Comprehensive Analyses Across Interventional and Observational Trials Show that Hippocampal Atrophy Closely Tracks with Memory Loss and Disease Progression, and Is Highly Sensitive to Effects of Disease-Modifying Therapies
Preservation of Hippocampal Volume, Complemented by Microstructural Imaging, Is Directly Associated with Clinical Improvement as Determined by Established Cognitive Assessment Measures
Study Published in CNS Drugs Highlights Potential of Hippocampal Volume as Surrogate Marker for Neuroprotection, Clinical Efficacy, and Disease Modification in Clinical Trials in Early Alzheimer’s Disease
Alzheon, Inc., a clinical-stage biopharmaceutical company developing a broad portfolio of investigational therapies and diagnostic assays for patients with Alzheimer’s disease (AD) and other neurodegenerative disorders, today announced the peer-reviewed publication: “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”, in the scientific journal CNS Drugs. The full text is available online at: https://link.springer.com/article/10.1007/s40263-025-01251-y
The AD field urgently needs to improve treatments, and surrogate biomarkers are essential for accelerating drug development. This review, co-authored by Alzheon’s scientists and leading AD neuroimaging researchers and clinicians, analyzes clinical evidence for using hippocampal volume as a surrogate marker.
The results show that shrinkage of the hippocampus is closely linked to memory decline and disease progression, and that the hippocampus of Early Alzheimer’s patients responds sensitively to disease-modifying therapies. Therefore, hippocampal volume (HV) may be a reliable and measurable surrogate used to assess clinical benefits in Early Alzheimer’s disease.
Key Findings
- Predictive biomarker: HV atrophy closely tracks cognitive decline in both observational and interventional data, making HV a reliable and sensitive marker of disease progression.
- Therapeutic sensitivity: Multiple clinical studies, including those evaluating lecanemab, donanemab, and valiltramiprosate/ALZ-801, have shown that interventions slowing cognitive decline are also associated with reduced hippocampal atrophy. These findings highlight the responsiveness of hippocampal volume to therapeutic intervention.
- Clinical relevance: The analysis established a hippocampal volume preservation threshold of ≥40 mm³ that correlates with significant cognitive improvement at the Mild Cognitive Impairment (MCI) stage, underscoring hippocampal volume as a potential regulatory endpoint for early Alzheimer’s disease.
“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 & biomarkers. “Hippocampal atrophy, a structural hallmark of neuronal losses and neurodegeneration in AD, reflects the neurodegenerative process more directly than amyloid plaque depositionor clearance. It could serve as a predictive regulatory endpoint for evaluating new therapies in early symptomatic AD targeting multiple pathways beyond amyloid.”
Clinical trials involving about 10,000 participants tested anti-amyloid and anti-oligomer treatments, finding that reduced hippocampal atrophy was accompanied by slower cognitive decline over 18–24 months. Specifically, valiltramiprosate trials showed notable links between preserving hippocampal volume and better cognitive results for individual patients (r = –0.40 to –0.44, p <0.005), as well as consistency between hippocampal volume and microstructural integrity on diffusion tensor imaging scans. The research also identified that protecting 40 mm³ of hippocampal tissue was the minimum amount needed to see meaningful cognitive benefits in people with mild cognitive impairment (MCI).
“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 the study’s lead author. “By confirming this association across both observational studies and randomized controlled trials—including data from valiltramiprosate/ ALZ-801 demonstrating 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.”
These results reinforce the consideration of hippocampal volume as an early, robust, sensitive, and clinically significant indicator of neurodegeneration, underscoring its prospective utility in forthcoming Alzheimer’s disease clinical trials. The hippocampus is essential for memory function, so its preservation provides a demonstrable measure of neuroprotection.
“Our analyses highlight the role of hippocampal volume as an important intermediary linking biomarker changes to clinically meaningful benefits,” stated John Hey, Ph.D., Chief Scientific Officer at Alzheon. “Hippocampal atrophy is a key marker within the ‘N’ neurodegeneration category of the A/T/N classification, reflecting neuronal loss and the structural decline characteristic of Alzheimer’s disease. Consequently, mitigating brain atrophy is among the most significant indicators of disease modification in Alzheimer’s disease. These results further substantiate our clinical findings in two valiltramiprosate studies involving APOE4 homozygotes and carriers, where retention of hippocampal integrity was strongly associated with reduced cognitive decline.”
* Dr. Doraiswamy is an advisor to Alzheon, Inc. and a minor shareholder. He also serves as an advisor to several other businesses, government agencies and advocacy groups.
