Evidence map›Paper›PMID 41324786›Full record

ReviewCNS drugs2026

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.

Susan Abushakra, P Murali Doraiswamy, John A Hey, Duygu Tosun, Frederik Barkhof, Jerome Barakos, Jeffrey Petrella, J Patrick Kesslak, Aidan Power, Marwan Sabbagh and 19 more

Abstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in CNS drugs, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Trial
  2. Article
  3. Article
  4. Article
  5. Article
  6. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

29 authors.

Susan AbushakraAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. susan.abushakra@alzheon.com.
P Murali DoraiswamyDepartments of Psychiatry and Medicine, Duke University School of Medicine, Durham, NC, USA.
John A HeyAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Duygu TosunDepartments of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Frederik BarkhofDepartment of Neuroradiology, VU University Medical Center, Amsterdam, The Netherlands.
Jerome BarakosCalifornia Pacific Advanced Imaging and Sutter Health, San Francisco, CA, USA.
Jeffrey PetrellaDepartment of Radiology, Duke University School of Medicine, Durham, NC, USA.
J Patrick KesslakAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Aidan PowerAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Marwan SabbaghDepartment of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.
Anton PorsteinssonDepartments of Psychiatry, Neurology, Neuroscience, and Medicine/Geriatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Sharon CohenToronto Memory Program, Toronto, Canada.
Serge GauthierDepartments of Neurology and Neurosurgery, Psychiatry, and Medicine, McGill University, Montreal, Canada.
Craig RitchieUniversity of St. Andrews Medical School and Scottish Brain Sciences, Edinburgh, Scotland, UK.
David WatsonAlzheimer's Research and Treatment Center, Wellington, FL, USA.
Emer McSweeneyRe:Cognition Health, London, UK.
Merce BoadaAce Alzheimer Center, Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
Earvin LiangAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Luc BracoudClario Inc, Lyon, France.
Rosalind McLaineAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Susan FlintAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Jean F SchaeferAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Jeremy YuAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Margaret BrayAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Suzanne HendrixPentara Corporation, Salt Lake City, UT, USA.
Sam DicksonPentara Corporation, Salt Lake City, UT, USA.
Abe DurrantPentara Corporation, Salt Lake City, UT, USA.
Adem AlbayrakAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.
Martin TolarAlzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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

Indexed as

Alzheimer DiseaseHippocampusAtrophyBiomarkersCognitive DysfunctionCross-Sectional StudiesHumansMagnetic Resonance ImagingObservational Studies as TopicBiomarkers

Identifiers

PMID41324786
PMCPMC12855230

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.