Mounting evidence suggests that early life factors have an important impact on the occurrence of late-life neurological diseases. From a public health perspective this is of particular relevance for dementia. With increasing longevity the number of persons affected by dementia is increasing drastically, with no available preventive treatment, resulting in a major burden at the individual and socio-economic level. Converging evidence indicates that pathological processes likely begin many years before clinical diagnosis. Interestingly, measures of brain structure on magnetic resonance imaging (MRI) that were shown to be powerful determinants of dementia in older persons can already show subtle alterations in young and middle-aged adults. The SEGWAY project aimed to: (i) explore the contribution of variations in the genetic make-up of individuals to structural brain measures in young adults in their early twenties participating in the i-Share study, the largest ongoing study on student’s health; (ii) take a lifetime perspective by examining the shared genetic contribution to alterations in brain structure in young adulthood (i-Share study) and late-life, among participants of a large French population-based study, aged 65 years and older (3C-Dijon study); (iii) explore whether the impact of genetic factors on brain changes is modulated by the exposure to vascular risk factors (hypertension, hypercholesterolemia, obesity, smoking…) with an established impact on brain aging; (iv) examine the clinical significance of genes associated with changes in brain structure by testing their association with cognitive performance in both age groups, and with dementia risk in older adults. Identifying common biological mechanisms underlying both early and late-life structural brain changes may provide important information on the mechanisms and time-course of brain aging throughout a lifetime and could be of major importance for identifying novel drug targets and characterizing high risk populations most likely to benefit from early preventative interventions. Over the course of the project we have contributed to the discovery of >50 novel genetic risk variants associated with MRI-markers of brain aging in older adults, in collaboration with additional population-based studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. We found that several of these genetic variants already showed strong associations with structural brain variations in young adults in their twenties. We found this to be particularly prominent for genetic risk variants for MRI-markers of vascular brain aging, i.e. for white matter hyperintensity volume (WMH), strongly associated with changes in diffusion tensor imaging in young adults, and for perivascular space burden (PVS), strongly associated with PVS burden in the brain white matter of young adults. Genetically determined WMH was associated with an increased risk of ischemic stroke, hemorrhagic stroke and Alzheimer type dementia. We found that, in aggregate, genetic risk variants for WMH showed significant interaction with hypertension in relation with WMH burden.
