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

Authors

Susan Abushakra, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. susan.abushakra@alzheon.com.
P Murali Doraiswamy, Departments of Psychiatry and Medicine, Duke University School of Medicine, Durham, NC, USA.
John A. Hey, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Duygu Tosun, Departments of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Frederik Barkhof, Department of Neuroradiology, VU University Medical Center, Amsterdam, The Netherlands.
Jerome Barakos, California Pacific Advanced Imaging and Sutter Health, San Francisco, CA, USA.
Jeffrey Petrella, Department of Radiology, Duke University School of Medicine, Durham, NC, USA.
J Patrick Kesslak, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Aidan Power, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Marwan Sabbagh, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.
Anton Porsteinsson, Departments of Psychiatry, Neurology, Neuroscience, and Medicine/Geriatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Sharon Cohen, Toronto Memory Program, Toronto, Canada.
Serge Gauthier, Departments of Neurology and Neurosurgery, Psychiatry, and Medicine, McGill University, Montreal, Canada.
Craig Ritchie, University of St. Andrews Medical School and Scottish Brain Sciences, Edinburgh, Scotland, UK.
David Watson, Alzheimer's Research and Treatment Center, Wellington, FL, USA.
Emer McSweeney, Re:Cognition Health, London, UK.
Merce Boada, Ace Alzheimer Center, Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
Earvin Liang, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Luc Bracoud, Clario Inc, Lyon, France.
Rosalind McLaine, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Susan Flint, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Jean F. Schaefer, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Jeremy Yu, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Margaret Bray, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Suzanne Hendrix, Pentara Corporation, Salt Lake City, UT, USA.
Sam Dickson, Pentara Corporation, Salt Lake City, UT, USA.
Abe Durrant, Pentara Corporation, Salt Lake City, UT, USA.
Adem Albayrak, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Martin Tolar, Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.

Document Type

Article

Abstract

Amyloid-plaque reduction is currently the only recognized surrogate outcome for Alzheimer's disease (AD) trials, allowing accelerated approval of plaque-clearing amyloid antibodies. However, plaque reduction does not facilitate the development of new non-plaque-clearing treatments. The hippocampus is among the first brain regions affected by AD pathology, exhibiting synaptic dysfunction and neurodegeneration that manifests as hippocampal atrophy and memory decline. We evaluated hippocampal volume (HV) as a potential surrogate outcome that can predict clinical benefit in disease-modification trials. Using published data from observational and interventional studies that examined both cognition and HV on volumetric magnetic resonance imaging (vMRI), we evaluated the cross-sectional correlations of HV to cognitive performance, the longitudinal correlations of HV atrophy to cognitive decline, HV sensitivity to drug effects, and the correlations between drug effects on HV atrophy and cognitive decline. We also examined the magnitude of HV protection that corresponds to meaningful clinical benefit. Analyses from 30 observational studies encompassing 13,187 individuals (2633 cognitively normal; 10,554 early AD) showed significant cross-sectional correlations between baseline HV and cognition, and longitudinal correlations between HV atrophy and cognitive decline over ≥ 1 year. The relationship of HV-cognitive drug effects was examined at the group level in nine placebo-controlled trials of five antiamyloid agents that evaluated HV in early AD trials of at least 18 months' duration. These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). Individual-level HV-cognition relationships were examined in two valiltramiprosate studies, one of which included diffusion tensor imaging (DTI) providing microstructural correlates of HV drug effects and helping distinguish neuroprotection from brain edema. Across these anti-amyloid drug trials (total N ~10,000), there was a linear relationship between drug effects on slowing of cognitive decline and slowing of HV atrophy. Two anti-oligomer trials (valiltramiprosate) reported significant subject-level correlations between drug effects on HV and cognition over 18-24 months (r = -0.40 to -0.44, p < 0.005, N = 50/69), with significant correlations of drug effects on brain microstructure (decreased mean diffusivity) with both HV and cognitive benefits, supporting reduced neurodegeneration. The minimal HV preservation at the mild cognitive impairment (MCI) stage that is associated with clinical benefit is estimated to be ≥ 40 mm or ≥ 10% of atrophy in the placebo arm over 18 months. Our findings demonstrate that hippocampal atrophy is an early indicator of cognitive decline in AD, linked to amyloid and tau-related neurodegeneration. HV on standardized vMRI is sensitive to anti-amyloid treatments, demonstrating strong correlations between slowed hippocampal atrophy and slowed cognitive decline. Data from over 23,000 subjects over three decades support HV as a surrogate marker for predicting clinical benefit in early symptomatic AD.

Publication Date

12-1-2025

Publication Title

CNS drugs

E-ISSN

1179-1934

PubMed ID

41324786

Digital Object Identifier (DOI)

10.1007/s40263-025-01251-y

Recommended Citation

Abushakra, Susan; Doraiswamy, P Murali; Hey, John A.; Tosun, Duygu; Barkhof, Frederik; Barakos, Jerome; Petrella, Jeffrey; Kesslak, J Patrick; Power, Aidan; Sabbagh, Marwan; Porsteinsson, Anton; Cohen, Sharon; Gauthier, Serge; Ritchie, Craig; Watson, David; McSweeney, Emer; Boada, Merce; Liang, Earvin; Bracoud, Luc; McLaine, Rosalind; Flint, Susan; Schaefer, Jean F.; Yu, Jeremy; Bray, Margaret; Hendrix, Suzanne; Dickson, Sam; Durrant, Abe; Albayrak, Adem; and Tolar, Martin, "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" (2025). Neurology. 2027.
https://scholar.barrowneuro.org/neurology/2027