The bidirectional causal effects of brain morphology across the life course and risk of Alzheimers disease: A cross-cohort comparison and Mendelian randomization meta-analysis

Neuropathological changes associated with Alzheimers disease (AD) can occur decades before clinical symptoms. We investigated whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or accelerating brain atrophy, respectively. We used bidirectional two-sample Mendelian randomization to estimate the effects of genetic liability to AD on global and regional cortical thickness, total intracranial volume, volume of subcortical structures and cerebral white matter in 36,842 participants aged eight to 81 years across five independent cohorts, and the effects of global and regional cortical thickness and subcortical volumes on AD risk in 94,337 participants. Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. We also found little evidence to suggest brain morphology alters AD risk. Thus, genetic liability to AD is likely to alter mechanisms and/or rates of neurodegeneration, rather than reduce structural brain reserve.