The Viability of Treatment Conditioned to the Pathophysiology of Alzheimer’s Disease

Abstract

In Alzheimer’s disease, amyloid-β biomarkers become abnormal decades before cognition starts to decline and also before detectable biomarkers of neurodegeneration. Reduced levels of acetylcholine receptors and loss of cholinergic neurons are among the major neuropathological events, usually precipitated by the accumulation of extracellular amyloid-β plaques and followed by the formation of intracellular neurofibrillary tangles. While synaptic dysfunction precedes the physical degeneration of the synapses, measures of synaptic density correlate better with dementia stage than amyloid-β or tau pathology. The cholinergic hypothesis states that degeneration of cholinergic neurons located in basal forebrain nuclei disrupts neurotransmission in presynaptic cholinergic terminals located in the limbic system and in the neocortex as a whole. These neurodegenerative mechanisms compromise hippocampal function leading to memory disturbances and then impair other higher cortical functions eventually leading to behavioral disturbances and, finally, to functional impairment. All of the mechanisms involved in amyloidogenesis and tau hyperphosphorylation show that therapeutic targets should include not only these molecules but also neurons, brain endothelium, pericytes, glial cells, and the myelin sheath. It remains to be seen if viability of treatment is actually related to amyloid-β and tau or if other key toxic misfolded proteins should be targeted as a priority.