Current and Emerging Drug Treatment Options for Alzheimer’s Disease
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Alzheimer’s disease (AD) is a progressive and ultimately fatal condition that causes debilitating memory loss and extensive deterioration of cognitive and functional abilities. Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. These therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability. The search for disease-modifying interventions has focused largely on compounds targeting the amyloid-β pathway. To date, the treatments targeting this pathway, such as tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in clinical stages of testing. At this point, it is likely that not only amyloid-β aggregation but other possible neuronal mechanisms — such as hyperphosphorylated tau, neuro-inflammation and other processes — play important roles in the pathophysiology of this multifactorial disorder. Development of better disease models and biomarkers is essential for the advancement of knowledge of the disease mechanisms. This systematic review critically examines the efficacy and safety data for currently approved drugs and emerging treatments in AD, as well as discussing the present and future directions of innovation in this field.
Alzheimer’s disease (AD) is the most common form of dementia and neurodegenerative disorder.[1,2] It has reached epidemic proportions in developed countries and is expected to rise due to growth in aging populations. The worldwide prevalence of dementia in 2006 was over 25 million, and epidemiologists forecast this number to reach over 80 million by 2040, fostering increased concern about the future social and economic burden. AD and other dementias are currently the sixth highest cause of death in the US, generating an annual cost of $US183 billion (in 2011 dollars) to the US economy.[1,5] AD is devastating to patients and their families due to the irreversible and progressive nature of the disease. Although the expression of symptoms is heterogeneous in affected individuals, a progressive decline in memory and reasoning is characteristic of the condition. Symptoms often begin as minor difficulties with recalling new information, and evolve into a gradual deterioration of memory and spatial orientation, along with increasing disability in daily function and changes in personality, mood and behaviour.[1,6] In the final stages of the disease, occurring roughly a decade after diagnosis, many patients lose basic functions such as motor control and are completely dependent on caregivers, which often leads to institutionalization.[7,8]
At present, there are no available therapeutic interventions that halt or reverse disease progression. Five medications are approved for treatment of AD in North America and most countries in Europe: memantine (an NMDA receptor antagonist) and four cholinesterase inhibitors (ChEIs): tacrine, donepezil, galantamine and rivastigmine. Tacrine was approved for use by the US FDA in 1993, but it is rarely used due to risks of significant hepatotoxicity[9, 10, 11] and contentious efficacy. Because of the risk of serious adverse effects, it was never made available in numerous countries, such as Canada, and thus are not further discussed in this review. Donepezil is indicated for all stages of AD in North America and for mild to moderately severe AD in numerous countries in Europe. Rivastigmine and galantamine are indicated for mild to moderate AD. In contrast, memantine has been approved for moderate to severe stages of AD. The medications currently in use principally ameliorate symptoms, and have been shown to have modest, but significant, therapeutic effects on global function, cognition and activities of daily living (ADL). There is, however, little evidence to indicate that any of the available drugs is more effective than the rest. In a review and pooled analysis, one group concluded that the three ChEIs had comparable efficacy on cognition and global measures.[15,16] Similarly, a recent comparative randomized controlled trial (RCT) in 63 patients with mild to moderate AD demonstrated that there were no significant differences on clinical scales between memantine-treated and donepezil-treated patients. These two treatment groups also demonstrated similar metabolite levels, including N-acetyl-aspartate, a surrogate marker of neuronal density.
None of the presently available medications target the pathways that currently dominate the proposed aetiopathology of AD. The modest symptomatic benefits of the approved drugs underscore the need for disease-modifying therapies. The amyloid and tau hypotheses have emerged as leading theories, accounting for the manifestation of regional neurodegeneration and consequent cognitive decline and neuropsychiatric disturbances. These theories are based on observations of protein aggregate formation in the brains of AD patients.[18,19] The complexities of these pathways have yet to be completely unravelled and their roles in disease trajectory, as well as their therapeutic values, are not well understood. Nonetheless, a number of drugs currently in the clinical phases of testing are aimed at regulating targets within these two pathways. The most popular current focus is on development of drugs targeting amyloid-β (Aβ) proteins. However, other disease-modifying approaches such as interventions aimed at tau pathology, as well as pathways of neuroinflammation, mitochondrial dysfunction and neuroprotection, are all viable strategies currently under investigation. Though many disease-modifying treatments are under investigation (see section 3), none are currently approved for AD. The purpose of this review is to summarize the existing information on the efficacy and safety of available and emergent therapeutic interventions for AD by critically examining the course of past research. We also discuss possible directions for future studies and highlight the necessity for long-term trials, novel disease models and more effective biomarkers.
1.1 Search Criteria
Two independent reviewers systematically searched electronic databases and commercial websites for published and unpublished studies, applied inclusion and exclusion criteria, and performed quality appraisals. The databases searched include PubMed, MEDLINE, EMBASE, PsycINFO, Web of Science, the Cochrane Library and the controlled trials registry clinicaltrials.gov. A manual search from the reference lists of relevant articles was conducted and pharmaceutical companies were contacted when further information on trial outcomes was necessary.
The following search terms were used either independently of each other or in combination: ‘Alzheimer’s disease’, ‘treatment’, ‘cholinesterase inhibitors’, ‘meta-analysis’, ‘donepezil’, ‘rivastigmine’, ‘galantamine’, ‘memantine’, ‘cerebrolysin’, ‘long-term safety’, ‘observational studies’, ‘amyloid hypothesis’, ‘beta-secretase inhibition (rosiglitazone)’, ‘gamma-secretase inhibition (semagacestat)’, ‘NSAIDs (rofecoxib, indomethacin, tarenflurbil)’, ‘statins (atorvastatin, simvastatin)’, ‘tramiprosate’, ‘epigallocatechin gallate (EGCg)’, ‘bapineuzumab’, ‘solanezumab’, ‘intravenous immunoglobulin’, ‘tau hypothesis’, ‘methylene blue’, ‘dimebon’ and ‘omega-3 fatty acids’.
1.2 Inclusion/Exclusion Criteria
Eligible studies were required to report results on adults diagnosed with AD on the basis of validated diagnostic criteria including the Diagnostic and Statistical Manual of Mental Disorders 4th edition, the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association, and the International Classification of Diseases. Findings in patients diagnosed with mixed dementia, vascular dementia, dementia with Lewy Bodies or Parkinson’s dementia were not included. Furthermore, inclusion limits required journal articles to have been published between January 1995 and June 2011, to ensure the inclusion of all relevant publications since the approval of the second-generation ChEIs. All articles were required to be complete and available in English.
As the ChEIs and memantine have been in clinical use for the treatment of AD for a number of years and have been extensively investigated, we focused on meta-analyses in the review of the efficacy of these drugs. Large-scale RCTs may not be representative of real-life clinical settings due to a short duration and strict enrolment criteria. Therefore, observational studies such as case control, as well as prospective and retrospective cohort studies, were used to appraise the safety profiles of ChEIs and memantine. For compounds that are still in pre-regulatory approval phases of clinical testing, RCTs assessing efficacy were evaluated.
1.3 Quality Appraisal
2. Available Therapies
2.1 Cholinesterase Inhibitors
One of the major neurotransmitters found at the synaptic cleft within the memory-associated regions of the brain is acetylcholine. In the pathophysiology of AD, there is an excessive loss of cholinergic neurons in the basal forebrain, resulting in pathologically low levels of cholinergic transmission. The extent of cholinergic loss is associated with the degree of cognitive impairment and density of amyloid plaques.[26,27] There are also decreased levels of the acetylcholine-synthesizing enzyme, choline acetyltransferase, in the hippocampus and cortex. Current therapeutic agents for AD seek to improve cognitive function through regulation of the cholinergic system via modulation of acetylcholinesterase, a major enzyme that hydrolyzes acetylcholine within the brain. ChEIs elevate levels of acetylcholine in the synaptic cleft by blocking the hydrolyzing activity of acetylcholinesterase, thereby improving central cholinergic transmission. This is thought to improve cognition, as well as overall functioning and behaviour in patients with AD.
While all available ChEIs are thought to work primarily based on their ability to inhibit acetylcholinesterase, other mechanisms have been described. One particular study emphasized the potential ability of ChEIs to influence the expression of various isoforms of acetylcholine, increase expression of nicotinic acetylcholine receptors, mediate amyloid precursor protein (APP) processing and attenuate Aβ-induced toxicity, as these actions have been shown to be associated with cognitive improvement in AD patients. That study suggests that ChEIs do possess some degree of disease-modifying abilities, but are being used too late within the disease trajectory.
Another ChEI that is becoming increasingly considered as a possible treatment for AD is huperzine A. This Chinese club moss derivative is a linearly competitive and reversible inhibitor of acetylcholinesterase. It is thought to have protective properties against Aβ protein or peptide, glutamate toxicity, ischaemia and even hydrogen peroxide- and staurosporine-induced toxicity. A review published by the Cochrane Collaboration in 2008 concluded that this agent has shown some benefits for cognition, global status, function and behavioural symptoms, but that this evidence is inconclusive due to the weak methodology and small sample sizes employed in the trials conducted. The results of a phase II trial in 210 patients with mild to moderate AD were published in 2011. Huperzine A 200 μg twice daily did not substantially affect the Alzheimer’s Disease Assessment Scale — cognitive subscale (ADAS-cog) scores at 16 weeks. The secondary analyses revealed a statistically significant effect of the 400 μg twice daily dosage on cognition at 11 and 16 weeks, but no effects on the Clinical Global Impression of Change (CGI-C), ADL or behaviour. Huperzine A is approved in China for mild to moderate AD, but is not available in the US, Canada or any countries within the EU. It is therefore not discussed further in this review. The currently approved medications for treatment of AD are discussed in the following sections.
Donepezil, marketed by Eisai Pharmaceuticals and Pfizer, Inc., first gained approval from the FDA for mild to moderate AD in 1996; its indication was amended to include severe AD in 2006.[34,35] Conventional 5 mg and 10 mg immediate-release tablets of donepezil are available, to be taken with or without food. A 23 mg sustained-release tablet formulation of donepezil was recently approved based on the results of an international RCT of 1371 patients.[37,38] This study compared donepezil 23 mg/day sustained-release with the conventional 10 mg/day immediate-release form and found that the sustained-release treatment resulted in improved cognition in moderate to severe AD patients.
This second-generation ChEI binds to acetylcholinesterase in a reversible and non-competitive manner and is subsequently hydrolyzed in place of acetylcholine. It is potent and highly selective for acetylcholinesterase, as opposed to butyrylcholinesterase, which is present at higher levels peripherally than within the CNS. Donepezil can be administered once daily due to its limited peripheral anticholinesterase activity and its intrinsically long plasma half-life. There is some evidence indicating that donepezil protects cortical neurons against glutamate toxicity, prevents apoptotic cell death, increases expression of nicotinic receptors and decreases Aβ production and Aβ-induced toxicity.[25,40]
Another analysis by Ritchie et al. examined the effects of dose on completion rates, in addition to clinical outcomes, such as cognitive measures (ADAS-cog and MMSE) and global measures (CIBIC-Plus, CDR-SB, CGI-C and Global Deterioration Scale [GDS]). Of the nine papers included, most used daily doses of 5 mg or 5–10 mg, with only one study examining 3–5 mg. It was noted that the magnitude of the effect was dose dependent, with 10 mg producing increased benefit compared with 5 mg. This dose-dependent effect was not apparent on global outcomes, although donepezil-treated patients were more likely to improve than placebo-treated patients.
The American College of Physicians published a clinical guideline for the treatment of AD, where the effects of donepezil 5–10 mg/day were measured on cognitive and global domains, as well as behaviour. The effect on the cognition of patients of all severities, as assessed by the ADAS-cog, MMSE and SIB, was statistically significant compared with placebo, and there was no evidence of heterogeneity, with the exception of MMSE scores. In terms of global status, the donepezil-treated patients were more likely to improve or stabilize than placebo-treated patients. Effects on behaviour were also statistically significant.
A review published in 2008 also concluded that the effects of donepezil 5 mg and 10 mg treatment were beneficial on the four outcome domains mentioned above. In addition, that meta-analysis discussed two open-label, head-to-head comparative trials in mild to moderate AD comparing the effects of donepezil with galantamine. The first trial lasted 52 weeks and found no significant differences on cognition, function and behaviour, whereas the second trial, lasting 12 weeks, uncovered a significant difference favouring donepezil on cognition and function. Flexible doses of donepezil and rivastigmine were also compared in one 2-year, double-blind RCT and one 12-week open-label trial. The results of the 2-year trial indicated that there were no discernible differences in cognition and behaviour, but that rivastigmine-treated patients exhibited better function and global status. However, there were more premature discontinuations in the rivastigmine group than in the donepezil group during the 16-week titration period (18.8% and 9.2%, respectively). The shorter trial examined cognition only, which was not substantially different between the two drugs. In general, direct-comparison RCTs with a sufficient number of subjects and a duration of at least 6 months offer the most convincing evidence of comparative efficacy.
It is also important to highlight the results of the controversial AD2000 study (see table II), a 2-year RCT of long-term donepezil treatment in 565 patients with AD. Donepezil produced significant benefit in cognition and function over placebo, as is consistent with the majority of published findings. However, significance was not demonstrated on the primary outcomes, progression to disability (loss of two basic or six instrumental ADL) and nursing home admission rates. There were also no significant differences in behavioural and psychological symptoms, formal care costs, unpaid caregiver time, adverse events/deaths or carer psychopathology.
Numerous commentaries[60, 61, 62, 63, 64, 65, 66] on the AD2000 trial have emphasized substantial methodological limitations in the study design. The initial recruitment goal called for 3000 patients over 2–3 years, but due to recruitment problems only 565 patients were enrolled, leading many to believe that the study was underpowered. Additional concerns included patient selection (based on the uncertainty of drug benefit), a high attrition rate, contentious outcomes, submaximal dosing and multiple washout periods.
One commentary pointed out the AD2000 trial recruited more ‘typical’ community-dwelling patients, referred from memory clinics by physicians who were uncertain whether the patient would benefit from donepezil therapy. Despite its shortcomings, this trial managed to confirm the cognitive and functional benefits of donepezil therapy beyond the span of 1 year and to show that discontinuing donepezil treatment for short periods of time did not provoke an irreversible decline.
Taken as a whole, this evidence indicates that donepezil modestly improves cognitive function in AD patients in a dose-dependent manner. This ChEI also increases the likelihood of global improvement, but its effects on behaviour are still inconsistent and necessitate further research on the matter.[67,69]
Rivastigmine is approved in all countries in the EU, Canada and the US. The inhibitory effect of rivastigmine on acetylcholinesterase is termed ‘pseudo-irreversible’ due to its persistent action, long after plasma concentrations of the drug have declined. The carbamyl moiety of rivastigmine remains bound to its substrate after the acetyl moiety dissociates via hydrolysis, resulting in inactivation of the acetylcholinesterase enzyme for more than 24 hours. Rivastigmine exhibits selectivity for predominant forms of acetylcholinesterase, but is also known to inhibit butyrylcholinesterase. There is some agreement that changes in butyrylcholinesterase are associated with the progression of AD. One study demonstrated that the level of butyrylcholinesterase increases, as that of acetylcholinesterase decreases, in affected areas of the brain. The activity of this enzyme in the temporal cortex has also been shown to correlate with the rate of cognitive decline. Furthermore, rivastigmine may affect cerebral blood flow levels, which is a known risk factor for AD.[71,72]
Rivastigmine is not significantly metabolized by cytochrome P450s, nor is it considerably bound to plasma proteins; therefore, no relevant drug-drug interactions are anticipated. The oral formulation is generally taken twice daily with food at a dosage of 1–4 mg/day or 6–12 mg/day. A once-daily transdermal patch was approved by the FDA in 2007 and is thought to potentially improve compliance in elderly patients who receive multiple drugs daily.[74,75]
A review conducted by the Cochrane Collaboration investigated the effects of high- and low-dose rivastigmine on the full range of AD severity. High-dose treatment (6–12 mg daily) generated a 2-point improvement in cognition measured by the ADAS-cog and a 2.2 point improvement in function on the Progressive Deterioration Scale (PDS) at 26 weeks. Low-dose treatment (1–4 mg daily) also produced improvements, but these were only significant for cognition. There were global improvements associated with both high- and low-dose rivastigmine treatment on the CIBIC-Plus and Alzheimer’s Disease Cooperative Study — Clinical Global Impression of Change (ADCS-CGIC); however, benefits on the GDS were observed exclusively with high doses. Only two studies included the Neuropsychiatric Inventory (NPI) as an outcome measure and rivastigmine treatment was not found to be better than placebo for behavioural disturbances. This review also included the results of the IDEAL study, which compared the effects of a once-daily, small (9.5 mg/day) transdermal rivastigmine patch with a large patch (17.4 mg/day) and oral rivastigmine capsules (6–12 mg/day). There were no differences between the small transdermal patch (mean exposure 9.8 mg/day) and oral rivastigmine (mean exposure 9.7 mg/day) on cognition (ADAS-cog, MMSE), function (ADCS-ADL), behaviour (NPI) or global impression of change (ADCS-CGIC). Similarly, there were no significant differences between the large transdermal rivastigmine patch (mean exposure 16.5 mg/day) and the small one on the same outcomes.
Another analysis by Ritchie et al. demonstrated that rivastigmine has significant effects on both cognition, as measured by the ADAS-cog, and global status, as measured by the CIBIC-Plus and CGI scales. The dose range administered in the five trials included in this analysis was 1–12 mg, with signs of a dose-dependent effect on cognition. Just one study reported the effects of rivastigmine on global outcome measures; treatment was favoured on the CIBIC-Plus, but no dose-dependent relationship was demonstrated.
Raina et al. assembled the evidence from six studies to assess the effects of rivastigmine on cognitive (ADAS-cog, MMSE), global (CIBIC-Plus, GDS) and functional (PDS, Nurses’ Observation Scale for Geriatric Patients [NOSGER]) outcomes. The duration of trials ranged from 14 to 48 weeks and included patients of all severities, randomized to either rivastigmine 1–12 mg or placebo. Results pertaining to cognitive outcomes were inconsistent; significant benefits were measured on the ADAS-cog (with heterogeneity), whereas non-significant outcomes were detected on the MMSE and the SIB. Treatment with rivastigmine appeared to produce improvements in global status, with no evidence of heterogeneity. However, the advantage of rivastigmine for functional ability was inconsistent; a non-significant effect was observed on the PDS while a significant benefit was identified on the NOSGER.
The meta-analysis by Hansen et al. included three trials comparing rivastigmine (6–12 mg/day) with placebo for 13–26 weeks — two of these trials were also used in the Raina et al. meta-analysis. Active treatment had a modest benefit in measures of cognition (ADAS-cog), function (PDS, NOSGER) and global assessment of change (CIBIC-Plus).
On the whole, this research suggests that rivastigmine exhibits a dose-dependent effect, with the higher dose range providing benefits on cognitive, functional and global domains, although one study concluded that the cognitive and functional effects are somewhat inconsistent across trials. Results on behaviour were not found to be significant.
Galantamine, a tertiary alkaloid, was first approved in 2001 by the FDA and is commonly marketed by Janssen, Inc. It is also approved in most countries within the EU. In addition, being a reversible and competitive ChEI, galantamine also allosterically modulates nicotinic acetylcholine receptors to improve nicotinic transmission — another pathway implicated in the pathogenesis of neurodegenerative disorders. It has a low plasma clearance rate of about 300 mL/min, a moderate volume of distribution, low plasma protein binding (18%) and a fairly high bioavailability. Cytochrome P450 (CYP) enzymes (mainly CYP2D6 and CYP3A4) are thought to glucuronidate galantamine and assist in its excretion through urine. Originally, galantamine was available as a twice-daily immediate-release preparation. An extended-release capsule formulation taken once daily is now available (taken with or without food) and shows a similar adverse event profile as the immediate-release form.
A meta-analysis consisting of six RCTs by Ritchie et al. examined the effects of galantamine on cognitive and global function using a dosage range of 8–36 mg/day. The evidence modestly favoured treatment on both cognition (ADAS-cog) and global status (CIBIC-Plus and CGI), but did not demonstrate a substantial dose-dependent effect in either one. Overall, higher odds ratios were achieved for the number of patients showing improvement on the CGI scale.
In another meta-analysis including a total of eight trials, galantamine treatment appeared to produce a significant improvement on the ADAS-cog scores in the six trials that used this scale, although this effect was found to be heterogeneous. Furthermore, galantamine was shown to significantly enhance the relative probability of improvement or stabilization in treated patients, using the CIBIC-Plus. The functional (ADCS-ADL, Disability Assessment for Dementia [DAD]) and behavioural (NPI) scales also demonstrated a beneficial effect.
In an analysis by Loy and Schneider for the Cochrane Collaboration, which included ten studies in AD, statistically significant effect sizes in cognition (ADAS-cog) were achieved at all dose levels of galantamine. These effects were significant at 3 months and even more pronounced at 6 months. Treatment with galantamine also increased the proportion of patients who experienced improvement or no change on global measures compared with placebo at all dosage levels, apart from 8 mg daily. ADCS-ADL, DAD and NPI outcome data were provided in very few trials, but generally reported effects in favour of galantamine.
Hansen et al. combined results from seven placebo-controlled trials of galantamine (16–24 mg/day) with study durations ranging from 12 to 26 weeks. Small improvements were observed in outcomes of cognition (ADAS-cog), function (ADCS-ADL, DAD), behaviour (NPI) and global change (CIBIC-Plus). There were no significant differences in outcomes when different dose ranges were compared.
In general, effect sizes of galantamine treatment across studies were small, but statistically significant for cognitive, global, functional and behavioural domains. A dose-dependent effect was not clearly established.
2.1.4 Pooled Effects of Cholinesterase Inhibitors
In a study by Hansen et al. examining the pooled effects of ChEIs, with a specific focus on functional outcomes, effect sizes showed a small (Cohen’s d = 0.1–0.4) but generally consistent benefit for drug over placebo. The authors discussed the ambiguity of the clinical relevance of such an effect, and contend that clinical-psychological research often yields small effect sizes due to the subtlety of the differences and attenuation of the validity of measures used.
The Cochrane collaboration assessed the efficacy of the three ChEIs in mild to severe AD. A significant average improvement of 2.7 points on the ADAS-cog was achieved with ChEI treatment, as well as an improvement in MMSE scores after 6 months. Rivastigmine trials showed the most variation. Global clinical state was assessed by the CIBIC-Plus scale and demonstrated homogenous improvement after 6 months in terms of the proportion of patients who experienced improvement or no change. ChEIs did display benefit over placebo on the PDS scale, an estimate of ADLs, as well as on behavioural disturbance assessed by the NPI. The authors noted that, although ChEI treatment was favoured on all outcomes, none of these effects were large and the outcomes for severe AD were assessed by only two trials.
Lanctôt et al. quantified the pooled mean global responders and the numbers needed to be treated (NNT) as measures of the efficacy of ChEIs in mild to moderate AD. The proportion of responders to treatment overall, and for each of the individual drugs, was significantly higher than the proportion of responders to placebo. The NNT with ChEIs so that one additional patient could experience a global improvement was 12. This meta-analysis revealed similar proportions of global responders for both low and high doses of ChEIs, although the outcome pertaining to high-dose treatment exhibited unexplained heterogeneity.
One study looked at the pooled effects of donepezil and galantamine on cognitive function in mild to moderate AD patients. Three studies on donepezil and five on galantamine, looking at daily dose ranges of 5–10 mg and 8–36 mg, respectively, were included. Neither drug proved to be more efficacious than the other. It is noted that most of the subjects in both the donepezil and galantamine treatment groups displayed the same deficits in cognitive function as those in the placebo-treated groups, although it is unclear from this article whether the differences were statistically significant. The extent of the clinical benefits of donepezil and galantamine were brought into question by the authors in the discussion, since the effect sizes (Cohen’s d) were small and bordering on low to moderate efficacy of this drug as judged by Cohen’s benchmarks.
Campbell et al. performed a meta-analysis to investigate the management of behavioural and psychological symptoms of dementia (BPSD) by treatment with donepezil, galantamine or rivastigmine. Based on the effect sizes obtained, they concluded that ChEIs are beneficial for the treatment of behavioural disturbances, though more so for mild than for severe AD.
Overall, treatment with ChEI therapy provides modest benefits on cognitive and global status, as well as on function and behaviour. Improvements seem to be more pronounced in mild AD than in severe AD.
It is also valuable to mention a controversial review written by Kaduszkiewicz et al., which examined the effects of ChEI therapy on cognition (ADAS-cog) and global improvement (CIBIC-Plus) using similar inclusion criteria to other systematic reviews. Although moderate differences favouring treatment were noted in this review, it was asserted that the significant methodological flaws of nearly all the trials included greatly overstated the beneficial effects of ChEI therapy. The major methodological shortcomings listed included the use of primary endpoints without correcting for multiple comparisons, missing ITT analyses, use of the LOCF imputation method for missing data and other inappropriate aspects of study design. Ultimately, the authors concluded that the scientific basis for recommending ChEI therapy as the preferred treatment for AD was questionable.
Others have since contested this conclusion, including Herrmann, who noted that Kaduszkiewicz et al. did not statistically combine the results of individual trials, which likely concealed the compelling consistency in the results favouring treatment and the apparent dose-response relationship. In a commentary to the review, Luckmann noted that the authors rightfully emphasized the potential for substantial bias owing to absence of final outcome measures in drop-out patients, but that they overstated the significance of other methodological flaws. According to Luckmann, excluding patients after randomization due to withdrawal of consent would likely not induce bias, and reporting more than one outcome without correcting for multiple comparisons is not as considerable a concern as Kaduszkiewicz et al. suggested it was. Furthermore, Birks responded to this review and opined that multiple comparison corrections should be employed in post hoc analyses, rather than in RCTs where the outcomes are determined before the beginning of the trial. She also noted that it is possible to carry out analyses that estimate the bias resulting from missing endpoint data, and that data from three included trials show that the bias is not considerable.
Memantine is a specific, non-competitive, moderate-affinity NMDA receptor antagonist.[14,83] Over-activity of the NMDA receptor, due to excessive glutamate release, causes an increased entry of calcium ions into the cell, resulting in excitotoxicity and has been linked to memory impairment in AD. The voltage dependency and rapid kinetics of memantine allow for reduced receptor blocking at regular glutamate levels and increased blocking at pathological levels. This is believed to improve both synaptic function and memory, and decrease loss of cognitive function.
This agent was first approved in Europe for moderately severe to severe AD in 2002, but this indication was subsequently amended to include moderate to severe AD in 2005. Approval for marketing was obtained in the US by Forest Laboratories in 2003. It is available in 5 or 10 mg tablets or as an oral solution (2 mg/mL) and can be taken with or without food. Also approved in some countries is a 28 mg extended-release capsule formulation of memantine for once-daily administration.
According to a meta-analysis by Raina et al., memantine significantly improved scores on the SIB for patients with moderate to severe AD compared with placebo; however, these results were based on only two studies, which displayed significant heterogeneity. Memantine also increased the likelihood of improvement on the CIBIC-Plus, for which tests of heterogeneity were not significant. Measures of function (ADSC-ADL) and behaviour (NPI) also favoured treatment. Memantine was shown to be effective in moderate to severe AD and is indicated for this population in countries around the world. This drug was not approved by the FDA in 2005 in the mild to moderate population, in part due to two RCTs demonstrating that it is not significantly superior to placebo on primary and secondary outcomes (MEM-MD-12, LU-99679).
The results of a meta-analysis performed by Doody et al., which combined six RCTs with a 24- to 28-week timeline, appeared contrary to what was found by the majority of previous studies. Three studies included in this meta-analysis dealt with mild to moderate AD (LU-99679, MEM-MD-10, MEM-MD-12) and the other three dealt with moderate to severe AD (MRZ 90001-9605, MEM-MD-01, MEM-MD-02). An effect size was obtained for each of the two groups, as well as for the full range of severity. Memantine was found to be significantly better than placebo on cognition, global status, function and behaviour for moderate to severe AD, with heterogeneity appearing on cognitive evaluations. For mild to moderate AD, memantine demonstrated significantly more benefit than placebo in cognition and global status (both homogeneous effects), but not for function and behaviour. Overall, for mild to severe AD, Doody et al. concluded that effect sizes favoured treatment on cognitive, global and functional, but not behavioural, measures.
Two critical commentaries were subsequently published in response to this analysis.[93,94] The first pointed out that three largely negative trials included in this analysis were unpublished by their respective corporate sponsors (MEM-MD-01, MEM-MD-12 [Forest Laboratories, Inc.] and LU-99679 [H. Lundbeck A/S]) at that time. Two of three trials in the mild to moderate population were negative on their primary outcomes, yet when statistically combined, memantine was found to have significant benefit over placebo. This surprising result may be attributed to a very large number of subjects (>1300) when the trials are combined, which would increase power. In addition to the many considerations concerning the methodology, the second commentary noted that the results of the mild to moderate group and the moderate to severe group should not have been statistically combined to reach the conclusion that memantine is effective across the entire spectrum of AD severity.
A recent meta-analysis of memantine by Schneider et al. concluded that there is no benefit of this drug for patients with mild AD. In moderate AD, small but significant benefits were observed in cognition and global change, but none in function or behaviour. The authors concluded that there is insufficient evidence to support the use of memantine in mild AD, despite its common off-label use in this population.
The Cochrane Collaboration meta-analysis by McShane et al. reviewed the same RCTs as Doody et al. and estimated effects of memantine 20 mg on both mild to moderate and moderate to severe AD separately. In moderate to severe AD, a small beneficial effect of memantine on cognition (SIB), clinical impression of change (CIBIC-Plus), function (ADCS-ADL) and behaviour (NPI) were observed. However, in the mild to moderate sample, a significant effect on cognition was shown, though there was a barely detectable effect on global clinical change. No overall benefits on functional and behavioural outcomes over placebo were demonstrated.
Maidment et al. specifically examined the effect of memantine on symptoms of BPSD. Five RCTs had sufficient NPI outcome data to be included in the analysis. The authors note that, although memantine did produce an overall statistically significant effect size on the NPI, this effect was quite small and the clinical benefit is unclear.
An observed-cases analysis was conducted when combining the results of the six pivotal memantine trials in a meta-analysis by Winblad et al. The LOCF analysis, for which the numerical outcomes are not reported except to say that similar effect sizes were obtained as for the observed-cases analysis, was conducted as part of a sensitivity analysis. Overall, the effect sizes were in favour of memantine on cognitive, global, functional and behavioural domains, with no heterogeneity in the results, except for that of behaviour.
In summary, this body of evidence suggests that memantine treatment provides clinical benefit on cognitive and global function, ADLs and behaviour in the moderate to severe AD population. Treatment of mild to moderate AD with memantine does not generate improvement in function and behaviour, but slightly improves cognitive and global status.
Another non-cholinergic treatment, cerebrolysin, is approved for AD and other dementias in several countries in Europe and Asia. This drug is manufactured from purified brain proteins, enzymatically cleaved to yield active small peptides and single amino acids, which can cross the blood-brain barrier. Its neurotrophic effects, specifically the support and protection of neuronal function, are similar to that of endogenous nerve growth factors, which may play a role in AD pathogenesis. In addition to preservation of neural function and structure under conditions of stress and promotion of neuronal plasticity and differentiation, AD mice models have also shown improved performance in cognitive and memory tasks. However, the mechanisms by which cerebrolysin exerts its therapeutic effect are still unclear. Studies have suggested interactions with inhibitory neurotransmitter receptors (adenosine A1 and GABAB),[100,101] inflammatory pathways, amyloid peptides and neuroprotective proteins such as glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase-5. Cerebrolysin is available intravenously with a recommended dosage of 5–30 mL/day for 10–20 days, after which the dosage should be reduced to two or three times per week. Intramuscular preparations are also available for use at lower doses.
There is one published meta-analysis of cerebrolysin in AD patients (mild to moderate severity). This analysis was based on six double-blind, placebo-controlled RCTs, ranging from 4 to 12 weeks in duration. A total of 772 patients who received intravenous cerebrolysin (usually 30 mL/day, 5 days/week) or matched placebo were included in the analysis. The results indicated no significant effects on the ADAS-cog, nor on any of the scales used to measure ADL (Katz Index of ADL, DAD, Nuremberg Age Inventory). Conversely, CGI-C scores in the cerebrolysin group improved significantly compared with the placebo group. A small but statistically significant effect was observed on the MMSE. Overall, this indicates that cerebrolysin might have some benefits regarding global change and cognition, but further evidence from large-scale RCTs is needed to verify these findings. Furthermore, the relatively small sample sizes in the included trials, ranging from 53 to 178 subjects, is a limiting factor for this analysis.
Active-comparator trials of cerebrolysin have also been performed in patients with mild to moderate AD. One multicentre, double-blind RCT compared the safety and efficacy of cerebrolysin (n = 64), donepezil (n = 66) and a combination of both therapies (n = 67). Cerebrolysin and combination treatment provided benefits on the global domain; however, between-group differences were not significant on the cognitive, functional and behavioural domains. Cognition improved in all groups, but was best in the combination group. This comparative trial suggests that cerebrolysin has similar efficacy to donepezil and that a combination of the two therapies might possess synergistic properties. Additionally, this neurotrophic and cholinergic treatment combination proved to be safe and tolerable.
A smaller, placebo-controlled trial was also conducted in patients with mild to moderate AD: patients received intravenous cerebrolysin 30 mL/day or placebo for 5 days/week for 6 weeks. The treatment group experienced improvements from baseline on all psychometric scales (ADAS-cog, DAD, CIBIC) over the treatment period, which were maintained 12 weeks after cessation of the drug.
In summary, while some RCT data are available to support the use of cerebrolysin in mild to moderate AD, larger placebo-controlled and comparative studies are required to better establish its efficacy and safety, as well as compare its patient acceptance as an intramuscular or intravenous preparation versus available orally administered medications.
2.4 Safety of Available Treatments
Randomized trials provide the strongest evidence of drug effects in a controlled environment. However, in order to achieve homogeneity, large RCTs focused on the evaluation of efficacy and safety use strict enrolment criteria, which exclude many patients in the general AD population. These trials are, therefore, not truly representative of the ‘real-life’ clinical setting in which the approved drugs function. It is thus important to also consider observational studies to achieve a complete understanding of the safety and effectiveness of these drugs. Observational studies such as case-controls, and prospective and retrospective cohorts, can provide information on adverse events (AEs) associated with the ChEIs and memantine in a naturalistic clinical environment incorporating a broader range of typical patients. It is also particularly important to examine long-term studies, as the RCTs for symptomatic treatments described above only provide data for up to a year.
A systematic review by Lockhart et al. integrated results from retrospective and prospective studies on the safety of the three approved ChEIs. In retrospective studies, donepezil and rivastigmine were generally associated with comparable frequencies of total AEs, although one study reported higher incidences in galantamine recipients. Gastrointestinal AEs, including nausea, vomiting, diarrhoea and abdominal cramps, occurred significantly more often in rivastigmine than donepezil treatment groups. Additionally, nausea leading to drug discontinuation was higher with rivastigmine,[110,112] whereas galantamine was more frequently associated with diarrhoea. CNS- and cardiovascular-related AEs had much lower incidences than gastrointestinal AEs and were comparable for all three ChEIs. A case-time-control study using retrospective information from Ontario health databases found that ChEI-treated patients were at a higher (more than 2-fold) risk for hospitalization due to bradycardia. Interestingly, in a retrospective cohort study, Gill et al. showed that syncope-related events were increased in the ChEI-treated dementia population compared with their untreated cohorts. Bradycardia, pacemaker insertion and hip fracture, all events connected with the brief loss of consciousness observed in syncope, were associated with ChEI use.
In prospective studies, the total frequency of AEs was lowest for donepezil when compared with rivastigmine and galantamine. In particular, gastrointestinal AEs were reported to be significantly lower with donepezil — both rivastigmine and galantamine were associated with higher incidences of vomiting, nausea, diarrhoea and abdominal pain.[117,118] Similar to results from retrospective studies, CNS- and cardiovascular-related AEs occurred in a very small number of patients. Two studies suggested that both rivastigmine and galantamine resulted in higher discontinuation rates than donepezil.[116,119]
Data sheet safety, taken largely from clinical trial results for the four approved drugs, appears to favour memantine in tolerability (based on withdrawal rates, which were comparable to placebo) and safety (lower number of AE types in relation to the ChEIs). However, comparisons of safety data on memantine and the ChEIs from observational studies have not, to our knowledge, been reviewed. A postmarketing surveillance study of 1845 AD patients in Germany receiving memantine monotherapy found a low incidence of AEs, over half of which were thought to have no association with memantine. Also, unlike the ChEIs, the most frequent AEs were observed to be psychiatric or neurological, not gastrointestinal. Another postmarketing observational study completed in 451 memantine-treated patients in Italy found a higher proportion of AEs in the memantine-treated sample than in the placebo group and reported an 8% withdrawal due to AEs.
Taken together, safety data from naturalistic studies parallel those of RCTs: gastrointestinal AEs are more prevalent with ChEIs than with memantine. In the clinical setting, donepezil appears to have the lowest rate of reported AEs. However, all of the approved drugs have an acceptable safety profile, which in addition to a proven efficacy provides justification for their use in the symptomatic treatment of AD.
3. Emerging Therapies
3.1 Amyloid Pathology Targets
Hydrophobic Aβ is formed via proteolytic cleavage of the transmembrane protein APP, first by β-secretase, followed by γ-secretase.[123,124] In an alternative non-amyloidogenic pathway, APP is cleaved by α-secretase to produce a soluble peptide (sAPPα). Two major species are formed in the amyloidogenic path: the fragment consisting of 40 amino acids (Aβ40) occurs more frequently while the 42 amino acid fragment (Aβ42) is more susceptible to aggregation.
3.1.1 Reducing Amyloid-β (Aβ) Production
The amyloidogenic pathway is activated by β-secretase or β-site APP-cleaving enzyme 1 (BACE1). The thiazolidinedione class of drugs for type 2 diabetes mellitus, including rosiglitazone and pioglitazone, used principally to regulate glucose and lipid metabolism, can also down-regulate β-secretase and APP expression through stimulation of the nuclear peroxisome proliferator-activated receptor γ (PPARγ). Diabetes appears to increase the risk of dementia[143,144] and, further, insulin resistance has been postulated as an underlying mechanism of AD pathogenesis.[145,146] Thus, the action of the drugs to increase insulin sensitivity and decrease insulin levels may reduce Aβ as both compete for degradation by the insulin-degrading enzyme.
The bioavailability of rosiglitazone has been questioned, providing a possible explanation for the lack of efficacy in the phase III trial. In animal models, active efflux of rosiglitazone following CNS penetration at the blood-brain barrier hinders the effect of the drug. In contrast, pioglitazone can cross the blood-brain barrier[147,168] and reduce AD pathology in mice models. A phase II RCT evaluating the safety of pioglitazone 45 mg in 29 AD patients for 18 weeks found good drug tolerability but limited clinical benefits. There are no ongoing phase III trials for β-secretase inhibitors, though larger trials of pioglitazone to further examine efficacy for earlier stages of AD may be warranted.
The action of γ-secretase on β-secretase-processed APP signifies the final step in the production of Aβ. γ-Secretase is additionally involved in the cleavage of other substrates, including Notch receptors. This represents a challenge in developing γ-secretase inhibitors to block amyloidogenesis, given that Notch is important for neural signalling and cell development.
Semagacestat, thus far the only γ-secretase inhibitor to have been studied extensively in AD trials, can reduce CNS Aβ production in healthy volunteers in a dose-dependent manner. In an initial phase II RCT, AD patients receiving 30–40 mg daily for 6 weeks had non-significant decreases in CSF Aβ40. Another phase II trial, administering a higher dose (up to 140 mg daily) for 14 weeks, did not result in reductions in Aβ levels in the CSF. Aside from skin and subcutaneous tissue concerns, semagacestat was well tolerated in both trials. Two large phase III trials, the IDENTITY and the IDENTITY-2 trials, which included over 2600 participants, were recently discontinued after failure to demonstrate efficacy. Compared with placebo, patients receiving semagacestat, in fact, worsened more significantly in both cognition and daily function and were at a higher risk of developing skin cancer.
Since phase II trials revealed limited changes in Aβ levels in CSF but clear changes in the plasma, semagacestat may have rapid efflux or may require more time to reach equilibrium in the CSF.[174, 175, 176] Furthermore, the inhibition of Notch proteolysis may have clinical consequences, such as those detected in the phase III trials. Thus, it is necessary to develop Notch-sparing γ-secretase inhibitors with improved CNS equilibration. Second-generation inhibitors with high selectivity for APP are currently in early-phase trials.[178, 179, 180]
α-Secretase, the competing enzyme of β-secretase for APP, initiates a non-amyloidogenic pathway, which results in a protein with lower propensity to aggregate. sAPPα, the soluble product of this pathway, has also been shown to have neuroprotective, memory-enhancing and anti-apoptotic properties. Up-regulation of this pathway offers an alternative mode of blocking the Aβ expression and subsequently, plaque formation. Stimulators of α-secretase have reached early-phase clinical trials: etazolate, a selective modulator of GABAA receptors, can promote α-secretase activity and increase production of sAPPα, while bryostatin-1 up-regulates the α-secretase transduction pathway through activation of protein kinase C. Other treatments that affect α-secretase activity through modulation of other neurotransmitters (glutamate, serotonin), hormones (estrogen, testosterone) and statins (discussed in section 3.5) have also been studied. However, there are currently no ongoing phase III trials testing compounds that specifically target the α-secretase pathway.
3.1.2 Decreasing Aβ Aggregation
In recent years, soluble oligomers of Aβ, rather than large assemblies of fibrillary Aβs, have been strongly linked with neuro- and synapto-toxicity,[187, 188, 189] leading to AD pathology. Compounds that suppress the aggregation or reduce the stability of Aβ oligomers may exhibit disease-modifying effects. Such therapies can act to bind the monomers in order to attenuate formation of both the oligomeric and senile plaque constituents.
In pre-clinical studies, tramiprosate (3-amino-1-propanesulfonic acid [3APS]) reduced plaque levels in the mouse brain and plasma via interaction with Aβ40 and Aβ42 to prevent the conformational changes necessary for oligomer and fibril production. Results from a phase II trial indicate the ability of tramiprosate to safely reduce Aβ42 CSF levels when given at 150 mg/kg for 3 months, despite no change in cognitive function compared with placebo. In the subsequent phase III RCT (Alphase study), 1052 AD patients (stable on anti-dementia drugs) from the US and Canada were administered tramiprosate 100 mg or 150 mg or placebo twice daily for 18 months. Though no significant differences were detected on the ADAS-cog, an exploratory analysis of each ADAS-cog item showed improvements on memory, language and praxis skills. The clinical development of tramiprosate was subsequently halted, though the compound has since been marketed as a nutraceutical (Vivimind™, Bellus Health, Laval, QC, Canada).
The flavinoid epigallocatechin gallate (EGCg), a major polyphenolic component of green tea, possesses affinity for Aβ42 and shows protective effects against Aβ neurotoxicity[194, 195, 196] in vitro. Transgenic mice models of AD given EGCg demonstrated improved performance on memory tasks, along with reduced Aβ levels and tau deposition. The ongoing SUN-AK phase II/III trial in Germany aims to investigate the efficacy of EGCg as an add-on treatment for 18 months in early stage AD (table IV). Another aggregation inhibitor, PBT-2, which acts to prevent metal-mediated oligomerization of Aβ, has shown significant improvements in tests of executive function (category fluency and trail making part B) but not cognition (ADAS-cog) in a phase IIa trial. Other anti-aggregation therapies, such as ELND-005 (scylloinositol) and clioquinol, were evaluated in early-phase trials; however, none are currently being planned for phase III testing.
3.1.3 Facilitating Aβ Clearance
Removal of toxic aggregated Aβ deposits via immune response is another approach applied to attenuate the detrimental effects of AD. Four chief mechanisms of immune-mediated amyloid clearance have been proposed: (i) antibody binding and phagocytosis of Aβ by microglia;[201,202] (ii) direct solubilization through disruption of Aβ;[203,204] (iii) extraction of soluble Aβ from the CNS by plasma antibodies (peripheral sink hypothesis); and (iv) antibody binding to prevent oligomeric Aβ-induced toxicity without affecting amyloid load.
Two strategies can be utilized to induce antibody-mediated clearance of Aβ: active immunization involving inoculation with the full-length Aβ peptide and passive immunization through insertion of immunoglobulins raised against Aβ. In an early-stage clinical study, active immunization was associated with meningoencephalitis, thought to be caused by cytotoxic pro-inflammatory T-cell activation and subsequent neuroinflammation. Early-phase trials evaluating vaccines that stimulate B cells have shown good tolerability.[208,209] Current phase III clinical trials are being done on passive immunization agents.
Bapineuzumab is a monoclonal antibody selective for the N-terminus of Aβ, which contains the B-cell epitope. In a phase I study, a single-dose infusion of 1.5 mg/kg was found to be safe while 5 mg/kg was associated with vasogenic oedema. A phase II trial examined doses of 0.15, 0.5, 1.0 and 2.0 mg/kg in AD patients for 18 months (six 1-hour intravenous infusions 13 weeks apart). The prespecified analysis showed tolerability but no significance in cognitive tests between placebo and any of the different antibody doses. However, exploratory analysis revealed a trend in cognitive improvements within the ITT population and significant improvements in study completers. An international, phase III, double-blind, placebo-controlled, multicentre trial plans to enrol 800 APOE ɛ4 carriers and another trial will enrol 1000 non-carriers to evaluate efficacy over 18 months (table III). Patients will also be entered into long-term extension trials for continued safety monitoring for 2 years.[212,213]
Solanezumab, a humanized monoclonal antibody that binds soluble Aβ, was found to be safe in both phase I and II[215,216] studies. In a phase II RCT, 12 weekly infusions of 100 and 400 mg given to both patients and healthy volunteers demonstrated no change in cognition but suggested normalization of CSF Aβ42 in patients. The 400 mg dose was also well tolerated in a phase II open-label trial. The phase III EXPEDITION trials, administering monthly infusions of 400 mg for 19 months to AD patients,[137,138] are currently ongoing. An open-label study also continues to collect data.
An alternative mode of achieving passive immunization is through the use of intravenous immunoglobulin, nonspecific polyclonal antibodies obtained from human donors. Decreases in CSF Aβ and increases in serum Aβ, in accordance with the peripheral sink hypothesis, along with small improvements in cognition, were found in two early-phase trials in mild to moderate AD patients.[218,219] Similar results were obtained from a phase II trial; changes in biomarkers and a trend towards improved cognition were observed in patients given intravenous immunoglobulin for 3, 6 and 9 months. A phase III RCT will randomize 360 mild to moderate AD patients in the US and Canada to intravenous immunoglobulin 400 mg/kg or 200 mg/kg or placebo (taken every 2 weeks) for 70 weeks. Primary outcome evaluation will be based on the ADAS-cog and ADCS-CGIC.
3.2 Tau Pathology Targets
Tau, a cytoplasmic protein that associates with tubulin to stabilize axonal microtubules during its polymerization, is also important in AD pathology. Hyperphosphorylation of the tau protein, which causes its detachment from microtubules, can lead to formation of neurofibrillary tangles of paired-helical shape. As cognitive deterioration is correlated with tangle load, neurodegeneration may be the result of loss of cytoskeletal structural support and accumulation of cytotoxic intraneuronal filaments. Inhibition of tau hyperphosphorylation and promotion of filament disassembly represent two viable strategies for disease-modifying therapies.[223,224]
Lithium and valproate are inhibitors of GSK-3, a protein kinase that mediates phosphorylation and neuroprotective up-regulation of the anti-apoptotic factor Bcl2. Administration of lithium to mild AD patients for 10 weeks did not significantly alter cognition or tau levels in a phase II RCT. In the VALID phase III trial of valproate for treatment of psychosis/agitation in AD, secondary outcomes of cognition and daily function did not demonstrate significant improvements (table IV). In Europe, another GSK-3 inhibitor, tideglusib, is currently being tested in phase IIb for efficacy, using the ADAS-cog to detect cognitive changes during 26 weeks of treatment.
Methylthioninium chloride (methylene blue) can dissolve tau filaments in vitro, with additional roles in the neurotransmitter systems, oxidation and mitochondrial function.[230,231] A phase II trial of moderate AD patients given oral methylthioninium chloride 30, 60 or 100 mg three times daily (monotherapy) found significant improvements on cognitive tests after 50 weeks on the 60 mg dose. TauRx Pharmaceuticals (Singapore, Republic of Singapore) is preparing to initiate a phase III RCT to test the efficacy of a second-generation tau anti-aggregant with higher bioavailability — leuco-methylthioninium chloride.
3.3 Neuro-Inflammatory Pathway
The presence of activated microglia and inflammatory substances such as cytokines and cyclo-oxygenase (COX)-2 enzymes has been associated with plaques and tangles found in AD.[234, 235, 236, 237] Epidemiological studies show that NSAIDs have protective effects and are associated with a reduced incidence of AD, lending further support for the inflammatory hypothesis.[238,239] However, clinical trials investigating the disease-modifying potential of anti-inflammatory drugs have been unsuccessful.
Early studies used anti-inflammatory drugs with a diverse range of activities in order to target the numerous inflammatory processes involved in AD progression. Prednisone, a glucocorticoid with broad immunosuppressant effects, was evaluated in a 52-week, multicentre, phase III RCT[156,191] of 138 AD patients (table IV). Differences in cognitive decline were not found between the 10 mg/day oral dosage and placebo, though greater behavioural symptoms were noted with prednisone treatment. Hydroxychloroquine, an antimalarial drug with effects on inflammatory processes such as lymphocyte responsiveness, macrophage activity and cytokine release, was also tested for efficacy in AD. The trial, which included 168 patients randomized to placebo or hydroxychloroquine (200 or 400 mg/day, depending on weight), showed no improvements in cognition following 18 months of treatment.
NSAIDs with more restrictive anti-inflammatory pharmacology were subsequently tested in late-phase clinical trials. The efficacy of rofecoxib, an inhibitor of COX-2, was evaluated in a multicentre phase III trial with 692 AD patients. Participants receiving ChEIs given rofecoxib 25 mg/day or placebo for 12 months did not improve in cognition or global function. It was suggested that COX-2 is not the correct target for AD pathology and that inhibitors of COX-1, the molecule more highly up-regulated in microglia, is more important in reducing neuro-inflammation. The effects of naproxen (a non-selective NSAID that also inhibits COX-1), rofecoxib and placebo were tested in a phase III trial of 351 AD patients receiving concomitant anti-dementia drugs. Participants given either rofecoxib 25 mg daily or naproxen 220 mg twice daily for 12 months did not improve significantly in the cognitive and daily functioning domains compared with those treated with placebo.
Indomethacin is a non-selective NSAID with anti-amyloidogenic effects, through its action as a Notch-sparing γ-secretase modulator. The decreased production of Aβ is due to allosteric stabilization of a γ-secretase conformation, which favours production of less toxic forms. In an early clinical trial of 44 AD patients, indomethacin 100–150 mg/day taken for 6 months appeared to have cognitive benefits compared with placebo. However, the study had a high drop-out rate and, in a Cochrane review, re-analysis of the data found no significant differences between treatment and placebo on cognitive tests. A phase III trial conducted in the Netherlands was discontinued after 4 years due to recruitment difficulties. The available data on 51 patients revealed that indomethacin 100 mg/day taken for 12 months had no cognitive benefits.
Tarenflurbil (the R enantiomer of flurbiprofen) is another Notch-sparing NSAID that modulates γ-secretase without interacting with COX.[246,247] This treatment (up to 800 mg daily) was safe and tolerable in early-phase trials[248,249] for AD. Over 12 months, the phase II trial found trends for lower rates of decline in ADLs and global function but not cognition. A large phase III trial conducted in the US found no difference in cognition and daily activities between the 809 patients given tarenflurbil 800 mg twice daily and the 840 patients receiving placebo. These negative results might have been related to the low potency for inhibiting secretion of Aβ42, poor CNS penetration, residual NSAID activity or simply the fact that γ-secretase is not the right target.
3.4 Mitochondrial Dysfunction Pathway
At the early stages of AD, mitochondrial dysfunction can occur, leading to apoptosis and damage at synaptic sites. Additionally, soluble APP and Aβ proteins can disrupt the regular mitochondrial biochemical pathways, inducing oxidative stress and promoting further neurodegeneration. Thus, improving metabolic function represents another approach for development of disease-modifying therapies.
Latrepirdine (dimebon), prescribed as an antihistamine in Russia, has a broad spectrum of mechanistic actions, including weak inhibition of acetylcholinesterase, butyrylcholinesterase and NMDA signalling.[253,254] However, its main therapeutic action has been proposed to be enhancement of mitochondrial function through inhibition of permeability transition pores, which are susceptible to apoptosis by Aβ. In addition, latrepirdine is also hypothesized to be neuroprotective through blockade of Aβ toxicity and promotion of adenosine triphosphate production.[253,256] In a 26-week phase II study in Russia, 183 AD patients were randomized to 20 mg latrepirdine or placebo three times daily. Compared with placebo, patients given the active treatment showed significant improvements in cognition and daily functioning. However, a phase III multinational trial (CONNECTION), which enrolled 598 patients for 6 months found no significant differences in cognition, daily and global function between latrepirdine monotherapy and placebo. Another phase III RCT (CONCERT), planning to randomize 1050 AD patients, stable on donepezil, is currently underway.
3.5 Other Approaches
Other disease-modifying approaches are based on observations of lower AD incidence in association with ingestion of substances such as omega-3 polyunsaturated fatty acids and cholesterol-lowering medications. Epidemiological studies have found evidence for a link between high omega-3 fatty acid diets and reduced risk of cognitive decline and dementia.[258, 259, 260] Docosahexaenoic acid (DHA) is highly expressed in the CNS of unaffected individuals and significantly diminished in AD brains, while other fatty acids such as eicosapentaenoic acid (EPA) are not typically found in the CNS.[261,262] The OmegAD study in Sweden administered EPAX® 1050 TG 1000 mg (containing DHA 430 mg and EPA 150 mg; EPAX AS, Aelesund, Norway) or placebo four times daily to 204 AD patients for 6 months. While the active drug had a good safety profile, primary outcomes of cognitive and global function did not differ between treatment groups. Interestingly, there was a significant decrease in decline of MMSE scores in the mildest population, suggesting a benefit for less impaired patients. A recent phase III trial of DHA (510 mg twice daily) in 402 patients found similar results; there were no improvements in cognition, global and ADL function for the 18-month duration. In post hoc analyses, the MMSE scores did not differ for mild AD patients but there was less cognitive decline in APOE-ɛ4-negative participants.
Though the mechanism is not clear, statins used for reducing serum cholesterol have been shown to down-regulate Aβ production,[263, 264, 265] as well as to possess anti-inflammatory and anti-oxidant properties. Results from epidemiological studies have been inconsistent: some have reported a lower incidence of cognitive decline and AD in statin users[267, 268, 269] while others found no such relationship.[270, 271, 272] In the ADCLT trial, 67 mild to moderate AD patients were given either atorvastatin 80 mg/day or placebo, and there was significant improvement on cognitive tests for participants in the active treatment after 6 months. However, these results were not consistent with observations from the recent LEADe study. In this international phase III trial, enrolling 614 patients stable on donepezil for 72 weeks, cognition and global function did not change significantly between groups. A Cochrane meta-analysis of the two studies concluded no benefit of atorvastatin for the treatment of dementia. Simvastatin is more lipophilic and thus passes through the blood-brain barrier more efficiently than atorvastatin.[274,275] In addition to safety and tolerability, it has also demonstrated ability to reduce CSF Aβ40 in mild AD patients. A phase III RCT (CLASP study) of 400 patients across the US plans to evaluate the efficacy of simvastatin 20–40 mg/day for 18 months. The data collection phase has been completed but results have yet to be published.
Currently available treatments for AD modulate neurotransmitter activity in order to provide temporary symptomatic relief, but do not halt or slow the progression of the disease. In spite of this, and perhaps remarkably considering the recent experience with disease-modifying therapies, these symptomatic therapies provide modest but consistent benefits for cognition, function and behaviour. Large multicentre trials to investigate the efficacy of disease-modifying therapies, primarily with amyloid-targeting properties, have been unsuccessful thus far. The disappointing results in phase III RCTs, however, should not provide grounds for dismissal of the amyloidogenic cascade hypothesis. It is likely that Aβ is not the sole cause, but rather one of many factors — including hyperphosphorylated tau, neuro-inflammation and other neuronal dysfunctions — that contribute to AD pathogenesis. In order for research to move forward, re-evaluation of pre-clinical models and development of disease biomarkers are essential.
Negative clinical outcomes following encouraging results in the pre-clinical stage signal a need for development of better disease models. The widely used transgenic mouse models manipulated to over-express Aβ and tau do not capture the complete picture of the disease hallmarks and, furthermore, may only be good representations of the hereditary familial form of AD and not the more common sporadic AD. It is also difficult to measure the deterioration of memory and higher-order cognitive processes in mice. Thus, employing higher mammals with spontaneous plaque and tangle deposition, as well as measurable cognitive decline, may offer a more accurate depiction of the human disease.[278,279]
Development and incorporation of more effective biomarker detection tools offers a means of gauging drug-target interactions and subsequent biochemical changes relevant to AD pathology. In the pre-clinical setting, biomarkers verify drug mechanisms and determine therapeutic as well as toxic doses. In clinical trials, biomarker analyses have served as secondary outcomes. Typically, the measurement of Aβ and tau levels in the CSF and serum is conducted to assess the drug candidate’s effect on amyloid signalling and tau pathology.[281,282] The recent amendments to the amyloid hypothesis call for assessment of other biomarkers, including Aβ oligomers and species of oxidative stress and inflammation.
Clinical trials are also moving towards utilizing imaging technologies to detect structural and functional changes. MRI has been used to observe brain structural changes and atrophy as an indicator of AD progression.[284,285] Neuronal activity, indirectly measured by glucose metabolism, can be assessed with positron emission tomography (PET) and the radioligand 18F-2-fluoro-2-deoxy-d-glucose (FDG). In AD patients, diminished FDG uptake has been shown to correspond with neurodegeneration.[286,287] To explicitly evaluate the amyloid hypothesis, PET imaging with Aβ-specific radioligands can be used: 11C-labelled Pittsburgh Compound B (11C-PiB) is currently being employed in amyloid-PET.[288,289] Recent results demonstrate that another radioligand, florbetapir, was well correlated with Aβ density.[290,291] However, the uptake of these amyloid-associated compounds stabilize at the prodromal stage and do not change during AD progression, despite continued decline in cognition. This suggests that amyloid-PET may have more value as a diagnostic tool for participant selection in clinical trials. Alternatively, this technique could be used as a primary outcome in studies of preventative treatments targeting individuals from the high-risk population, who have initial reduced central amyloid burden. These studies provide validation for the usefulness of imaging as a diagnostic and primary outcome measure in clinical trials, in order to detect significant differences that psychological tests cannot.
Genetic biomarkers, such as mutations in APP, APOE and presenilin (PSEN), have predictive value in risk assessments.[293,294] In particular, APOE ɛ4 homozygosity is associated with later development of AD.[295,296] Genetic tests to screen for individuals in the high-risk population can be used to flag and diagnose susceptible individuals early on. Genotyping can also be used in clinical trials to explore drug response differences between carrier populations, thus predicting outcomes (both positive and negative) and allowing for personalized treatment plans.
It is becoming increasingly apparent from the lack of success of disease-modifying therapies that early diagnosis by means of biomarkers may result in more positive clinical outcomes. Researchers have assembled guidelines for revised diagnostic criteria of AD, which now includes the use of biomarkers. Disease-modifying therapies may be effective at the pre-symptomatic stage, when pathological events have yet to produce irreversible cognitive deficits. Also, the time-course of disease progression may not allow for subtle changes to be detected on neuropsychological tests; however, biomarkers can potentially be used as a more immediate indication of drug efficacy and can illustrate the differential effects of symptomatic and disease-modifying treatments.
Additionally, there is a pressing need for patient and caregiver participation in AD clinical trials. Trials often require considerable commitment from patients and their families (long testing sessions, lumbar puncture or numerous MRI scans); therefore, subject burden should be taken into consideration during trial design. Researchers also need to make study conditions comfortable and accommodating in order to enhance recruitment and reduce loss to follow-up.
It is likely that disease-modifying therapies will require many years of administration before differences can be observed on tests of cognitive, global and daily function. Thus, the importance of continuing to develop better symptomatic medications should not be discounted. The use of symptomatic and disease-modifying therapies in combination may provide the best therapeutic option. Causation has thus far not been definitively established between a single isolated pathway and disease expression. This calls for a continued search for these causative factors and further exploration of currently implicated pathways. As AD is a multifactorial disorder, the discovery of a sole cure is highly improbable. Future strategies, likely a combination of various pharmacological and non-pharmacological therapies, should be designed to target the multiple interacting pathways and be personalized to the individual.
Dr Nathan Herrmann has received research funding, consultation fees and (or) speakers’ honoraria from Lundbeck, Pfizer, Janssen-Ortho, Novartis and Sonexa Therapeutics. Sarah Chau and Ida Kircanski have no conflicts of interest that are relevant to this review. Dr Krista Lanctôt has received research funding, consultation fees and (or) speakers’ honoraria from Abbott, Lundbeck, Pfizer, Janssen-Ortho and Sonexa Therapeutics. None of the four authors is an employee of Lundbeck, Pfizer, Janssen-Ortho or Novartis (the makers of cholinesterase inhibitors and memantine in Canada) or is a shareholder in any of these companies. No sources of funding were provided for the preparation of this review.
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