Symptomatic treatment

Based on the known neurochemical derangements in AD, two classes of medication have been approved for treatment of cognitive symptoms: cholinesterase inhibitors, including donepezil, galantamine, and rivastigmine, and an N-methyl-d-aspartate (NMDA) receptor antagonist, memantine (Table 8.3). Cholinesterase inhibition is predicted to enhance cholinergic transmission, which is recognized as deficient because of basal forebrain AD pathology. These agents have demonstrated modest effects on cognition, activities of daily living, and global function versus placebo in a large number of randomized, double-blind trials [164], with efficacy demonstrated for up to 2 to 5 years [165, 166]. Rivastigmine differs from the other cholinesterase inhibitors in its inhibition of butyl-cholinesterase and its non-hepatic metabolism [167]. Galantamine also modulates presynaptic nicotinic receptors [168]. The clinical significance of these and other pharmacodynamic differences is unknown, as there is no evidence suggesting that the agents differ in efficacy [164]. Medication side effects are generally mild and may be limited with a gradual titration to the recommended dosage. Commonly reported complaints include gastrointestinal symptoms, which are limited if medication is taken with food, and insomnia or vivid dreams, which may be reduced with a morning dosing schedule. Other less common side effects include leg cramps and symptomatic bradycardia. The latter may prompt a baseline electrocardiogram before initiation of cholinesterase inhibition in a patient with cardiovascular risk factors. These medications are recommended as standard therapy for AD by the AAN [169]. Internationally, there may be less enthusiasm for continuing therapy without demonstrable benefit [170].

Memantine is a non-competitive NMDA-receptor antagonist thought to protect neurons from excitotoxicity associated with glutamatergic activity. Its precise mechanism of action in AD is not clearly defined; however, the glutamate transporter is known to be downregulated in AD, leading to changes in β-amyloid and tau burden [171–173]. Clinical trials of memantine in AD suggest improvement in cognition, behavior, and activities of daily living in moderate to severe disease [174]. Furthermore, added benefit was observed when used in combination with cholinesterase inhibition [175]. The medication is well tolerated with a side effect profile similar to placebo in randomized studies and is currently approved by the FDA for use in moderate to severe AD.

The treatment of commonly encountered behavioral signs and symptoms is paramount in AD. Strategies to adequately manage depression, anxiety, sleep disturbances, and psychosis continue to evolve, but these symptoms remain a considerable challenge for caregivers, in the home, and in the medical community.

Depression is common in AD, and several placebo-controlled treatment trials have demonstrated mixed results with both selective serotonin-reuptake inhibitors (SSRIs) and tricyclic antidepressants [176, 177]. As a result of the anticholinergic side effect profile of the tricyclic antidepressants, SSRIs (including those with combination noradrenergic–reuptake inhibitor activity) are chosen by many clinicians. In patients with AD, anxiety often manifests as a fear of being left unattended, a symptom that may also respond to SSRIs. Alternative anxiolytics such as benzodiazepines are less attractive candidates for long-term management because of their cognitive side effects. Sleep disturbance may also respond to atypical antidepressant medications such as mirtazapine and trazadone [100, 178].

Psychotic symptoms associated with AD include hallucinations, delusions, and agitation/aggression. It is important to rule out delirium as a result of a common medical illness, such as a urinary tract infection, as a mimicker of dementia-related psychosis. If pharmacotherapy is needed to treat psychotic symptoms, then most clinicians prefer newer generation antipsychotic medications [179], although this practice is not approved by the FDA. A double-blind, placebo-controlled trial observed only a small difference in perceived change in patients with AD-related psychosis treated with second-generation antipsychotic medications, such as olanzepine, quetiapine, and risperidone, when compared with placebo. This coupled with a black box warning label requirement from the FDA, suggesting increased mortality associated with these medications, led investigators to conclude that, “Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease”[180]. Unfortunately, clinicians have limited options in treating psychotic symptoms, as more traditional antipsychotic medications, such as haloperidol, are known to produce or exacerbate parkinsonism and may be more likely than newer antipsychotic drugs to increase mortality [181]. Notably, neuropsychiatric symptoms may respond to initiation of cholinesterase inhibition, memantine, or a combination of these approved AD medications [182].

Following a diagnosis of AD, interventions that are non-pharmacological will likely be required, emphasizing patient and caregiver safety. One issue that may dramatically change the lifestyle of a patient with AD is restriction or revocation of driving privileges. Current physician reporting standards vary by US state and country, and assorted medical governing bodies have determined different standards, as well [183, 184]. For example, the AAN recommends that patients with a functional measure signifying mild to moderate dementia with memory predominance be encouraged to discontinue driving, particularly when other potential risk factors, such as caregiver report of unsafe driving, history of crashes or citations, limited driving exposure due to situational or avoidance factors, and impulsivity or aggression, coexist [183]. While the up to eight-fold increase in collisions involving patients with AD who continue to operate a motor vehicle [185] must be addressed as a public health concern, current predictors of driver fitness, including on road driver assessments, may be inadequate and warrant further study [186, 187].

Investigational treatments

Currently available interventions improve symptoms associated with AD, but strategies to halt disease progression or prevent disease development are the major candidates for effecting change on the natural history and epidemiology of AD, a uniformly fatal illness with an increasing prevalence worldwide. Several investigational treatments and preventive strategies are currently in clinical trials or development:

Therapeutic targets for disease modification include both β-amyloid and tau.

Several approaches to modify the pathogenicity of β-amyloid have been undertaken, from reducing production to reducing aggregation to increasing clearance. Sequential cleavage of APP by β– and γ-secretase generate β-amyloid, rendering secretase modulators prime targets for drug development. Unfortunately, a multicenter Phase III (clinical) trial of the γ-secretase inhibitor semagacestat was halted due to clinical worsening of participants receiving active drug [188]. Of interest, beta-secretase inhibitors have reduced β-amyloid concentrations in AD transgenic mice [189]. Also in a transgenic mouse model of AD, an α-secretase enhancer, which shifts APP processing toward a non-amyloid generating pathway, has demonstrated efficacy in reducing brain β-amyloid [190].

Active immunization with a vaccine of pre-aggregated Aβ-42, hypothesized to induce an efflux of β-amyloid from the brain by activity of antibodies in the periphery or the activation of microglial clearance of plaques by antibody activity in the central nervous system [191, 192], was halted in a Phase II trial as a result of the development of presumably T-cell-mediated encephalitis [193]. Passive immunization remains a potential therapy for reducing amyloid burden. Failure to meet clinical and functional endpoints in recent Phase III trials of two such agents has prompted another Phase III trial of solanezumab with intervention at a milder clinical stage in only amyloid biomarker-positive subjects [194, 195]. Several small molecules that interfere with β-amyloid aggregation via different mechanisms are also at various stages of investigation.

Tau pathology represents another target for drug design, with molecules interfering with tau phosphorylation under preclinical investigation [84]; however, redundancy in tau kinases may render a single molecule clinically ineffective. Lithium, a known inhibitor of tau phosphorylation [196], has been explored for the treatment of AD, although side effects in an elderly patient population could be prohibitive.

Other therapeutic interventions currently under investigation are largely based on observational data, which are often difficult to reproduce with prospective study. Anti-inflammatory agents have been recognized to reduce risk of AD in epidemiological studies, [197, 198]; yet both steroids and non-steroidal anti-inflammatory drugs (NSAIDs), including flurbiprofen, have demonstrated no effect on cognitive outcomes in AD clinical trials so far [199, 200]. Estrogen replacement therapy in postmenopausal women was also associated with reduced risk for AD in epidemiological studies [201], although clinical trials have not supported the use of estrogen for AD risk reduction [202].

Antioxidants, including vitamins E and C, may reduce the risk of AD according to large observational studies [203], and recent treatment trials with vitamin E have yielded promising results [204]; however, evidence that high-dose vitamin E may increase cardiac risks [205] has tempered enthusiasm for supplementation above 400 IU daily. Also promising, B vitamins (folic acid, B6, B12) have been reported to slow brain atrophy in patients at risk for developing AD with high homocysteine levels [206].

Novel naturopathic intervention strategies, such as huperzine A, may show marginal benefit in the treatment of AD via multiple mechanisms [100] and warrant further investigation. Ginkgo biloba, a more commonly used naturopathic supplement, did not impact incidence of AD in normal elders or patients with MCI in a large clinical trial [207].