Duke University* and an expert in Alzheimer’s imaging and biomarkers. “Hippocampal atrophy, a structural hallmark of neuronal losses and neurodegeneration in AD, reflects the neurodegenerative process more directly than amyloid plaque deposition or clearance. It could serve as a predictive regulatory endpoint for evaluating new therapies in early symptomatic AD targeting multiple pathways beyond amyloid.”
The publication includes data from clinical trials involving nearly 10,000 participants, which showed that reduced hippocampal atrophy was associated with slower cognitive decline over 18 to 24 months. Trials of valiltramiprosate demonstrated clear links between preserving hippocampal tissue and achieving better cognitive outcomes, along with consistency between hippocampal volume and microstructural integrity measured through diffusion tensor imaging scans. The research also confirmed that protecting approximately 40 mm³ of hippocampal tissue is the minimum threshold needed to produce meaningful cognitive benefits in individuals with mild cognitive impairment.
“The hippocampus is among the first regions of the brain affected by Alzheimer’s disease. Our findings indicate that preservation of hippocampal volume, reflecting reduced atrophy, is directly associated with clinical improvement as determined by established cognitive assessment measures,” said Susan Abushakra, MD, Chief Medical Officer of Alzheon and lead author of the publication. “By confirming this association across both observational studies and randomized controlled trials—including data from valiltramiprosate/ALZ-801 showing microstructural integrity supporting hippocampal protection—we present strong evidence that hippocampal volume may serve as a surrogate marker for neuroprotection, clinical efficacy, and disease modification in early-stage Alzheimer’s disease.”
John Hey, Ph.D., Chief Scientific Officer at Alzheon, noted that hippocampal atrophy remains a key component of the neurodegeneration category in the widely used A/T/N Alzheimer’s classification system. He said the new analysis reinforces the importance of mitigating brain atrophy as one of the clearest indicators of disease modification. He added that Alzheon’s studies of valiltramiprosate in APOE4 homozygotes and carriers showed strong alignment between hippocampal preservation and reduced cognitive decline, further supporting the value of hippocampal volume as a clinically meaningful biomarker.
The publication adds to growing evidence that hippocampal volume could serve as an early, robust, and practical marker for neurodegeneration and therapeutic response in future clinical trials, potentially helping accelerate the development of new treatments for Alzheimer’s disease.
