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Basic Science and Pathogenesis.

Jing Qian1, Weidong Wang1, Bradley T Hyman2,3,4

  • 1University of Massachusetts, Amherst, MA, USA.

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Summary
This summary is machine-generated.

The APOE genotype influences frontotemporal lobar degeneration with tau pathology (FTLD-Tau) clinical outcomes, primarily by affecting Alzheimer's disease and other co-occurring pathologies, rather than directly impacting disease progression.

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Area of Science:

  • Neuroscience
  • Genetics
  • Neuropathology

Background:

  • The Apolipoprotein E (APOE) genotype is a significant genetic factor influencing Alzheimer's disease (AD) risk, onset age, and neuropathology.
  • The impact of APOE genotype on clinical and neuropathological outcomes in frontotemporal lobar degeneration with tau pathology (FTLD-Tau) remains less understood.

Purpose of the Study:

  • To investigate the association between APOE genotype and clinical/neuropathological features in FTLD-Tau patients.
  • To explore the mediating role of comorbid pathologies in the APOE genotype's effect on clinical outcomes.

Main Methods:

  • Utilized the National Alzheimer's Coordinating Center (NACC) database.
  • Included subjects with available brain autopsy, APOE genotype, and recent clinical evaluation (CDR-SOB).
  • Analyzed data using Cox proportional hazards, regression, and mediation models, adjusting for age, sex, and education.

Main Results:

  • APOEε4 carriers showed earlier onset and higher clinical dementia rating sum of boxes (CDR-SOB) scores compared to APOEε3/ε3.
  • APOEε4 was linked to increased neuritic plaques, Braak NFT stage, cerebral amyloid angiopathy (CAA), arteriolosclerosis, and Lewy bodies.
  • APOEε2 carriage was associated with lower neuritic plaques and a trend towards lower CDR-SOB.
  • Mediation analyses indicated that APOE's influence on CDR-SOB is largely indirect, mediated by neuritic plaques and arteriolosclerosis.

Conclusions:

  • APOE genotype significantly affects clinical outcomes in FTLD-Tau.
  • The APOE genotype's impact on FTLD-Tau clinical presentation is primarily mediated by its influence on co-occurring pathologies like Alzheimer's disease neuropathology.