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Clinical Manifestations.

Shalom K Henderson1, Alexander G Murley1, Thomas E Cope1

  • 1University of Cambridge, Cambridge, United Kingdom.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

Alzheimer's disease (AD) phenotypes show graded distinctions and overlap, supporting a multidimensional model. Including all AD subtypes in trials is crucial for effective treatments targeting transdiagnostic symptoms.

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Area of Science:

  • Neurodegenerative diseases
  • Cognitive neuroscience
  • Neurology

Background:

  • Debate exists on whether Alzheimer's disease (AD) phenotypes are distinct entities or part of a graded spectrum.
  • Confounding factors complicate definitive conclusions regarding AD phenotype classification.
  • This study addresses these complexities by investigating AD phenotypes in detail.

Purpose of the Study:

  • To compare cognitive performance across typical AD (tAD), logopenic variant PPA (lvPPA), and posterior cortical atrophy (PCA).
  • To explore the relationship between cognitive measures and brain structure in AD phenotypes.
  • To determine if AD phenotypes represent distinct entities or a multidimensional continuum.

Main Methods:

  • Retrospective analysis of cognitive data from 413 participants with tAD, lvPPA, and PCA.
  • Prospective deep phenotyping of 18 lvPPA and 9 tAD patients.
  • Principal component analysis of cognitive scores and Bayesian linear regressions correlating with grey matter volumes.

Main Results:

  • Both retrospective and prospective data showed graded distinctions and overlap in cognitive deficits across AD phenotypes.
  • lvPPA and tAD patients exhibited similar episodic memory impairments and verbal/non-verbal deficits.
  • Longitudinal data revealed varied phenotypic differentiation in tAD and a multidimensional decline in lvPPA.
  • Grey matter volumes in memory and language networks correlated with cognitive scores.

Conclusions:

  • Findings support a transdiagnostic, multidimensional phenotype geometry for all AD subtypes.
  • Clinical trials and treatments should include all AD phenotypes.
  • Focusing on transdiagnostic symptoms is critical for disease burden and intervention efficacy.