Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study

Topic: Risk, prevention and care in population studies

Background A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. Methods Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy. Findings Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD. Interpretation Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility. Funding Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

@article{wagen2022-36102775,
  author  = {Wagen, A. Z. and Coath, W. and Keshavan, A. and James, S. N. and Parker, T. D. and Lane, C. A. and Buchanan, S. M. and Keuss, S. E. and others},
  title   = {{Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study}},
  journal = {The lancet. Healthy longevity},
  year    = {2022},
  doi     = {10.1016/s2666-7568(22)00167-2},
  pmid    = {36102775},
  url     = {https://doi.org/10.1016/s2666-7568(22)00167-2}
}

Key findings

• Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex.
• An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]).
• Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD).
• Interpretation Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration.
• These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.

Why it matters

In this birth cohort, a higher brain-predicted age difference was associated with cardiovascular risk, cerebrovascular disease burden, lower cognitive performance, and future hippocampal atrophy. These are associations with brain aging markers and do not show that any treatment, cure, or prevention for Alzheimer's disease works.

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Study details

• Participants456
• Evidence strengthModerate

Read the original

• DOI: 10.1016/s2666-7568(22)00167-2
• PubMed: 36102775
• Original source →
• Free full text: The Lancet Healthy Longevity →

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• Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study The Lancet. Neurology · 2019-08-20 · usefulness score 71/100 · Biomarkers
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• Gray Matter Age Prediction as a Biomarker for Risk of Dementia Proceedings of the National Academy of Sciences of the United States of America · 2019-10-01 · usefulness score 58/100 · Long-term cohort studies

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