The heritability of cerebral amyloid in older people and its relationship to vascular risk factors, cerebral small vessel disease and cognition

Abstract

Abnormal β-amyloid (Aβ) plaque accumulation, a hallmark pathological feature of Alzheimer’s disease (AD), commonly co-occurs with cerebral small vessel disease (SVD). However, the nature of the relationship between AD pathology and SVD remains controversial. This thesis aimed to (1) determine the relative genetic and environmental contributions to cerebral Aβ; (2) investigate the role of vascular risk factors and cerebral SVD in Aβ accumulation; and (3) disentangle the relative genetic and environmental relationships of these pathologies with each other and with cognition. Participants were drawn from two cohorts of older adults who had undergone amyloid positron emission tomography: the Older Australian Twins Study (OATS) (n=206) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n=216). Aβ was quantified using the standardised uptake value ratio. SVD was quantified on magnetic resonance imaging by total white matter hyperintensity volume using T2-weighted FLAIR imaging and peak width of skeletonized mean diffusivity using diffusion tensor imaging. Using the classical twin design in the OATS cohort, the first study found that the heritability of cortical Aβ was moderate, suggesting that Aβ was susceptible to significant environmental influence. Contrary to expectation, cerebral SVD and Aβ did not have a shared genetic basis, although the sample size was a limitation. Using structural equation modelling in the ADNI cohort, study two showed that cerebral SVD had no significant direct effect on Aβ load over time. Fasting blood glucose level was the only vascular risk factor which had a direct influence on Aβ accumulation at 24-months. The third study, using the OATS cohort, found that higher white matter hyperintensity volume had significant inverse genetic correlations with processing speed, pointing to their shared genetic basis. There were no significant phenotypic or genetic correlations between Aβ load and cognition. Taken together, this research has significant practical implications as it indicates that Aβ is under strong environmental influences and may be amenable to intervention. Furthermore, although Aβ and cerebral SVD commonly co-occur, their deleterious effects on cognition likely occur via independent pathways. This thesis highlights the role of environmental determinants of cerebral Aβ which warrant further exploration, but suggests that vascular risk factors only make a minor contribution. It demonstrates the power of the twin method in determining the independence of AD and SVD pathologies, both of which are important for cognition