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 Aβ_N3pE and phosphorylated Aβ_pS8. B-CAA stage 2 showed additional Aβ_N3pE and B-CAA stage 3 additional Aβ_pS8. 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.

Figure 1

Stages of amyloid maturation in CAA. Detection of Aβ, Aβ _N3pE, and Aβ _pS8 in leptomeningeal (arrow) and parenchymal (open arrow) vessels of AD cases enabled the differentiation of three biochemical stages of amyloid deposition in the pathogenesis of CAA. B‐CAA stage 1 (A–C) was characterized by initial deposition of Aβ in the vessel (A) in the absence of Aβ _N3pE (B) and Aβ _pS8 (C) deposition. B‐CAA stage 2 (D–F), however, corresponded to the additional deposition of Aβ _N3pE (E) whereas the vessels were still devoid of Aβ _pS8 deposits (F, the intravascularly stained material in one vessel in F and F2 (no arrow) is related to insufficient peroxidase blocking in the erythrocytes and does not correspond to positivity for Aβ _pS8 as demonstrated in I, I1, and I2). Co‐deposition of Aβ (G), Aβ _N3pE (H), and Aβ _pS8 (I) in the vessel could be detected in B‐CAA stage 3 (G–I). The figure displays representative images of the temporal cortex of AD cases stained with DAB for Aβ (A, D, G), Aβ _N3pE (B, E, H), and Aβ _pS8 (C, F, I). Scale bar: (A, B, C, D, E, F, G, H, I) 350 μm, (A1, A2, C1, C2, D2, E2, F2, G1, H1, I1) 70 μm, (B1, B2, D1, E1, F1, G2, H2, I2) 35 μm.

Figure 2

Neuropathologic associations of Aβ pathology groups. Relation of case groups for Aβ pathology to CAA stage (of CAA distribution)30 and CAA severity29 (A), to Aβ‐MTL phases,27 Braak‐NFT stages,23 and CERAD scores26 (B), and to Aβ, Aβ _N3pE, and Aβ _pS8 plaque loads (C).

Figure 3

Amyloid maturation within Aβ pathology groups. Schematic representation of the biochemical (immunohistochemical) stages of CAA‐ (B‐CAA stage) and plaque‐ (B‐Aβ plaque stage) related Aβ maturation (A) and their balance in distinct Aβ pathology groups (B).