Abstract

As the global population is ageing, the number of older people affected by conditions leading to dementia such as Alzheimer’s disease (AD) is increasing. As AD pathology is thought to accumulate over many years before the onset of cognitive impairments, it may be possible to identify early warning signs associated with dementia risk so that asymptomatic individuals at heightened risk can be stratified into future clinical trials for novel preventative therapeutics. The objective of the Cardiff Ageing and Risk of Dementia Study (CARDS) (Metzler-Baddeley et al. 2019a,b) is to investigate the impact of ageing and genetic and lifestyle risk factors, i.e. APOE4 genotype, Family History (FH) of dementia and central obesity, on the brain and cognition in asymptomatic individuals. This was done in 166 cognitively healthy adults (38-71 years of age) using non-invasive, multi-parametric magnetic resonance imaging (MRI). More specifically, multi-component diffusion-based Neurite Orientation Density and Dispersion Imaging (NODDI) (Zhang et al 2012) was employed to gain metrics of neurite microstructure (apparent neurite density, orientation dispersion, and free water tissue content) and quantitative Magnetization Transfer (qMT) (Sled 2018) and T1-relaxometry were used to gain metrics that are sensitive to myelin and inflammation [macromolecular proton fraction (MPF), forward exchange rate kf, R1). Ageing was associated with a reduction of MPF , kf, and R1 and increases in free water signal and orientation dispersion in white and grey matter but no differences in apparent axon density. Furthermore, synergistic effects of FH, APOE and Waist Hip Ratio were observed in white and grey matter MPF and in grey matter kf. These results are consistent with neuropathological evidence of age-related loss of myelin rather than axons. They also suggest that genetic and lifestyle risk factors adversely impact myelination. These results will be discussed in light of a glia model of ageing and neurodegeneration (Bartzokis 2011).