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Basic Science and Pathogenesis.

Luke W Bonham1,2, Alexis P Oddi2, Valerie Drews Escobar2

  • 1Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
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Summary
This summary is machine-generated.

A common gene variant (IFI44L rs273259) influences neurodegenerative disease progression. The alternate allele is linked to faster clinical decline in normal aging and conditions like frontotemporal dementia and Alzheimer's disease.

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Area of Science:

  • Neuroscience
  • Genetics
  • Immunology

Background:

  • Interferon (IFN) response dysregulation is implicated in neurodegeneration.
  • Genetic variations in the IFN pathway's role in neurodegenerative disease are understudied.
  • Viral infections and vaccinations may modify neurodegenerative disease risk.

Purpose of the Study:

  • To investigate the association between common genetic variation in the IFN-stimulated gene IFI44L and clinical trajectories in neurodegenerative disease and normal aging.
  • To test the hypothesis that IFI44L variation modulates disease progression.

Main Methods:

  • Longitudinal analyses using linear mixed-effects models were performed on two independent cohorts (UCSF Memory and Aging Center and ADNI).
  • Clinical severity and cognitive impairment were assessed using measures like the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and Mini-Mental State Examination.
  • IFI44L rs273259 genotype was determined via whole-genome sequencing and Illumina GWAS BeadChips.

Main Results:

  • The IFI44L rs273259 alternate (G) allele showed a significant, dose-dependent association with worse clinical trajectories in clinically normal (CN) and mild cognitive impairment (MCI) individuals in the ADNI cohort.
  • In the MAC cohort, the alternate allele correlated with worse CDR-SB trajectories in CN, frontotemporal dementia, and early-onset AD.
  • IFI44L genotype was associated with clinical trajectories in neuropathologically defined frontotemporal lobar degeneration (FTLD) subtypes (tau and TDP-43 proteinopathy).

Conclusions:

  • A common IFI44L variant is significantly associated with clinical trajectories in normal aging and multiple neurodegenerative diseases.
  • This finding confirms a crucial role for interferon signaling in the aging and neurodegenerative processes.