Modified Amyloid Variants In Pathological Subgroups Of Beta-Amyloidosis

Objective: Amyloid beta (A beta) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified A beta in plaques characterizes distinct biochemical stages of A beta maturation. However, the molecular composition of vascular A beta deposits in CAA and its relation to plaques remain enigmatic. Methods: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated A beta in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. Results: Sequential deposition of A beta in CAA resembled A beta maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of A beta in the absence of pyroglutaminated A beta(N3pE) and phosphorylated A beta(pS8). B-CAA stage 2 showed additional A beta(N3pE) and B-CAA stage 3 additional A beta(pS8). Based on the A beta maturation staging in CAA and plaques, three case groups for A pathology could be distinguished: group 1 with advanced A beta maturation in CAA; group 2 with equal A beta maturation in CAA and plaques; group 3 with advanced A beta maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature A beta deposits. Notably, A beta pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. Interpretation: Balance of A beta maturation in CAA and plaques defines distinct pathological subgroups of -amyloidosis. The association of CAA-related A beta maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined A beta pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.