Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by ‘normal’ brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease.

Introduction: Typical brain development is characterized by specific patterns of maturation of functional networks. Cortico-cortical connectivity generally increases, whereas subcortico-cortical connections often decrease. Little is known about connectivity changes amongst different subcortical regions in typical development. Methods: This study examined age- and gender-related differences in functional connectivity between and within cortical and subcortical regions using two different approaches. The participants included 411 six- to ten-year-old typically developing children sampled from the population-based Generation R study. Functional connectomes were defined in native space using regions of interest from subject-specific FreeSurfer segmentations. Connections were defined as: (a) the correlation between regional mean time-series; and (b) the focal maximum of voxel-wise correlations within FreeSurfer regions. The association of age and gender with each functional connection was determined using linear regression. The preprocessing included the exclusion of children with excessive head motion and scrubbing to reduce the influence of minor head motion during scanning. Results: Cortico-cortical associations echoed previous findings that connectivity shifts from short to long-range with age. Subcortico-cortical associations with age were primarily negative in the focal network approach but were both positive and negative in the mean time-series network approach. Between subcortical regions, age-related associations were negative in both network approaches. Few connections had significant associations with gender. Conclusions: The present study replicates previously reported age-related patterns of connectivity in a relatively narrow age-range of children. In addition, we extended these findings by demonstrating decreased connectivity within the subcortex with increasing age. Lastly, we show the utility of a more focal approach that challenges the spatial assumptions made by the traditional mean time series approach.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.