Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers.

Alzheimer's disease (AD) is neuropathologically characterized by the extracellular deposition of the amyloid-β peptide (Aβ) and the intraneuronal accumulation of abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied by other co-pathologies in the brain that may contribute to cognitive impairment, such as vascular lesions, intraneuronal accumulation of phosphorylated transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate the extent of these AD and co-pathologies in patients, several biomarkers have been developed. Specific tracers target and visualize Aβ plaques, p-τ and αSyn pathology or inflammation by positron emission tomography. In addition to these imaging biomarkers, cerebrospinal fluid, and blood-based biomarker assays reflecting AD-specific or non-specific processes are either already in clinical use or in development. In this review, we will introduce the pathological lesions of the AD brain, the related biomarkers, and discuss to what extent the respective biomarkers estimate the pathology determined at post-mortem histopathological analysis. It became evident that initial stages of Aβ plaque and p-τ pathology are not detected with the currently available biomarkers. Interestingly, p-τ pathology precedes Aβ deposition, especially in the beginning of the disease when biomarkers are unable to detect it. Later, Aβ takes the lead and accelerates p-τ pathology, fitting well with the known evolution of biomarker measures over time. Some co-pathologies still lack clinically established biomarkers today, such as TDP-43 pathology or cortical microinfarcts. In summary, specific biomarkers for AD-related pathologies allow accurate clinical diagnosis of AD based on pathobiological parameters. Although current biomarkers are excellent measures for the respective pathologies, they fail to detect initial stages of the disease for which post-mortem analysis of the brain is still required. Accordingly, neuropathological studies remain essential to understand disease development especially in early stages. Moreover, there is an urgent need for biomarkers reflecting co-pathologies, such as limbic predominant, age-related TDP-43 encephalopathy-related pathology, which is known to modify the disease by interacting with p-τ. Novel biomarker approaches such as extracellular vesicle-based assays and cryptic RNA/peptides may help to better detect these co-pathologies in the future.