Genetic contribution to grey matter network disruptions and Alzheimer disease cerebrospinal fluid markers

© 2022 the Alzheimer's Association.Background: Grey matter covariance networks become disrupted early in Alzheimer’s disease (AD), when amyloid starts aggregating, and before the onset of irreversible atrophy. However, the precise relationship of grey matter network breakdown and the AD pathophysiological process remains unclear. Here, we studied to what extent shared familial (genes and family environment) or environmental factors unique to a twin contribute to these relationships in a sample of older monozygotic twins with intact cognition. Method: From the EMIF-AD PreclinAD study we included monozygotic twins who had at least an MRI scan (n=197) and CSF available (n=124). We assessed the upper limit of genetic contribution to grey matter network measures (size, degree, connectivity density, clustering, path length, small-world measures) with within-twin pair correlations. Associations between CSF AD markers (Aβ42/40, t-tau, p-tau) and other markers related to AD pathophysiology (neurogranin, Aβ38, Aβ40, BACE1) with grey matter network disruptions were assessed with linear mixed models. Twin analyses (cross-twin cross-trait, twin difference analyses) were used to assess the contribution of shared familial and/or unique environmental factors to these associations. Result: Twenty individuals (16%) had abnormal CSF Aβ42/40 levels. Grey matter network measures were highly correlated within twin pairs (r=0.54-0.97; all p<0.001, Fig.1), suggesting a moderate to strong genetic background. Across the whole sample, more abnormal Aβ42/40 ratios were moderately related to lower connectivity density (β±SE = 0.176±0.09, p=0.055, Fig.2). The strongest associations with grey matter network measures were observed for t-tau and p-tau levels (range β=-0.344-0.182), followed by Aβ production markers (Aβ38, Aβ40, BACE1) (range β=-0.202-0.165). We observed no relationships between neurogranin and grey matter network measures. Cross-twin cross-trait analyses showed that levels for t-tau, p-tau and Aβ38 in one twin were associated with grey matter network measures in their co-twin (r=-0.27 to -0.21; p range=0.02 to 0.07, Fig.3). Within-pair differences in BACE1 were related to within-pair differences in normalized path length values (r=0.35; p=0.01; Fig.4). Conclusion: Our results suggest a shared familial background for the relationship of grey matter network disruptions and AD-related processes as measured in CSF. In addition, unique environmental factors influencing BACE1 may also affect grey matter network disruptions.