Alzheimer’s disease

Neurogranin and BACE1

Neurogranin (Ng) is a postsynaptic protein which is mainly expressed in the cortex and hippocampus and is localised in the dendritic spines. It is considered a potential biomarker for the loss of synaptic integrity in the course of Alzheimer’s disease. Neurogranin plays an important role in the neuronal long-term potentiation and thus represents a decisive component of learning processes. In the cerebrospinal fluid (CSF), there are mainly C-terminal fragments of neurogranin present, which are mostly truncated by three amino acids (Trunc P75). Studies have shown that neurogranin concentrations are lower in the brains of patients with Alzheimer’s disease compared to healthy control persons, while being significantly higher in the CSF (De Vos et al., 2015; Kester et al., 2015). Moreover, increased neurogranin concentrations in CSF proved as predictive of the progression of Alzheimer’s disease from mild cognitive impairment (MCI) to dementia (Kester et al., 2015). Consequently, neurogranin is a very promising presymptomatic marker for synaptic damage. 

BACE1 (beta-site APP cleaving enzyme 1, also β-secretase 1) is a presynaptic protein and a potential biomarker for neurodegenerative processes in the course of Alzheimer’s disease. BACE1 is a transmembrane aspartyl protease, which is expressed e.g. in the brain. Its activity regulates the rate of sequential proteolysis of the transmembrane amyloid precursor protein (APP) to beta-amyloid (1-42) (Aβ_1-42) or beta-amyloid (1-40) (Aβ_1-40). (Hampel et al., 2020).

De Vos and colleagues have proven that the ratio of concentrations of neurogranin and BACE1 has an even higher prognostic value. In their study, an increased ratio was associated with a faster progression of cognitive impairment – a correlation that was not observed with the classic Alzheimer’s disease markers tau and Aβ (De Vos et al., 2016). Also in patients with subjective cognitive decline (SCD) or MCI and proven amyloid pathology, the studies found a significantly increased Ng/BACE1 ratio (Kirsebom et al., 2018) compared to healthy individuals. Moreover, the ratio enables differentiation of Alzheimer’s patients from patients with major depressive disorder (MDD) despite similar cognitive deficits (Schipke et al., 2018).

Alpha-synuclein

Alpha-synuclein is a cytoplasmic protein, which is enriched in the presynaptic terminals. Its physiological function has not been sufficiently clarified; however, several studies indicate a role in the vesicular transport and the release of neurotransmitters. Alpha-synuclein is associated with the development of synucleinopathies, a group of neurodegenerative diseases which include Parkinson’s disease (PD), Lewy body dementia (DLB) and multiple system atrophy (MSA) (Goedert et al., 2017).

The majority of studies show reduced CSF concentrations in patients with synucleinopathies in comparison with healthy individuals and patients with other neurodegenerative diseases. In contrast, the concentration of alpha-synuclein in the CSF of patients with Alzheimer’s disease is significantly higher than in patients with synucleinopathies and in healthy individuals. This has been shown in several large studies and may be specific for Alzheimer’s disease. When measuring the concentration of alpha-synuclein in CSF, it must be observed that the protein is also present in peripheral blood and that up to 20% of all lumbar punctures are contaminated with blood (Mollenhauer et al., 2017; Vanderstichele et al., 2017).

Preanalytics in dementia diagnostics

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