Modified amyloid variants in pathological subgroups of β ‐amyloidosis

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