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The deposition of the amyloid β-protein (Aβ) is one of the pathological hallmarks of Alzheimer's disease (AD). Aβ-deposits show the morphology of senile plaques and cerebral amyloid angiopathy (CAA). Senile plaques and vascular Aβ-deposits occur first in neocorti-cal areas. Then, they expand hierarchically into further brain regions. The distribution of Aβ plaques throughout the entire brain, thereby correlates with the clinical status of the patients. Imaging techniques for Aβ make use of the hierarchical distribution of Aβ to distinguish AD patients from non-AD patients. However, pathology seen in AD patients represents a late stage of a pathological process starting 10–30 years earlier in cognitively normal individuals. In addition to the fibrillar amyloid of senile plaques, oligomeric and monomeric Aβ is found in the brain. Recent studies revealed that oligomeric Aβ is presumably the most toxic Aβ-aggregate, which interacts with glutamatergic synapses. In doing so, dendrites are presumed to be the primary target for Aβ-toxicity. In addition, vascular Aβ-deposits can lead to capillary occlusion and blood flow disturbances presumably contributing to the alteration of neurons in addition to the direct neurotoxic effects of Aβ. All these findings point to an important role of Aβ and its aggregates in the neurodegenerative process of AD. Since there is already significant neuron loss in AD patients, treatment strategies aimed at reducing the amyloid load will presumably not cure the symptoms of dementia but they may stop disease progression. Therefore, it seems to be necessary to protect the brain from Aβ-toxicity already in stages of the disease with minor neuron loss before the onset of cognitive symptoms.
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 AβN3pE and phosphorylated AβpS8. B‐CAA stage 2 showed additional AβN3pE and B‐CAA stage 3 additional AβpS8. 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.