Albeit cholinergic depletion remains the key event in Alzheimer’s Disease (AD), recent information
describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin,
and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus
efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic
tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry
of AD involving monoamine systems. Then, we compiled the effects of monoamines found in
the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships.
Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine
models and humans. In some cases, the mechanism of action is clear, essentially through the interaction
on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of
enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others
for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines
and their derivatives attractive potential elements for AD therapy.