FIGURE 60–2 Some processes involved in Alzheimer’s disease. From the left: Mitochondrial dysfunction, possibly involving glucose utilization; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space, where it may interfere with synaptic signaling and accumulates in plaques. (Reproduced, with permission, from Roberson ED, Mucke L: 100 years and counting: Prospects for defeating Alzheimer’s disease. Science 2006;314:781. Reprinted with permission from AAAS.)
TABLE 60–3 Some potential strategies for the prevention or treatment of Alzheimer’s disease.
Aβ, amyloid beta; IL, interleukin; PERK, protein kinase RNA-like ER kinase; PPAR-γ, peroxisome proliferator-activated receptor-gamma.
Tacrine (tetrahydroaminoacridine, THA), a long-acting cholinesterase inhibitor and muscarinic modulator, was the first drug shown to have any benefit in Alzheimer’s disease. Because of its hepatic toxicity, tacrine has been replaced in clinical use by newer cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. These agents are orally active, have adequate penetration into the central nervous system, and are much less toxic than tacrine. Although evidence for the benefit of cholinesterase inhibitors (and memantine; see below) is statistically significant, the amount of benefit is modest and does not prevent the progression of the disease. The cholinesterase inhibitors cause significant adverse effects, including nausea and vomiting, diarrhea, and other peripheral cholinomimetic effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine; see Chapter 4). Preparations available are listed in Chapter 7.
Excitotoxic activation of glutamate transmission via NMDA receptors has been postulated to contribute to the pathophysiology of Alzheimer’s disease. Memantine binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade.
CHAPTER 60 Special Aspects of Geriatric Pharmacology 1063
Its modest efficacy in moderate-to-severe Alzheimer’s disease is similar to or smaller than that of the cholinesterase inhibitors. In contrast, a small study of memantine in Alzheimer’s disease in persons with
Down syndrome found no benefit. However, this drug may be better tolerated and less toxic than the cholinesterase inhibitors. Combina tion therapy with both memantine and one of the cholinesterase inhibitors has produced mixed results. Memantine is available as
Namenda in 5 and 10 mg oral tablets.
Recent research has focused on amyloid beta, because the char acteristic plaques consist mostly of this peptide. Unfortunately, two anti-amyloid antibodies, solanezumab and bapineuzumab, both failed to improve cognition or slow progression in recent clinical trials. Verubecestat, an inhibitor of beta-site amyloid pre cursor protein cleaving enzyme (BACE1), reduces the production of amyloid β. This drug showed safety in an early clinical trial, and longer-term phase 3 trials for efficacy are under way. Another effort suggests that the accumulation of filamentous tangles of tau protein is a critical component of neuronal damage in Alzheimer’s and several other neurodegenerative conditions. Accumulation of tau appears to be associated with dissociation from microtubules in neurons, which has stimulated interest in drugs that inhibit microtubule disassembly, such as epothilone-D.