Modified amyloid variants in pathological subgroups of -amyloidosis.

Objective: Amyloid (A) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer's disease (AD). Sequential deposition of post-translationally modified A in plaques characterizes distinct biochemical stages of A maturation. However, the molecular composition of vascular A deposits in CAA and its relation to plaques remain enigmatic.

Methods: Vascular and parenchymal deposits were immunohistochemically analyzed for pyroglutaminated and phosphorylated A 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 in CAA resembled A maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of A in the absence of pyroglutaminated A and phosphorylated A. B-CAA stage 2 showed additional A and B-CAA stage 3 additional A. Based on the A maturation staging in CAA and plaques, three case groups for A pathology could be distinguished: group 1 with advanced A maturation in CAA; group 2 with equal A maturation in CAA and plaques; group 3 with advanced A maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature A deposits. Notably, A pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia.

Interpretation: Balance of A maturation in CAA and plaques defines distinct pathological subgroups of -amyloidosis. The association of CAA-related A maturation with cognitive decline, the individual contribution of CAA and plaque pathology to the development of dementia within the defined A pathology subgroups, and the subgroup-related association with arterial hypertension should be considered for differential diagnosis and therapeutic intervention.