Abstract
As a cardinal marker of brain ageing, lifetime brain atrophy obtained from a cross-sectional magnetic resonance image promises to boost statistical power to uncover novel genetic mechanisms of neurodegeneration. By analysing five young and old adult cohorts, we perform the most definitive study on lifetime brain atrophy's measurement and correlates. It is simply calculated from the relationship between total brain volume and intracranial volume, using the difference, ratio, or regression-residual method. Lifetime brain atrophy is correlated with well-validated neuroradiological atrophy ratings (r = 0.37-0.44), cognitive decline (r = 0.36), frailty (r = 0.24), and longitudinally-measured atrophic changes (r = 0.36). Lifetime brain atrophy computed with the difference method yields phenotypic and genetic signal similar to baseline intracranial volume (r(g) = 0.75), in contrast to the residual method, which also best captures brain shrinkage. Lifetime brain atrophy is highly heritable (h(2)(SNP) = 41%[95%CI = 38-43%]), and the strongest genome-wide association (N = 43,110) implicates WNT16, a gene linked with neurodegenerative diseases.