asthenia
All three medications have shown efficacy through randomized, double-blind placebo-controlled trials (RCTs) with varying durations from 3 to 12 months. Compared with placebo, although with modest degree, the cholinesterase inhibitors delay decline in cognition, activities of daily living (ADLs), and global change, and may improve behavior [6, 7]. A small percentage of subjects have an immediate improvement in cognition and more patients are temporarily stabilized. Open-label extension studies suggest continued benefit for several years; decline occurs but function continued above anticipated non-treatment levels [8].
The most common adverse reactions are cholinergic related gastrointestinal side effects, including nausea, vomiting, and diarrhea. These side effects can be reduced by increasing the dose titration duration, by giving the medication with food, or reducing the dose.
Donepezil
Donepezil is available in tablets in three strengths (5 mg, 10 mg, and 23 mg) and in orally disintegrating tablets (ODT) in two strengths (5 mg and 10 mg). It is approved by the FDA for treatment of mild, moderate, and severe AD dementia.
Galantamine
Galantamine is available in extended-release capsules in three strengths (8 mg, 16 mg, and 24 mg) and as immediate-release tablets in three strengths (4 mg, 8 mg, and 12 mg). It is also available as a 4 mg/ml oral solution. It is approved for the treatment of mild to moderate AD dementia.
Rivastigmine
Rivastigmine is available as a 24-hour transdermal system (“patch”) in three strengths (4.6 mg, 9.5 mg, and 13.3 mg), in capsules in four strengths (1.5 mg, 3 mg, 4.5 mg, and 6 mg) and is available as a 2 mg/ml oral solution. It is approved for the treatment of mild, moderate, and severe AD dementia and mild and moderate dementia associated with Parkinson’s disease.
Management of cholinesterase inhibitors
Studies comparing the three cholinesterase inhibitors and meta-analyses have generally demonstrated similar levels of efficacy and adverse reactions among the three agents [6, 7, 9]. If therapy with one medication leads to intolerable adverse reactions or appears to be ineffective, it is reasonable to switch to an alternative agent. A prolonged washout period is not necessary, and the new agent should be started at the lowest dosage and titrated up as tolerated [10, 11].
Memantine
Excitotoxicity has been hypothesized to be involved in neurodegenerative processes such as AD. In this pathological process neurons are damaged or killed by excessive stimulation by excitatory neurotransmitters such as glutamate. This occurs when NMDA receptors are persistently activated. Memantine is a low to moderate affinity, non-competitive NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels and blocks excessive NDMA receptor activity [12, 13].
The clinical benefits of memantine have been demonstrated through RCTs of 6 months’ duration. There is a beneficial effect in cognition, ADLs, and behaviors in patients with moderate-to-severe AD dementia, which is its FDA-approved indication [14, 15].
Memantine is available in extended release capsule formulation in four strengths (7 mg, 14 mg, 21 mg, and 28 mg), in tablets in two strengths (5 mg and 10 mg), and is available as a 2 mg/ml oral solution (Table 24.2).
| Tablet and oral solution | Extended release capsule formulation | |
|---|---|---|
| Dosage and titration | Start at 5 mg once daily and increase by 5 mg daily every week at the minimum to maximum dosage of 10 mg twice daily (5 mg daily to 5 mg twice daily to 5 mg and 10 mg separately, and 10 mg twice daily) | Start at 7 mg XR once daily and increase by 7 mg daily every week at the minimum to maximum dosage of 28 mg XR daily |
| Conversion between formulations | Patients taking 10 mg twice daily of memantine tablet could be converted to 28 mg XR formation once daily after the last tablet dose | |
| Elimination half-life | 60–80 hours | |
| Absorption | Could be given with or without food | |
| Most common adverse reactions | Dizziness, confusion, headache, and constipation | Headache, diarrhea, and dizziness |
The principal side effects of memantine are dizziness, headaches, and somnolence.
Combination therapy
Because cholinesterase inhibitors and memantine have different and potentially complementary mechanisms of action, combination therapy of the two agents has been advocated. RCTs and meta-analysis have demonstrated benefits of combination therapy in cognition, ADLs, behavior, and global change in patients with moderate-to-severe AD dementia. Safety profile and tolerability are generally good [16–19]. In the studies, memantine is usually added to cholinesterase inhibitor after the patient has been on treatment with a ChEI for at least 6 months with a stable dosing regimen for at least 3 months. The trigger for complementary combination therapy is usually decline of a patient on monotherapy.
Medical foods
The term medical food, as defined in section 5(b) of the Orphan Drug Act (21 U.S.C. 360ee (b) [3]) is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” Medical foods must have constituents generally recognized as safe (GRAS) but do not have to undergo approval by FDA. Medical foods are also exempted from the labeling requirements for health claims and nutrient content claims under the Nutrition Labeling and Education Act of 1990 (see 21 U.S.C. 343 (q) [5] (A) (iv)). Currently there are three medical foods available to address the metabolic and nutritional needs of AD: Axona, CerefolinNAC, and Souvenaid (Table 24.3). Souvenaid is available in Europe and not in the USA.
Axona (caprylic triglyceride)
One of the metabolic signatures of AD is the progressive reduction of cerebral glucose metabolism in posterior cingulate, parietal, and temporal regions as measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) studies [20]. Axona is a proprietary formulation of caprylic triglyceride, a medium chain fatty acid. It is converted by the liver into ketone bodies, which is theorized to provide an alternative energy source for the brains of AD patients that are not able to utilize glucose efficiently [21].
A 3-month long Phase II RCT was carried out to assess the efficacy of Axona in patients with mild-to-moderate AD [22]. The study demonstrated statistically significant difference in cognition on Day 45 but not on Day 90. After the results were stratified by APOE4 (epsilon 4 variant of the apolipoprotein E gene) carrier status, statistically significant differences in cognition were observed on both Day 45 and Day 90 for those patients who do not possess APOE4. No significant difference in global change was observed. The most common adverse reaction was diarrhea; titration reduces the risk of occurrence of diarrhea.
CerefolinNAC
An elevated level of homocysteine has been associated with the development of AD and memory impairment in observational studies [23]. In addition, hyperhomocysteinemia has been shown to impair DNA repair in hippocampal neurons, to sensitize them to amyloid toxicity, and to increase β-amyloid by enhancing expression of γ-secretase in animal models of AD [24, 25].
Oxidative stress reflects an imbalance between the production of reactive oxidative species (ROS) and the antioxidant system that detoxifies ROS. Oxidative imbalance has been implicated in the pathogenesis of AD [26]. Levels of glutathione, which is part of the antioxidant system, have been observed to be decreased in AD [27].
The active ingredients of CerefolinNAC consist of methylcobalamine, L-methylfolate, and N-acetylcysteine. Methylcobalamine and L-methylfolate are proposed to decrease the level of homocysteine while N-acetylcystiene increases the level of glutathione.
The efficacy of CerefolinNAC has not been demonstrated by RCTs. There are open-label and case studies that have shown ingredients of CerefolinNAC to be beneficial in AD [28]. A recent RCT demonstrated clinical benefits and slowing of the rate of cerebral atrophy in patients with mild cognitive impairment treated with B vitamins over a 2-year period [29, 30].
Souvenaid
Synaptic loss is considered to be one of the important pathological features of AD because of its close correlation with onset of memory loss [31]. Souvenaid contains a patented combination of nutrients which includes omega-3 fatty acids, choline, uridine monophosphate, and a mixture of antioxidants and B vitamins. This mixture is theorized to restore synaptic function by providing rate-limiting precursors for membrane phospholipid synthesis, increasing levels of synaptic proteins, and promoting formation of dendritic spines [32, 33].
The results of two RCTs designed to assess the efficacy of Souvenaid in patients with mild AD have been published [34, 35]. The first trial was a 12-week trial with optional 12-week extension. The study demonstrated statistically significant improvement in delayed recall of verbal memory but no differences in ADL, behavior, or global change (the trial was not powered to show differences in these outcomes). The second trial was 24 weeks long and demonstrated significant increase in memory domain score of a neuropsychological test battery. The study also included functional status and electroencephalogram (EEG), which was used as a marker of synaptic connectivity, as secondary outcomes. There was no difference in functional status, but EEG delta bands were significantly different, suggesting that the treatment group had improved connectivity.
Implementing treatment with medical foods
Medical foods represent an “add on” alternative to standard therapy with ChEI and memantine. They are usually used in patients who are declining on standard pharmacotherapy. Side effect monitoring is important to enhance treatment adherence and patient safety.
Emerging therapies
Many drugs are currently in development for Alzheimer’s disease treatment. Approximately 100 agents are currently in clinical trials [36]. The drug development for Alzheimer’s disease includes agents with symptomatic effects, disease-modifying agents aimed at amyloid beta (Aβ), tau, and neuroprotection; metabolic disorders within the AD brain; and regenerative strategies including growth factors and stem cells [37, 38, 39].
Symptomatic agents
Symptomatic agents aim to improve cognitive decline in patients with AD without modifying the underlying pathophysiology that leads to cell death. The developmental pathway for clinical trials of symptomatic agents is well understood because of the success of cholinesterase inhibitors and memantine. The trials can be relatively short (6 months in duration); the metrics of the commonly used clinical trial instruments are well understood for symptomatic trials; no biomarker is required as an outcome measure; and regulatory authorities are experienced with this class of agents. All of these observations facilitate drug development of symptomatic agents. A variety of types of drugs with symptomatic effects are currently being studied. This includes nicotinic agents, adrenergic receptor antagonists, histaminergic antagonists, 5HT-6 antagonists, cannabinoid antagonists, phosphodiesterase inhibitors, and sigma receptor agonists. Alpha-7 nicotinic receptor agonists are progressing in clinical trials and appear to be promising in terms of producing symptomatic benefit [40]. Likewise, serotonergic 5HT-6 receptor antagonists have shown symptomatic benefit in phase 2 trials in AD and are being tested in confirmatory trials [41]. Histaminergic agents have been little explored in AD and also appear to have promising effects on apathy and cognition in early phase trials [42]. It is likely that given the time frames involved, new symptomatic agents for the treatment of AD may emerge prior to successful development of disease-modifying therapies.
Metabolic agents
Agents that a effect metabolic conditions are also being explored in patients with AD. These include anti-diabetic drugs and ketonurgic agents. Anti-diabetic agents including PPAR-gamma agonists and GLP-1 analogs as well as insulin are all in various stages of development for treatment of AD [43]. The brain of the patient with AD is insulin resistant and drugs that reduce insulin resistance, improve insulin availability, and enhance glucose utilization may prove to have therapeutic benefit. Ketonurgic agents such as caprylic triglyceride promote ketonuria and propose to provide an alternate energy source for neurons compromised in glucose utilization. Caprylic triglyceride is available as a medical food and is being tested in clinical trials as a drug treatment for AD.
Disease-modifying agents
Most of the current effort in AD drug development is in the area of disease modification. Disease modification trials are 12–24 months in duration, require large populations to show an altered trajectory of a slowly progressive disease, and typically involve biomarkers to support the occurrence of disease modification. No biomarkers predictive of a treatment effect have been developed and the role of biomarkers in disease modifying clinical trials is evolving. Disease-modifying agents may be directed at Aβ targets, tau protein-related targets or neuroprotection [37, 38, 39]. Among the targets for amyloid-related therapies are amyloid precursor protein (APP) synthesis reduction, beta-secretase inhibition, gamma secretase inhibition, gamma secretase modulation, alpha secretase enhancement, Aβ metabolism, Aβ aggregation inhibition, apolipoprotein-E (apoE) over-expression, blood–brain barrier agents reducing the entry of Aβ into the brain or enhancing its exit, and Aβ-related immunotherapies (Table 24.4). Some drug development programs such as those for gamma secretase inhibitors have been terminated because of substantial, unacceptable side effects. Immunotherapy approaches are robustly represented in AD drug development pipelines [44, 45]. Active vaccinations and passive immunotherapy are both under investigation. Bapineuzumab, one of the leading monoclonal antibodies, showed no drug–placebo difference and development has been discontinued. Solanezumab had a negative phase 2 trial but a possible effect on mild patients and further development is being pursued. Gantenerumab and crenezumab are being tested in both symptomatic populations and in autosomal dominant families. IVIg, a polyclonal antibody, produced no drug–placebo difference in a phase 2 trial and further development has been suspended. Active vaccination programs include both intramuscular and subcutaneous vaccines to stimulate production of endogenous antibodies to combat AD.
| Amyloid-related mechanism | Representative agent |
|---|---|
| Amyloid precursor protein decrease | Posiphen |
| Beta-secretase inhibition | MK-8931 |
| Gamma-secretase inhibition | Semagacestat, avagacestat |
| Alpha-secretase enhancement | EHT-0202 |
| Amyloid degradation | Neprilysin enhancers; insulin degrading enzyme enhancers |
| Aggregation inhibition | PBT-2; ELND005 |
| Amyloid removal | Solanezumab, crenezumab, gantenerumab |
| Receptor of advanced glycation end products inhibition (decrease BBB transport into brain) | PF-04494700 |
| Apoliprotein lipidation (enhances amyloid removal across the BBB) | Bexarotene |
BBB = blood–brain barrier.
Tau-related therapies are also in development and are aimed at a variety of tau-related targets. Tau therapeutics target kinases such as GSK3-beta, tau aggregation, microtubule stabilization, autophagy enhancement, and neuroprotection. Some drugs such as the neuroactive peptide AL108 have been tested in a trial for supranuclear palsy and shown to be without benefit. Further development of this agent has been terminated [46].
Neuroprotective agents are also promising as a means of intervening in cell death pathways. Neuroprotective agents include anti-inflammatory drugs, polyphenols, propargylamine agents, and monoamine oxidase inhibitors [47, 48]. Microglial modulators and statins are also being developed as possible neuroprotective agents.
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