Elevated BrainAGE precedes cognitive impairment and improves prediction of future cognitive decline.
Authors
Affiliations (10)
Affiliations (10)
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio 70150, Finland.
- Structural Brain Mapping Group, Department of Neurology, Jena University Hospital, Jena, Germany.
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
- Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
- Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Kuopio, Finland.
- Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland.
- Department of Technical Physics, University of Eastern Finland, Kuopio, Finland.
- Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institute, Sweden.
- Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, United Kingdom.
- Clinical Research Centre, Kuopio University Hospital, Kuopio, Finland.
Abstract
Magnetic Resonance Imaging (MRI) derived brain age varies substantially between individuals, but it remains unclear whether early deviations from normal brain ageing precede future cognitive decline and whether they provide predictive value beyond conventional MRI measures. Here, we investigated whether MRI-derived brain age gap estimation (BrainAGE) identifies early structural brain ageing differences among cognitively normal individuals who later develop mild cognitive impairment (MCI) or dementia. We analysed longitudinal structural MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and replicated the main findings in the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE). Individuals who later converted to MCI or dementia had higher BrainAGE values several years before diagnosis and, in ADNI, showed steeper longitudinal increases than stable individuals. Elevated BrainAGE values were also associated with increased risk of future conversion to MCI in cognitively healthy individuals and faster subsequent memory decline. Cross-sectional differences and the association between BrainAGE and risk of future conversion were replicated in OSTPRE. Importantly, adding BrainAGE to models including demographic, APOE4, cognitive, and MRI-derived measures consistently improved prediction of future cognitive outcomes, with the greatest benefit observed for individuals who converted after longer follow-up. These findings show that structural brain ageing begins to diverge years before the onset of MCI. BrainAGE captures this early divergence, providing complementary information beyond conventional structural MRI measures that may improve the early identification of cognitively normal individuals at increased risk of future cognitive decline when integrated with other biomarkers.