Abstract Body

Alzheimer’s disease (AD) is neuropathologically characterized by the presence of amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques consist of extracellular amyloid β-protein (Aβ) deposits. NFTs are intraneuronal aggregates of abnormal phosphorylated τ-protein. In addition, cerebral amyloid angiopathy (CAA), granulovacuolar degeneration (GVD) and cytoplasmic aggregates of TDP-43 are found in brains of AD patients. CAA can cause microbleeds, hemorrhages, infarcts and microinfarcts that can contribute to cognitive decline. GVD contains the active necrosome complex. Accordingly, it is tempting to speculate that GVD contributes to neuronal cell death in AD. Here, the density of neurons in GVD-affected regions inversely correlates with the percentage of neurons exhibiting necrosome-positive GVD. TDP-43 lesions are not seen in every AD case and show different types of distribution depending on the antibodies used for detection, suggesting that TDP-43 aggregates in AD show a spectrum from frontotemporal lobar degeneration (FTLD-TDP)-like features to age and AD-related aggregates that have been suggested to represent a limbic-associated age-related TDP-43 encephalopathy (LATE). The contribution of TDP-43 pathology and CAA may have significant impact on the clinical picture of patients and explain variabilities among patients with similar Aβ and τ biomarker status. End-of-life studies for amyloid and τ-PET have shown that τ-changes can be detected in symptomatic AD cases whereas preclinical stages of AD can be better picked up with amyloid biomarkers (amyloid PET). However, a large part of the preclinical AD cases that can be identified neuropathologically drop clinical attention today similar to TDP-43 pathology, CAA and GVD.