Alzheimer’s disease (AD) is the leading cause of dementia and sixth-leading cause of death in the US. Medication in the management of this disease can bring better symptomatic control and increase the quality of life. There are a variety of medications targeting different receptors in the brain in the management of Alzheimer’s disease. It is crucial for physicians to understand the neuropharmacology of therapeutic Alzheimer’s disease medications. Some of the neurotransmitters involved in memory processing, synaptic transmission, neuronal growth and differentiation, excitatory/inhibitory balance, concentration, the motor control includes; Acetylcholine (Ach), Glutamate, Gamma-aminobutyric acid (GABA), Histamine, Serotonin/5-hydroxytryptamine (5-HT), and Dopamine respectively. Our editorial briefly explains the mechanism of action of drugs linked to the neurophysiology of Alzheimer disease.
Alzheimer’s disease (AD) is the leading cause of dementia and sixth-leading cause of death in the US . This editorial is a snapshot of neurotransmitters involved in AD, as it is important to understand the mechanisms of therapeutic AD medications and the underlying pathophysiology of the disease.
Acetylcholine is crucial in memory processing in the central nervous system (CNS). Presynaptic cholinergic deficits, due to reductions in choline acetyl transferase and the loss of cholinergic generating neurons in the nucleus basalis of Meynert leads to low levels of acetylcholine, which can manifest in the form of cognitive, behavioral, and functional symptoms in AD patients. Therapy for AD begins with the goal of increasing acetylcholine levels by inhibiting acetylcholinesterase, which catalyzes the cleavage of acetylcholine into choline and acetate. Drugs providing symptomatic improvement by increasing acetylcholine levels through acetylcholinesterase inhibition include donepezil, rivastigmine, galantamine, and tacrine .
Glutamate, an abundant excitatory neurotransmitter in the CNS, has various functions, including learning and memory pro
cesses, synaptic transmission, neuronal growth and differentiation, and synaptic plasticity. Glutamate primarily works through N-methyl-D-aspartate (NMDA) receptors located in the postsynaptic membranes of neurons. In AD, there is an increased presynaptic release of glutamate, as well as failed reuptake of released glutamate by astroglial cells in the synaptic cleft, causing tonic activation of NMDA receptors. The increased glutamate concentration in the synaptic cleft can trigger neuronal death due to Ca+2-induced excitotoxicity via an NMDA receptor-mediated increase in intracellular Ca2+ concentration; this causes neuronal death through apoptosis and increased release of reactive oxygen-free radicals. Moreover, high glutamate levels in AD increase β-amyloid production; this positive feedback causes symptomatic deterioration. Memantine, an FDA-approved non-competitive glutamate-NMDA receptor antagonist, positively impacts cognition, mood, and behavior in AD patients by protecting cholinergic neurons from excitotoxicity .
Gamma-amino butyric acid (GABA), an inhibitory neurotransmitter in the CNS, is involved in learning and memory by maintaining the excitatory/inhibitory balance. GABAergic neurons are indirectly involved in memory processing by their extensive conAbstract nections with cholinergic and glutaminergic neurons. GABAergic
pathways are involved in the regulation of cognition, motor function,
circadian rhythms, neural development, and adult neurogenesis.
Most post-mortem studies of tissues from patients with AD
have shown moderate to significant reductions in GABA levels in
various cortical areas of the brain; particularly affected areas include
frontal, temporal, and parietal cortices, possibly contributing
to the behavioral and psychological symptoms of AD. Benzodiazepines
and similar therapeutic agents act on GABA and help to
control agitation and aggression in AD; otherwise, these therapies
are of limited use in AD, as their side effects greatly outweigh their
Histamine plays a major role in cognitive function, along
with the sleep-wake cycle, sensory and motor functions, energy,
and endocrine homeostasis. Its function is mediated through H1,
H2, H3, and H4 receptors. Particularly, the H3 receptor is crucial
in the CNS, as it inhibits histamine release. Studies have shown
contradictory results regarding the histaminergic system in AD.
Some studies showed a reduced concentration of histamine
levels in the hippocampus, and frontal/temporal cortices of AD
patients. Other studies have reported elevated levels of histamine
in the frontal cortex, basal ganglia, and hippocampus. Histamine
receptor antagonists have been studied in animal models;
thioperamide, clobenpropit, and pitolisant an H3R antagonist,
useful in narcolepsy and schizophrenia) could reverse partial loss
of cognitive functions in mouse and rat models of amnesia .
Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter
that is active in short and long-term memory processing in
the frontal cortex and hippocampus. It is also responsible for pain,
hunger, emotions, sleep-wake cycle, motor, and sexual functions.
In AD, abundant Aβ plaques and neurofibrillary tangles can damage
serotonergic neurons in the dorsal and median raphe nuclei.
This loss of neurons progresses with age due to increased accumulation
of Aβ plaques and neurofibrillary tangles. Reduced serotonergic
neurotransmission in AD also results from reductions in
serotonin transporter binding sites and pathologic modifications
of 5-HT receptor subtypes. Several studies have examined the effects
of 5-HT drugs on cognitive function in AD.
Notably, selective serotonin reuptake inhibitors (SSRIs; e.g.,
citalopram, sertraline, or fluoxetine) have shown consistent
improvement in behavioral symptoms in AD patients, including
depression, agitation, irritability, anxiety, affective symptoms, and
aggressive behavior. Another approach involves a combination
of acetylcholinesterase inhibitors (AChEIs) and SSRIs; this
treatment induces significant improvement in memory and
cognition by increasing cerebral metabolism. Notably, clinical
studies have reported improvement in the performance of daily
activities in patients with AD who are treated by this combined
approach. In AD patients with depression, treatment with a
combination of AChEIs and monoamine oxidase inhibitors
resulted in improvements in agitation, depressive behavior,
and episodic memory. Serotonin and norepinephrine reuptake
inhibitors (venlafaxine or milnacipran) have also shown benefits
in depressive behavior in AD patients [6,7].
Dopamine, a neurotransmitter, plays a significant role in executive
function, motor control, motivation, arousal, reinforcement,
and reward responses. Dopamine-containing neurons are primarily
located in the midbrain, within the substantia nigra and ventral
tegmental areas. During aging, there is a decline in dopamine neurotransmission
and release from synaptic terminals, thus inducing
hypoactivity, gait disturbances, and reduced executive functioning.
Extrapyramidal signs, such as bradykinesia, face masking,
tremors, and gait disturbances may occur in AD, especially in patients
treated with neuroleptics. Apathy and extrapyramidal motor
deficits are secondary to dopamine dysfunction; their appearances
have a negative prognostic value and they indicate disease
progression in AD patients. Earlier DA dysfunction indicates faster
cognitive decline. Electrophysiological studies performed on AD
patients showed positive effects of DA drugs on cortical neurotransmission,
synaptic plasticity, and cognitive performance, suggesting
therapeutic benefits of these drugs in the treatment of AD.
Rotigotine, a dopamine agonist, has beneficial effects on some
cognitive domains in AD patients [8,9].