RESUMO
OBJECTIVE: Amyloid ß (Aß) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified Aß in plaques characterizes distinct biochemical stages of Aß maturation. However, the molecular composition of vascular Aß deposits in CAA and its relation to plaques remain enigmatic. METHODS: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated Aß in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. RESULTS: Sequential deposition of Aß in CAA resembled Aß maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of Aß in the absence of pyroglutaminated AßN3pE and phosphorylated AßpS8. B-CAA stage 2 showed additional AßN3pE and B-CAA stage 3 additional AßpS8. Based on the Aß maturation staging in CAA and plaques, three case groups for Aß pathology could be distinguished: group 1 with advanced Aß maturation in CAA; group 2 with equal Aß maturation in CAA and plaques; group 3 with advanced Aß maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature Aß deposits. Notably, Aß pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. INTERPRETATION: Balance of Aß maturation in CAA and plaques defines distinct pathological subgroups of ß-amyloidosis. The association of CAA-related Aß maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined Aß pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.