DOI: 10.1002/alz.078359 ISSN: 1552-5260

Brain age gap, dementia risk factors and cognition in middle age

James D Stefaniak, Elijah Mak, Li Su, Stephen F Carter, Maria‐Eleni Dounavi, Graciela Muniz‐Terrera, Katie Wells, Karen Ritchie, Brian Lawlor, Lorina Naci, Ivan Koychev, Paresh A Malhotra, Craig W Ritchie, John T O'Brien
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Brain Age Gap (BAG) represents the difference between an individual’s predicted age, derived from machine learning models trained on neuroimaging data, and their chronological age. BAG has been associated with dementia and cognition in old age. Less is known relating BAG to dementia risk‐factors or cognitive performance in middle‐age.


Cognitively healthy, middle‐aged (40‐59 years) subjects from PREVENT‐Dementia had an array of neuropsychological, neuroimaging and genetic assessments. Brain Ages were predicted from T1‐weighted 3T MRI scans. Cognition was assessed using COGNITO. Multiple linear robust regression models tested hypotheses that: (i) BAG is positively associated with dementia risk‐factors; (ii) increased BAG is associated with worse cognition; (iii) longitudinal BAG change is positively associated with longitudinal cognitive deterioration. A range of machine learning algorithms with nested cross‐validation was used to assess whether BAG and cognition could predict each other.


552 middle‐aged participants (median age 52.8 years) had all baseline assessments; 68 had amyloid PET data and 138 had longitudinal data. Median BAG was ‐2.0 years with a range from ‐21.2 to 18.4 years (Figure 1). BAG in middle‐age was associated with hypertension (p = 0.007) and alcohol intake (p = 0.008) but not APOE4 carrier status (p = 0.14) or amyloid centiloids (p = 0.53). BAG was not associated with cognitive performance either cross‐sectionally (p = 0.74) or longitudinally (p = 0.30), and there was no added predictive value between BAG and cognition. More education was associated with better cognition (p = 4.7×10−11) but not with BAG (p = 0.32).


Even in midlife, substantial inter‐individual heterogeneity exists in the extent to which brains have aged. BAG in middle‐age is associated with modifiable dementia risk‐factors, suggesting that lifestyle risk‐factor modification needs to start at, or before, midlife to optimise brain health. BAG in middle‐age was not associated with risk‐factors for Alzheimer’s disease (APOE4, amyloid deposition) or cognitive performance, despite there being a plausible and expected association between more education and better cognitive performance. These results are important for understanding brain‐age in middle‐aged populations who might be the target of future dementia‐preventing therapies.

More from our Archive