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Pathogenesis and early diagnosis of Alzheimer’s disease: involvement of the monoaminergic system

Pathogenesis of Alzheimer’s disease (AD) is still not elucidated. There are several different views regarding the occurrence of two main features of AD: amyloid β (Aβ) and tau protein pathology. Generally, it is considered that the increase in the amount of Aβ is an initiating event in AD (particularly in familial cases), while tau protein hyperphosphorylation and aggregation occur consequently. On the other hand, based on postmortally analysed brains Braak and Del Tredici documented that intraneuronal tau aggregation precedes diffuse plaque deposition, but Aβ changes occur before increases of tau in cerebrospinal fluid (CSF). Some of the new hypotheses stressed the possibility that the first pathological changes in AD could occur in brainstem nuclei: noradrenergic locus coeruleus (LC), serotonergic dorsal raphe (DRN) and cholinergic nucleus basalis complex. Our recent study summarized all these findings into a unifying hypothesis: long projection fibers from brainstem nuclei release Aβ that could induce neurofibrillary changes within vulnerable cortical glutamatergic pyramidal neurons. The involvement of monoaminergic nuclei in the pathogenesis of AD was further elaborated in an ongoing study showing that exposure to heavy metals (such as inorganic mercury) can lead to AD-like pathology in LC neurons that may spread to neighbouring DRN neurons. Since current biomarkers of AD detect the disease in symptomatic individuals (in whom neurodegeneration is already substantial), novel biomarkers are essential for early AD detection at preclinical stages. Encouraged by the finding of early monoaminergic nuclei degeneration in AD, many investigators tried to assess diagnostic potential of monoamine metabolites in CSF. However, due to the differences between studies and methodological limitations, these biomarkers have not been proven as diagnostically useful. Although no individual CSF neurotransmitter proved to be specific for AD, usage of more sophisticated techniques could enable the development of several monoamine metabolites profile, and possibly improve early AD detection (in addition to currently established core biomarkers).

Alzheimer’s disease; pathogenesis; brainstem nuclei; dorsal raphe nucleus; locus coeruleus; early diagnosis; cerebrospinal fluid; monoamine metabolites

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