Patterns of tau, amyloid and synuclein pathology in ageing, Alzheimer's disease and synucleinopathies

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and amyloid-beta. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterized pathologically by alpha-synuclein aggregates. HP-tau and amyloid-beta can also occur as co-pathologies in LB dementia, and a diagnosis of (mixed)AD/DLB can be made if present in sufficient quantities. We hypothesized that the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, amyloid-beta, alpha-synuclein) and investigate the spatial distributions from tissue microarray post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 (mixed)AD/DLB, 19 PDD). The burden of HP-tau, amyloid-beta and alpha-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, amyloid-beta and alpha-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical ((PC1)-P-tau) and temporo-limbic ((PC2)-P-tau) patterns were observed for HP-tau. For amyloid-beta, a cortical-subcortical pattern ((PC1)-P-amyl) was identified. For alpha-synuclein, four patterns emerged: 'posterior temporal-occipital' ((PC1)-P-syn), 'anterior temporal-frontal' ((PC2)-P-syn), 'parieto-cingulate-insula' ((PC3)-P-syn), and 'frontostriatal-amygdala' ((PC4)-P-syn). Distinct (PC)-P-syn scores were apparent among DLB, (mixed)AD/DLB and PDD, and may relate to different spreading patterns of alpha-synuclein pathology. In dementia, cognitive measures correlated with (PC1,)-P-tau (PC2)-P-tau and (PC1)-P-amyl pattern scores (P <= 0.02), whereas such variables did not relate to alpha-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of (PC1)-P-amyl, (PC1)-P-tau had a direct effect on global cognition in dementia (n = 65, P = 0.04), while (PC1)-P-tau mediated the relationship between (PC1)-P-amyl and cognition through the indirect pathway ((PC1)-P-amyl -> (PC1)-P-tau -> global cognition) (P < 0.05). Last, in synucleinopathies, (PC1)-P-syn and (PC4)-P-syn pattern scores were associated with visual hallucinations and motor impairment, respectively (P = 0.02). In conclusion, distinct patterns of alpha-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific alpha-synuclein topographies in LB dementia that may be important to the clinical phenotype and could, after necessary testing/validation, be integrated into semiquantitative routine pathological assessment.