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Clinical Manifestations.

Nicholas Magill1,2, Christopher S Parker3,4, Chloe Young1

  • 1Dementia Research Centre, Queen Square Institute of Neurology, London, United Kingdom.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 26, 2025
PubMed
Summary
This summary is machine-generated.

Accelerated long-term forgetting (ALF) is linked to early prefrontal cortex changes in autosomal dominant Alzheimer's disease (ADAD). ALF testing can predict clinical onset, aiding in presymptomatic ADAD trials.

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Area of Science:

  • Neuroscience
  • Neurology
  • Cognitive Science

Background:

  • Sensitive cognitive measures are needed for early Alzheimer's disease (AD) detection.
  • Accelerated long-term forgetting (ALF) is observed in presymptomatic AD cohorts.
  • Key questions involve the neuroanatomy of ALF and its predictive power for symptom onset.

Purpose of the Study:

  • Investigate neuroanatomical changes associated with ALF in presymptomatic ADAD.
  • Determine if ALF testing can predict the timing of clinical symptom onset in ADAD.

Main Methods:

  • Assessed ALF using verbal and visual memory tasks in asymptomatic ADAD mutation carriers and non-carriers.
  • Acquired baseline MRI (T1 and diffusion-weighted) to measure cortical thickness and structural connectivity.
  • Conducted annual clinical follow-up for up to 7 years to track symptom development.

Main Results:

  • ADAD mutation carriers showed significantly lower ALF scores compared to non-carriers.
  • Lower verbal ALF scores correlated with reduced prefrontal cortex (PFC) cortical thickness in carriers.
  • Lower baseline ALF scores predicted subsequent clinical symptom onset in mutation carriers.

Conclusions:

  • ALF in presymptomatic ADAD is associated with early structural changes in the PFC.
  • ALF testing is a biologically relevant measure that predicts clinical onset and identifies individuals at high risk.
  • ALF shows promise for presymptomatic trial recruitment, as a cognitive endpoint, and as a potential screening tool.