A new study has revealed that hippocampal volume (HV) may be a reliable and measurable surrogate used to assess clinical benefits in early Alzheimer’s disease. 

The study results, published in the scientific journal CNS Drugs, 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. 

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. 
  • Clinical relevance: The analysis established a hippocampal volume preservation threshold of ≥40mm³ 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, Professor of Psychiatry and Medicine at Duke University. “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.” 

Links with cognitive decline

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, as well as consistency between hippocampal volume and microstructural integrity on diffusion tensor imaging scans. The research also identified that protecting 40mm³ of hippocampal tissue was the minimum amount needed to see meaningful cognitive benefits in people with mild cognitive impairment (MCI). 

Valiltramiprosate/ALZ-801 is an investigational oral agent currently in Phase III development as a potential first-in-class, disease-modifying treatment for Alzheimer’s disease. It is designed to inhibit the formation of neurotoxic soluble beta amyloid oligomers that contribute to cognitive decline in individuals with AD. 

“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 Dr Susan Abushakra, Chief Medical Officer of Alzheon and the study’s lead author.

Diana Turner, Deputy Editor, DDW