White matter microstructure changes across the lifespan: a meta-analysis of longitudinal diffusion MRI studies

White matter in the human brain is known to play a critical role in facilitating communication between different brain regions. White matter microstructure is often quantified using fractional anisotropy (FA) derived from diffusion-weighted MRI and is often considered a key measure of neural efficiency that is positively associated with motor and cognitive functioning. While lifespan trajectories of FA have been well studied in cross-sectional designs, it remains less clear how FA changes longitudinally with age across the lifespan, and whether the rates of change are influenced by genetic variation.

We systematically reviewed the evidence of white matter changes, as measured by fractional anisotropy (FA) with diffusion magnetic resonance imaging longitudinally across the lifespan, and the genetic influences on this change. Searches were conducted in Medline, PsycInfo, and EMBASE up to August 2023 with terms related to DTI/FA and longitudinal/change. Following this, genetic-related search terms were applied to the results, and the search was broadened to include other measures of white matter change. Our systematic search resulted in 29 studies that met our criteria. In addition, 14 studies investigated genetic influences on FA change rates across the lifespan. A meta-regression using a thin-plate spline model was conducted to examine annual whole-brain FA change as a function of age.

Across childhood and adolescence, FA increased, and the rate of increase slowed into early adulthood. Between ages 20 and 35, changes in FA were not statistically significant. This was followed by a significant decline in FA between ages 36 and 50. The decreases plateaued between ages 51 and 61 and then continued at a slightly slower rate towards the upper end of the age range assessed (77 years). Average FA change per year relative to baseline assessment reached a maximum of +1.1% during development, and -0.6% per year, during ageing. Significant heritability was found for change in local but not global FA during development. During ageing, common variants in genes that have been related to increased risk for neuropsychiatric disorders (APOE, HTT, MAPT) were associated in some studies with accelerated local FA decreases over time.

In conclusion, there are changes in white matter microstructure within individuals across the lifespan, with increases during childhood, adolescence and early adulthood, followed by a period of relative stability during early to mid-adulthood, and subsequent gradual declines from midlife onwards. Evidence is emerging for genetic influences on white matter changes over time, shaping individual trajectories.