Interactions between vascular burden and amyloid-β pathology on trajectories of tau accumulation

Abstract

Cerebrovascular pathology often co-exists with Alzheimer's disease pathology and can contribute to Alzheimer's disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer's disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ɛ4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ɛ4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = -0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = -0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology-in the presence of amyloid-β pathology-modifies tau accumulation in early stages of Alzheimer's disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer's disease.

Keywords: Alzheimer’s disease; amyloid-β; tau; vascular burden; vascular risk.

Figure 1

Cerebrovascular pathology per group in the Swedish BioFINDER-2 study. Shown are white matter lesion (WML) volume (adjusted for intracranial volume and log-transformed), the prevalence of having one or more microbleeds (as well as their location), and the prevalence of having one or more stroke-related events for each group. Estimates and P-values for group comparisons are shown in Supplementary Table 2. Amyloid-β (Aβ)-positive participants showed significantly more (lobar) microbleeds compared to Aβ-negative participants at the same cognitive stage. Also, both Aβ-positive and Aβ-negative cognitively impaired (CI) participants showed significantly more (lobar) microbleeds compared to Aβ-negative cognitively unimpaired (CU) participants. Furthermore, CI participants showed significantly larger WML volume compared to CU participants, irrespective of Aβ-status.

Figure 2

Interactions between cerebrovascular pathology and amyloid-β pathology on baseline tau load and longitudinal tau accumulation in the Swedish BioFINDER-2 study. Visualized are the interaction effects between each cerebrovascular factor and amyloid-β (Aβ) on baseline tau load and longitudinal tau accumulation derived from linear mixed models. Estimated baseline and longitudinal tau pathology is shown based on different levels of Aβ and vascular burden for visualization purposes. For cognitively unimpaired (CU) participants, A− reflects the effect for the average amyloid-PET standardized uptake value ratio (SUVr) of Aβ-negative individuals, and A+ reflects the effect for the average amyloid-PET SUVr of Aβ-positive individuals. For cognitively impaired (CI) participants, Aβ− reflects the effect for the average Aβ-negative individual, and Aβ+ reflects the effect for the average Aβ-positive individual. For the longitudinal results with white matter lesion (WML) volume, Vascular− and Vascular+ reflect the effect of −1SD and +1SD from the mean WML volume. For longitudinal results with microbleeds and stroke characteristics, Vascular− and Vascular+ reflect the effect for the average individual with and without microbleeds or stroke characteristics, respectively. ICV = intracranial volume; ROI = region of interest.

Figure 3

Interactions between cerebrovascular pathology and amyloid-β plaque density on tau tangle density in the Arizona-based neuropathology cohort. Visualized are the interaction effects between each cerebrovascular factor and amyloid-β plaque density on tau tangle density derived from linear models. Estimated tau tangle density is shown based on different levels of plaque density: A− reflects the effect for the average plaque density of amyloid-β low individuals (i.e. CERAD non-to-sparse), and A+ reflects the effect for the average plaque density of amyloid-β high individuals (i.e. CERAD moderate-to-frequent). Aβ = amyloid-β; CAA = cerebral amyloid angiopathy; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; WM = white matter.