MRI-derived brain aging trajectories across the Alzheimer’s continuum: links to cognition, pathology and lifestyle risk factors

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Abstract
Background: The brain age gap (BAG), the difference between neuroimaging-predicted and chronological age, captures inter-individual variation in brain aging. Although sensitive to Alzheimer’s disease (AD) pathology, its longitudinal patterns across the clinical AD continuum and prognostic relevance remain unclear. Methods: 577 participants from the DELCODE cohort (>2,100 MRI scans) were analysed: healthy controls individuals (HC, N=202), and patients with subjective cognitive decline (SCD, N=248), mild cognitive impairment (N=93), and AD dementia (N=34). All underwent structural MRI, amyloid (Aβ 42/40 ) and phosphorylated tau181 assessment, and lifestyle-related dementia risk profiling (LIBRA). BAG was derived using brainageR. Associations with baseline cognition, cognitive decline, and clinical progression (up to eight years) were examined using mixed-effects and Cox models. Mediation analyses tested whether BAG accounted for LIBRA-cognition associations. Biomarker-related and clinical findings were replicated in ADNI (N=461). Findings: BAG showed excellent short-term reliability, increased stepwise across the clinical spectrum and was elevated in amyloid-positive SCD, but not in asymptomatic amyloid-positive HC. Longitudinal BAG increases were strongest in amyloid- and tau-positive participants (Aβ+T+). Higher BAG was associated with poorer baseline cognition and predicted cognitive decline, with strongest effects in Aβ+T+. All main findings replicated in ADNI. BAG was associated with LIBRA only in biomarker-negative participants and partly mediated associations with cognitive outcomes in DELCODE. Interpretation: BAG is a reliable non-invasive marker of structural brain health sensitive to AD pathology and to modifiable AD risk. Detectable divergence prior to objective cognitive impairment supports its relevance for early risk stratification and prevention-oriented research. Funding: Helmholtz AI Cooperation Unit (ZT-I-PF-5-163).
Funding Information
  • Helmholtz Artificial Intelligence Cooperation Unit, DE (ZT-I-PF-5-163)
  • Deutsches Zentrum für Neurodegenerative Erkrankungen, DZNE (BN012)
  • National Institutes of Health (AG024904)
  • National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering
  • Alzheimer's Association
  • Alzheimer's Drug Discovery Foundation
  • Araclon Biotech, US
  • CereSpir, Inc., US
  • Cogstate
  • Eisai
  • Elan Pharmaceuticals
  • Eli Lilly
  • EuroImmun
  • Roche
  • Genentech
  • Fujirebio
  • GE Healthcare
  • IXICO
  • Janssen Alzheimer Immunotherapy Research & Development, LLC
  • Johnson & Johnson Pharmaceutical Research & Development LLC
  • Lumosity
  • Novartis Pharmaceuticals Corporation
  • Servier
  • Takeda Pharmaceutical Company
  • Transition Therapeutics
  • Canadian Institutes of Health Research
  • Foundation for the National Institutes of Health

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