Modified amyloid variants in pathological subgroups of β-amyloidosis

Abstract

Objective: Amyloid β (Aβ) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified Aβ in plaques characterizes distinct biochemical stages of Aβ maturation. However, the molecular composition of vascular Aβ deposits in CAA and its relation to plaques remain enigmatic. Methods: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aβ in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. Results: Sequential deposition of Aβ in CAA resembled Aβ maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of Aβ in the absence of pyroglutaminated AβN3pE and phosphorylated AβpS8. B-CAA stage 2 showed additional AβN3pE and B-CAA stage 3 additional AβpS8. Based on the Aβ maturation staging in CAA and plaques, three case groups for Aβ pathology could be distinguished: group 1 with advanced Aβ maturation in CAA; group 2 with equal Aβ maturation in CAA and plaques; group 3 with advanced Aβ maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature Aβ deposits. Notably, Aβ pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. Interpretation: Balance of Aβ maturation in CAA and plaques defines distinct pathological subgroups of β-amyloidosis. The association of CAA-related Aβ maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aβ pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.