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The aim of this thesis was to investigate the radiological phenotype of the human brain in familial longevity with regard to brain structure. This study was performed as part of the Leiden Longevity Study __ a study population consisting of offspring of long-lived Dutch people who are genetically predisposed to become long-lived as well and their environmentally and age-matched spouses. Dedicated MR imaging techniques were applied to study the phenotype of the human brain on the macrostructural as well as microstructural level. Both features which are most likely caused by early development and a lower susceptibility to known age-related structural brain changes on the macro- as well as microstructural level are hallmarks of the brain phenotype in longevity. The contributing mechanisms have yet to be identified but may involve homeostatic control and body function. Keeping in mind that there is a gradual transition from healthy brain aging to what is generally accepted as __normal__ brain aging and pathological brain changes as disease correlates, our study results implicate that the brains of offspring of nonagenarian siblings are less susceptible to neurodegenerative brain changes such as (vascular) dementia, Alzheimer__s disease and cerebrovascular disease. Our findings should be considered as starting points for future studies on the functional implications of the presented results and studies on the underlying pathways of brain structure preservation in human longevity.

Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10 -8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10 -5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.