Cognitive Enhancers in Moderate to Severe Alzheimer's Disease

Abstract

The treatment of moderate to severe Alzheimer's disease is reviewed with regard to mechanisms of action, pharmacokinetics, metabolism, safety/tolerability, and efficacy in reducing cognitive, behavioral/psychiatric, functional and global symptoms. The cholinesterase inhibitors donepezil, rivastigmine and galantamine and the N-methyl-d-aspartate receptor channel blocker memantine are moderately beneficial. Small improvements over a few months are followed by slowed mental decline. Concerning cognitive, functional and global functions, these drugs are similarly effective. Cholinesterase inhibitors also reduce apathy, memantine counteracts agitation and aggression. Serious adverse effects are rare with all four drugs. Cholinesterase inhibitors bear a risk for patients with cardiac diseases. Adverse emetic events are typical for oral formulations of these drugs, but less for rivastigmine transdermal patches. Other routes of administration and use of a galantamine prodrug are currently investigated. The superiority of combination therapies over monotherapies requires further support. Promising investigational drugs include the copper/zinc ionophore PBT2 and multifunctional hybrid molecules.

Melatonin and inflammation—Story of a double‐edged blade

“…In the case of AD, several peculiarities have to be considered that exceed the usual interplay of neuronal excitation, astrocytic and microglia activation, with consequences for expression and release of proinflammatory cytokines. These specific changes concern additional proinflammatory signals, among which the most important effects are caused by Aβ peptides and oligomers, which fuel neuroinflammation in multiple ways . Toxicity of amyloid plaques seems to be less severe and to be largely related to two effects.…”

“…Physical contact with cells, especially microglia but also astrocytes and neurons, leads to responses of activation and enhanced generation of free radicals. Additionally, amyloid plaques are capable of sequestering copper and zinc and, therefore, can deplete the stores of these metals which are required for a functional Cu,Zn‐superoxide dismutase . This may cause impairments of superoxide removal.…”

Melatonin and Phytomelatonin: Chemistry, Biosynthesis, Metabolism, Distribution and Bioactivity in Plants and Animals—An Overview

“…Finally, some scientific evidences suggested that melatonin administration in AD patients can significantly delay the progression of the disease and decrease brain atrophy [ 323 ]. However, AD is usually diagnosed relatively late in the life cycle, and experimental data report no substantial benefits after a later onset of melatonin treatment [ 324 , 325 ]. Most of the neuroprotective properties and anti-aging effects of melatonin seems to be related to the antioxidant activities of this indolamine.…”

Circadian dysfunction and Alzheimer's disease – An updated review

“…Melatonin production decreases with aging which can be considered a critical factor for the onset of AD. When impairment or disruption is seen in the suprachiasmatic nucleus (SCN), melatonin levels are reduced, resulting in circadian rhythm disruption 21–23 . Even reduction in CSF is linked with melatonin, and, finally, melatonin progresses AD by causing oxidative damage in the AD brain.…”

“…When impairment or disruption is seen in the suprachiasmatic nucleus (SCN), melatonin levels are reduced, resulting in circadian rhythm disruption. [21][22][23] Even reduction in CSF is linked with melatonin, and, finally, melatonin progresses AD by causing oxidative damage in the AD brain. Patients with AD have a low level of melatonin as compared with healthy patients.…”