64 | CURRENT THERAPIES FOR ALZHEIMER’S DISEASE

MARY SANO AND JUDITH NEUGROSCHL

The awareness of cognitive loss and dementia has grown dramatically in the past 20 years. The most common etiology of dementia is Alzheimer’s disease (AD), a neurodegenerative condition characterized by progressive cognitive and functional deterioration. Alzheimer’s disease has an estimated prevalence of approximately 5.2 million in the United States Alzheimers (Alzheimers Association, 2012), with an estimated 36 million people worldwide currently suffering with dementias (Prince et al., 2011). The CDC has estimated that the US population older than age 65 will more than double from 2010 to 2050, with the population older than 85 more than tripling Administration on (Administration on Aging, 2010). Age is the greatest risk factor for Alzheimer’s disease and other dementias, thus the number of individuals with dementia will continue to rapidly rise unless significant advances are made. In January 2011, the National Alzheimer’s Project Act was signed into law in the United States, establishing a national project to facilitate and coordinate research efforts on Alzheimer treatment and prevention and to improve diagnosis and coordination of care, particularly in minority populations.

Although five medications representing two classes of drugs were approved by the US FDA for the treatment of Alzheimer’s disease since 1994, there have been no approved agents since 2003. However, several randomized trials have provided additional information about the efficacy of these FDA-approved medications in subgroups of patients with AD. The development of these agents preceded the most current approaches to diagnosis including imaging confirmation of cerebral amyloid, which might yield a somewhat different patient population in trials. This specificity of diagnosis may or may not change the efficacy of the current agents. Currently there are approximately 330 trials registered in the US and recruiting subjects for the treatment of AD and there are over a thousand that have been registered and completed.

This chapter will review the pharmacology underlying the currently approved treatments, and the data supporting efficacy. Several approaches have also been well studied in rigorously conducted clinical trials, which have increased our knowledge about what primarily does not work. These include hormones, agents that modify cardiovascular and metabolic risk as well as a number of vitamins and nutritional approaches. We also review this evidence.

FDA-APPROVED TREATMENTS FOR ALZHEIMER’S DISEASE

CHOLINESTERASE INHIBITORS

Acetylcholine has long been known to effect memory. Reductions in the activities of acetylcholinesterase and choline acetyltransferase, enzymes involved in the synthesis and degradation of acetylcholine, were found in brain tissues from Alzheimer’s disease patients Davies and Maloney(Davies and Maloney, 1976). According to the cholinergic hypothesis of Alzheimer’s disease, the destruction of cholinergic neurons in the basal forebrain and the resulting deficit in central cholinergic transmission contribute substantially to the cognitive deficits and behavioral symptoms observed in patients suffering from AD (Bartus et al., 1982).

After its release into the synaptic cleft the acetylcholine is degraded rapidly by the hydrolytic activity of cholinesterases, the most prominent being acetyl-cholinesterase, although butyryl-cholinesterase can also hydrolyze acetylcholine in the human brain (Mesulam et al., 2002). Inhibition of cholinesterases leads to an increase of acetylcholine concentration in the synaptic cleft and is thought to enhance cholinergic transmission and ameliorate cholinergic deficit. In 1983 the first acetyl-cholinesterase inhibitor (AChEI) was approved (tacrine [Cognex]). It was not well tolerated, with four times per day dosing, reversible hepatocellular injury in up to 50% of patients (Watkins et al., 1994), and significant procholinergic side effects of nausea, vomiting, and diarrhea. The three other AChEIs donepezil, rivastigmine, and galantamine, were released between 1996 and 2001 and have very similar efficacy. They have slightly different mechanisms of action. For example, rivastigmine also inhibits butyrylcholinesterase, and galantamine is an allosteric modulator of the nicotinic receptor. In general, these medications tend to effect a 3–18 month improvement in cognitive functioning, followed by deterioration along a parallel path. Rivastigmine has received an additional indication for dementia caused by Parkinson’s disease (Olin et al., 2010). Systematic reviews of all available randomized, double-blind, multicenter and placebo-controlled studies by the Cochrane Collaboration showed moderate benefits of cholinesterase inhibitors on cognitive, behavioral, and functional symptoms (e.g., Birks, 2006), and they are considered standard of care for patients with Alzheimer’s disease by the American Academy of Neurology (Doody, 2005)

Originally, AChEIs were approved for the treatment of patients with mild-to-moderate disease. However, since 2007 the indications have been expanded to severe dementia. There have been numerous studies supporting the ­efficacy of donepezil (Cummings et al., 2010), rivastigmine (Farlow et al., 2011), galantamine (Burns et al., 2009), with ­significant ­cognitive effects for all medications in severe AD. Continuing treatment into moderate and severe AD also has been shown to improve cognition and function over placebo, in a one year trial of patients with moderate to severe AD who were randomized to either continue or stop donepezil and add either placebo or active memantine. Combined treatment did not suggest an additional benefit (Howard et al., 2012). A similar positive finding was seen in trials of galantamine withdrawal (Gaudig et al., 2011). Of note, a trial examining the use of donepezil for agitation in AD did not show a significant placebo medication difference, although interestingly about 20% in both groups had a greater than 30% reduction in agitation scores (Howard et al., 2007).

Some of the cholinesterase inhibitors have been tried in higher doses (Farlow et al., 2010; Grossberg et al., 2011), with donepezil receiving FDA approval for a 23-mg formulation of Aricept in moderate to severe AD. Although there were data showing mild benefit in cognition there was no statistically significant difference in global functioning, a requirement for FDA approval, and significantly more procholinergic side effects such as nausea and vomiting, suggesting that the risk benefit ratio does not support the use of this higher dose. Other studies have suggested that the side effects are most pronounced in the first few weeks of treatment (Tariot et al., 2012), but given the lack of improvement in global functioning there is debate as to the true benefit of this dose.

Another significant question is the utility and efficacy of AChEIs in mild cognitive impairment (MCI). To date, trials of cholinesterase inhibitors in MCI have not shown a significant effect on progression to AD (Petersen et al., 2005; Winblad et al., 2008), but some studies have suggested that they may delay the conversion (Petersen et al., 2005) or possibly have a differential effect on subgroups based on genetics or gender (Ferris et al., 2009).

Recently, a placebo-controlled trial of a Chinese herb, Huperzine A, which is a cholinesterase inhibitor, was conducted in 210 individuals with mild-to-moderate AD. Huperzine A did not meet the primary efficacy endpoints of cognition, functional, or global change (Rafii et al., 2011).

There are numerous areas for further study ­concerning the cholinesterase inhibitors that will be ­facilitated by greater understanding of biomarkers in this disease as well as the newly available amyloid imaging. One is whether early or even presymptomatic treatment affects the course of disease, amyloid deposition, and/or later ­functional changes. As the prodromal stages of AD are better defined, this will open up many avenues of inquiry concerning the AChEIs as well as various other treatment strategies.

MEMANTINE

Glutamate is the main excitatory neurotransmitter in the central nervous system and a physiological level of glutamate-receptor activity is essential for normal brain function. Glutamate excitotoxicity, mediated through excessive activation of N-methyl-D-aspartate (NMDA) receptors is believed to play a role in the neuronal cell death observed in Alzheimer’s disease and other neurodegenerative diseases by causing increases in intracellular calcium which then triggers downstream events that cause cell death (Hynd et al., 2004). Thus, NMDA-receptor antagonists may have a therapeutic potential for neuronal protection from glutamate-mediated neurotoxicity.

Memantine is a low-to-moderate affinity, voltage-
dependent, noncompetitive NMDA receptor antagonist with
rapid gating kinetics (Danysz et al., 2000). Its fast on/off kinetics and low-to-moderate affinity are key to memantine’s action because it ameliorates the effects of excessive glutamate while preserving the physiologic activation of NMDA-receptors required for learning and memory. Like other NMDA-receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory, but studies have shown that at lower, clinically relevant concentrations memantine actually promotes synaptic plasticity and preserves or enhances memory in animal models of Alzheimer’s disease (Johnson and Kotermanski, 2006).

Memantine was approved in the United States for treatment of moderate to severe AD in 2003, and the FDA rejected a request to extend its approval to mild AD in 2005. Systematic reviews of all available randomized, double-blind, multicenter and placebo-controlled studies by the Cochrane Collaboration showed that memantine treatment resulted in significant benefits in cognitive, functional, and behavioral assessments in the treatment group compared with placebo in patients with moderate to severe Alzheimer’s disease (McShane et al., 2006). It is usually well tolerated; adverse effects included confusion, insomnia, and headache that occurred in a small percentage of the study participants (Tariot et al., 2004).

Memantine does not affect the inhibition of acetyl-
cholinesterase by cholinesterase inhibitors. It is well tolerated with cholinesterase inhibitors, (Choi et al., 2011; Tariot et al., 2004). In some studies, memantine was shown to enhance AChEI therapy (Atri et al., 2008; Tariot et al., 2004), whereas others have not seen an effect (Choi et al., 2011; Howard et al., 2012).

The question of whether memantine affects the rate of decline in mild AD is being addressed in a current trial (http://clinicaltrials.gov ID: NCT00235716). This study examines the effect of vitamin E 2,000 IU, versus vitamin E plus memantine, versus memantine, versus placebo in a group of approximately 600 individuals with mild-to-moderate AD over the course of up to four years to see if the rate of decline is modified. Data collection began in August 2007, and was expected to be completed in the fall of 2012.

OTHER TREATMENT STRATEGIES

Based on epidemiologic studies and basic science research, a number of FDA-approved drugs, as well as vitamins, supplements, medical foods, and herbal medications have been considered in the treatment of AD.

ANTIINFLAMMATORY DRUGS

A number of lines of evidence supported the hypothesis that neuronal damage caused by increased immune system activity is a mechanism of AD pathogenesis. Increased concentrations of cytokines, acute phase reactants, and complement protein have been found on autopsy in the brains of Alzheimer patients compared with aged matched controls (e.g., Bauer et al., 1992; Fillit et al., 1991). Senile plaques are often surrounded by activated astrocytes and microglia cells and can also induce activation of the complement cascade (McGeer and McGeer, 2001). Epidemiologic studies looking at the risk for AD have suggested that use of nonsteroidal antiinflammatory or corticosteroids lessened the risk of developing Alzheimer’s disease (e.g., Hayden et al., 2007; McGeer and McGeer, 2007).

Cyclooxygenase (COX) enzymes mediate the conversion of arachidonic acid to prostaglandins, which are crucial components of the proinflammatory process. The main target of nonsteroidal antiinflammatory drugs (NSAIDs) is COX enzymes. The inducible COX isoform, COX2, is upregulated in the brains of patients with AD (Yasojima et al., 1999), suggesting that NSAIDs might be beneficial in AD by reducing neurotoxic inflammation. A subset of NSAIDs have been found to lower Aβ levels independently of COX enzyme activity, apparently by directly modulating γ-secretase activity, which enzymatically cleaves Aβ from its larger precursor protein (Weggen et al., 2001). Flurizan (tarenflurbil) was shown to be effective in modulating γ-secretase activity and ultimately in selective Aβ42 lowering in animal models. In a phase II study the agent had no effect on a group of cognitive outcomes in mild-to-moderate AD, but a post hoc analysis showed some benefit at the highest dose for those with the mildest disease (Wilcock et al., 2008). This finding led to an 18-month phase III trial, which was also negative (Green et al., 2009). This is particularly interesting in light of the fate of semagacestat (LY450139), a gamma secretase inhibitor, which was shown to worsen patient outcomes more than placebo in two phase III trials (NCT00762411 and NCT00594568) (Lilly, 2010).

There have been a number of clinical trials that have examined a variety of antiinflammatory agents ranging from NSAIDS to prednisone, which have unfortunately shown no benefit as a treatment for AD (discussed in Aisen, 2008). Primary and secondary prevention trials with NSAIDS have also been negative (e.g., Lyketsos et al., 2007; Thal et al., 2005). In addition, the dropouts from many of these trials have been high, owing to significant side effects of NSAID use such as renal insufficiency and gastrointestinal intolerance or, more seriously, gastrointestinal bleeding. A trial of 2,538 elderly patients without AD called the Alzheimer’s Disease Anti-inflammatory Prevention Trial, has led to a number of publications suggesting a possible deleterious cognitive effect with both naproxen and celecoxib (Lyketsos et al., 2007). Although the trial was halted early, observation was continued for two subsequent years, and models have been reported to explain the findings based on disease stage and rapidity of decline. All of these analyses are post hoc and many characterize subjects in idiosyncratic ways, leaving doubt to their value (Breitner et al., 2011; Leoutsakos et al., 2012).

ANTIOXIDANTS

Oxidative stress and free radicals have been implicated in cell damage and aging in general, and in neurodegenerative diseases in particular, including MCI and AD (Lovell and Markesbery, 2007). Vitamin C and E have been found to protect from oxidative DNA damage (Huang et al., 2000) and vitamin E protects nerve cells from amyloid-β peptide toxicity (Behl et al., 1992).

Several population-based prospective observational studies that have used questionnaires to monitor the intake of vitamins C and E on the risk of developing dementia revealed mixed results (Boothby and Doering, 2005). A placebo-controlled, clinical trial of vitamin E and selegiline in patients with moderately advanced Alzheimer’s disease was conducted by the Alzheimer’s Disease Cooperative Study (Sano et al., 1997). Subjects in the vitamin E group were treated with 2,000 IU of vitamin E. The results indicated that vitamin E may slow functional deterioration. A more recent study looking at markers of oxidation in the CSF of patients with AD treated with vitamins E and C, and alphalipoic acid (ALA) ; or coenzyme Q3; or placebo (Galasko et al., 2012) showed no effect on CSF Abeta or tau and although the vitamin E/C/ALA group had lower CSF oxidative markers, they also showed worse mini mental scores over the four months. Other clinical trials with ­vitamin E were conducted in patients with MCI (2002; Petersen et al., 2005) that failed to demonstrate a significant difference in the rate of progression to Alzheimer’s disease between the vitamin E and placebo group.

Unfortunately there are safety concerns with the use of vitamin E. A clinical trial of long-term vitamin E supplementation studying the effects on cardiovascular events and cancer showed no effect on cancer or major cardiovascular events but an increase in the risk of heart failure (Lonn et al., 2005). A metaanalysis of randomized controlled trials examined the potential dose-response relationship between vitamin E supplementation and total mortality showed dose-dependent and significantly increased all-cause mortality with the use of vitamin E (Miller et al., 2005). Recent recommendations are therefore not to advocate the use of vitamin E in individuals at risk or affected by Alzheimer’s disease (Ames and Ritchie, 2007).

Interest remains in clarifying the risk/protective effects of vitamin E and two important ongoing studies will be informative. There is a current trial mentioned previously (http://clinicaltrials.gov ID: NCT00235716) looking at the effect of either vitamin E 2,000 IU versus memantine vs. a combination or placebo, in approximately 600 individuals for up to four years, to see if the rate of decline is affected. Another trial is an “add-on” (called PREADVISE [http://clinicaltrials.gov ID: NCT00040378]) to a trial evaluating the use of vitamin E and/or selenium, to prevent prostate cancer (the SELECT trial with 35,533 participants). This trial was halted in 2008 because there was a nonsignificant increased risk of prostate cancer in the vitamin E group, and a nonsignificant increased risk of type 2 diabetes in the selenium only group (Lippman et al., 2009). The PREADVISE study continues to follow more than 5,000 individuals who had been taking vitamin E 400 IU alone or in combination with 200 mcg of selenium, or placebo, and will evaluate their effect on developing risk.

B VITAMINS/LOWERING HOMOCYSTEINE

Elevated plasma homocysteine levels are a risk factor for cardiovascular disease and stroke (e.g., Bostom et al., 1999; Stampfer et al., 1992) and may be related to an increased risk of Alzheimer’s disease (Seshadri et al., 2002). Deficiencies of folic acid and vitamin B12 and B6 intake increase homocysteine plasma levels. Folic acid and vitamin B12 are needed for the conversion of homocysteine to methionine, and vitamin B6 is needed for the conversion of homocysteine to cysteine. High dietary intake of folic acid and vitamin B12 and B6 decreased homocysteine levels in adults (2005). Theories about how homocysteine might act as a risk factor for AD range from potentiating Abeta production (Zhang et al., 2009) or toxicity to vascular-related effects.

A recent longitudinal cohort study reported higher folate intake decreased the risk of incident Alzheimer’s disease independent of levels of vitamin B6 and B12 (Luchsinger et al., 2007). However, metaanalyses of clinical trials addressing the influence of folic acid, vitamin B6, and vitamin B12 intake failed to show any beneficial effect on cognitive function (e.g., Malouf and Grimley Evans, 2008). Furthermore, two clinical trials on folic acid and vitamins B6 and B12 failed to show any reduction of the risk of major cardiovascular events and stroke (Bonaa et al., 2006; Lonn et al., 2006). To see if lowering homocysteine in patients with AD would change the course of the illness, an 18-month prospective trial in 400 mild-to-moderate AD patients was done. The intervention (folate and vitamins B6 and B12) was quite successful at lowering homocysteine, but it did not slow cognitive decline, with no difference between the active and placebo groups on the rate of change of a cognitive measure (ADAS-cog) (Aisen et al., 2008). This was confirmed in a recent two-year trial looking at both vascular dementia and AD (Kwok et al., 2011).

Prevention trials have also been generally negative. One study of supplementation over a three-year period in nondemented older individuals selected on the basis of relatively high homocysteine levels indicated a favorable influence on cognitive function (Durga et al., 2007), whereas a two-year study in older individuals not selected on the basis of homocysteine levels did not (McMahon et al., 2006). Another trial of two years of vitamin supplementation in hypertensive men confirmed that lowering homocysteine did not significantly alter the risk of cognitive decline, either in the whole sample, or when individuals with baseline high homocysteine were analyzed separately. Of the 299 patients assessed at baseline, 73 were followed a mean of 7.7 years for long-term follow-up, and again no significant differences were seen, although a trend toward less cognitive impairment was seen in the treatment arm (Ford et al., 2010).

Overall there is no convincing evidence that supplementation of B vitamins significantly changes either risk of AD or subsequent decline in AD, although it remains possible that lowering homocysteine in individuals with high levels at baseline might decrease risk.

OMEGA-3 FATTY ACIDS

Several epidemiologic studies showed a protective effect of increased fish consumption and omega-3 fatty acid intake for the development of Alzheimer’s disease (Barberger-Gateau et al., 2002; Morris et al., 2003). Docosahexanoic acid (DHA) is an omega-3 polyunsaturated fatty acid found in some marine algae as well as fish. These fatty acids are a component of synaptic plasma membranes. Animal research suggests a number of roles in the brain including neuroprotection, affecting the rate of signal transduction, and regulating gene expression.

A Cochrane metaanalysis of all available biological, epidemiological, and observational data suggested a protective effect of omega-3 fatty acids (Lim et al., 2006), but the author concluded that until there was significant randomized prospective data, no conclusions could be drawn. Since then clinical trials have been published examining both AD treatment, as well as dementia prevention.

One placebo-controlled treatment trial demonstrated that in 204 patients treated over a year, no effect was seen in patients with mild-to-moderate stage disease, but in a subset with very mild AD (MMSE >27), omega-3 fatty acids slowed cognitive decline, as evaluated by MMSE (Freund-Levi et al., 2006). An 18-month trial followed 402 patients with mild-to-moderate AD who had low dietary intake of DHA at baseline who were given either DHA or placebo. The two outcome measures, a cognitive outcome (ADAS-Cog) and a global one (Clinical Dementia Rating Scale Sum of Boxes), as well as other behavioral outcome measures, did not differ between the placebo and active group, and in a subset of 102 patients who underwent volumetric MRI there was no difference in the rate of brain atrophy (Quinn et al., 2010).

Other trials have looked at DHA for primary and secondary prevention. A trial looking at high- and low-dose DHA and eicosapentaenoic acid (EPA) in 302 cognitively healthy older adults (MMSE >21), showed no cognitive benefit over the 26 weeks of the trial van de (van de Rest et al., 2008). A six-month trial of DHA versus placebo in 485 elderly patients with a memory complaint using a visuospatial episodic memory test as the primary outcome measure demonstrated significantly fewer errors in the treatment group, as compared with their baseline scores (Yurko-Mauro et al., 2010). However, a large trial of 1,748 individuals aged 45–80 at risk for cognitive decline because of a history of myocardial infarction, unstable angina, or ischemic stroke, did not show any significant effects on cognitive function after four years of treatment with either B vitamins (folate, B6, and B12) ; omega-three fatty acids (EPA and DHA) ; B vitamins and omega-3 fatty acids; or placebo (Andreeva et al., 2011).

Overall, the majority of data suggests that omega-3 fatty acids do not significantly alter the course of AD. The possibility remains that it may have an effect in individuals with only memory complaints. Given the short duration (six months) of that one positive trial, it is impossible to say anything about secondary prevention, although clearly in cardiovascular at-risk groups there was no benefit over four years.

GINKGO

Extracts of the leaves of the maidenhair tree, ginkgo biloba, have long been used in China, but also in several European countries as a traditional medicine for various disorders of health. A one-year randomized placebo-controlled treatment trial of 309 AD patients demonstrated a modest improvement on some measures (Le Bars et al., 1997), although two later six-month trials of 214 (van Dongen et al., 2000) and 513 Aisen, P.S., (Schneider et al., 2005) patients, showed no benefit. Two recent metaanalyses of ginkgo for the treatment of AD suggested that overall there was a modest treatment effect, but again the trials were very heterogeneous concerning duration and patients included in the trials, as well as outcomes (Janssen et al., 2010; Weinmann et al., 2010). A Cochrane review in 2009 called the research on ginkgo is at best “inconsistent and unconvincing” (Birks and Grimley Evans, 2009).

In terms of prevention, the best trial to date was a placebo-controlled trial of gingko. Evaluations were done at six-month intervals for incident dementia. In this trial, 3,069 elderly individuals, approximately 16% of whom met criteria for MCI at the start of the trial, were followed for a median of six years. The rates of all-cause dementia, AD, as well as conversion to dementia from MCI were not statistically different in the two groups. In addition, there was no improvement on any secondary outcome, such as overall morbidity (DeKosky et al., 2008), nor did it have any effect on cognitive decline in any cognitive domain (Snitz et al., 2009).

The overall results are at best inconsistent Aisen, P.S., (Schneider, 2008) and the British Association for Psychopharmacology concluded that ginkgo cannot be recommended for the prevention or treatment of AD (O’Brien and Burns, 2011).

CURCUMIN

Because curcumin has antiinflammatory and antioxidant properties, it has engendered interest in the AD community. In animal models it was found to decrease brain amyloid plaques (e.g., Frautschy et al., 2001)). A population-based cohort study found better cognition in elderly Asian subjects with high curcumin consumption (Ng et al., 2006). A small clinical trial in Hong Kong did not show any significant cognitive results (Baum et al., 2008). A trial has been completed in the United States and results were negative, but the preparation of curcumin was poorly absorbed with little to no curcumin found in the bloodstream of participants (Ringman et al., 2008). Additional trials with other formulations are planned, such as a trial (http://clinicaltrials.gov ID: NCT01383161) that began recruitment in March 2012, looking at the effect of curcumin in 50–90 year olds with a cognitive complaint but no dementia over the course of 18 months.

RESVERATROL

Several observational studies have demonstrated that moderate consumption of wine is associated with a lower incidence of Alzheimer’s disease. Wine is enriched in antioxidant compounds, with potential neuroprotective activities. Resveratrol, a polyphenol that occurs in abundance in grapes and red wine, is used by the plant to defend itself against fungal and other attacks. In the early 1990s the presence of resveratrol was detected in red wine wherein it is suspected to afford antioxidant and neuroprotective properties (Miller and Rice-Evans, 1995) and therefore to contribute to the beneficial effects of red wine consumption on neurodegeneration (Savaskan et al., 2003). In animal studies, resveratrol has a variety of antiaging effects, including extending the lifespan in C. elegans (Wood et al., 2004). In mice, it seemed to improve a variety of aging outcomes (bone health, cholesterol, coordination), but did not increase longevity (Pearson et al., 2008).

Resveratrol promotes intracellular degradation of Abeta via a mechanism that involves the proteasome (Marambaud et al., 2005), and it protected rats from Abeta-induced neurotoxicity (Huang et al., 2011). Resveratrol does not influence the Abeta-producing enzymes and therefore does not inhibit Abeta generation. In a transgenic Alzheimer model of Abeta amyloidosis, resveratrol significantly reduced amyloid plaque formation (Karuppagounder et al., 2009). A small clinical trial of low dose resveratrol in patients with Alzheimer’s disease has shown encouraging results (Blass and Gibson, 2006), and another low-dose trial was recently completed (http://­clinicaltrials.gov ID: NCT00678431). A large multicenter clinical trial of high dose resveratrol (ID: NCT01504854) began recruiting in May 2012.

MEDICAL FOODS

Medical foods for Alzheimer’s disease have been marketed over the past decade. A medical food is defined as a specially formulated and processed product (as opposed to a naturally occurring food) required for the dietary management of the patient under medical supervision, which cannot be achieved by normal diet. This category of products does not undergo premarket review or approval by the FDA. Also individual medical food products do not have to be registered with FDA. However, ingredients used in medical foods must be approved or exempted food additives, and ingredients are “Generally Recognized as Safe” (GRAS). Axona (previously known as Ketasyn) is an example of a Medical Food marketed for AD. The product proposes to provide an alternative energy source for the production of glucose in the brain through a proprietary formulation of caprylic triglycerides that increases plasma concentrations of ketone bodies. A clinical trial in mild-to-moderate AD demonstrated improvement in a cognitive test, though not in other outcomes (Henderson et al., 2009).

Another medical food, Souvenaid, which is not currently available in the United States, has been used in clinical ­trials for AD. The development of this product is based on the notion that coadministration of rate-limiting precursors for membrane phosphatide synthesis, such as the nucleotide uridine, omega-3 polyunsaturated fatty acids, and choline, can restore synapses, increase hippocampal dendritic spines, and surrogate markers of new synapses. In a “proof of concept,” placebo-controlled study of 212 drug naive subjects with AD, Souvenaid improved scores on a delayed memory score but not on other cognitive and functional measures (Scheltens et al., 2010). In a preliminary report of the The Souvenir II, a 24-week international study of 259 individuals with AD, Souvenaid significantly improved the memory domain of a neuropsychological test battery. No significant intervention effect was observed on other cognitive or functional outcomes (Scheltens et al., 2011). The S-Connect study, a 24-week randomized, controlled, double-blind study conducted in the United States in 527 subjects with AD who were on standard drug therapy reported no differences in any cognitive or functional outcome (Shah et al., 2011). Since it is likely that most individuals with AD will receive treatment with conventional medication, there is no indication that supplementation with medical foods has an additive benefit on clinical outcomes. Additionally, there are no trials of treatment in those who have failed other medications.

It is noteworthy that nether the mechanisms of intervention nor the efficacy of medical foods are well established, and are not supported. Despite this, the use of nutritional and dietary supplements in the United States is extensive. It is estimated that 65% of adults are self-described supplement users, according to a 2009 survey conducted by Ipsos-Public Affairs for the Council for Responsible Nutrition (Hlasney, 2009). Thus, patients and families are likely to be exploring these treatment options.

GONADAL HORMONAL TREATMENT OF DEMENTIA

Interest in a beneficial role on cognition and prevention of dementia for gonadal hormone, specifically estrogen and testosterone, has a long history with little to recommend these agents. As treatments for dementia there is little positive data to support a role for estrogen. A comprehensive metaanalysis of trials assessing forms of estrogen in the treatment of AD identified seven studies with over 350 women (Hogervorst et al., 2009). The cumulative summary of these results indicates worsening on clinical global measures, verbal memory, and finger tapping. Since that review several other trials have been described. A randomized trial using transdermal estrogen for up to three months in a small study of postmenopausal women with AD (N = 43) described improvements in visual and semantic memory (Wharton et al., 2011). Also a 12-month trial with low-dose estradial with norethisterone in women with AD (N = 65) yielded non-signficant treatment differences on cognitive outcomes, although a benefical treatment effect on mood was noted in those who did not possess the ApoE ε4 allele (Valen-Sendstad et al., 2010). In a small study of women with mild-to-moderate (N = 27) cognitive impairment, otherwise unspecified, Yamada et al. (2010) found improved cognition and function with six months of treatment with dehydroepiandrosterone, which increased plasma testosterone (Yamada et al., 2010).

In a randomized, double-blind, placebo-controlled design, women with surgically induced menopause (N = 50; mean [SD] age, 54.0 [2.9] years) received estradiol valerate in combination with testosterone undecanoate or placebo. The women were assessed with a self-report questionnaire regarding memory and neuropsychological tests for verbal and spatial episodic memory and incidental learning at baseline, at the time of crossover, and after completion of treatment. Results indicate testosterone had a negative effect on immediate but not delayed recall. Overall no treatment benefit was noted (Moller et al., 2010). Taken together, there is little consistent evidence that there is a benefit to estrogen or testosterone treatment in women with AD.

Several studies have examined testosterone in males with AD, though the trials have been small and brief. In one small study (N = 16) using testosterone in the form of hydroalcoholic gel (75 mg) applied topically for 25 weeks, there were no differences in cognition or behavior but a benefit was seen in the patient’s quality of life as reported by a caregiver. (Lu et al., 2006). In another small (N = 32) study of men with AD or MCI treated with intramuscular injections of 100 mg T enanthate for six weeks, improvements compared to placebo were seen in spatial memory and constructional tests (Cherrier et al., 2005).

A third small study (N = 10) of hypogonadal males (total testosterone <240 ng/dl or 7 nmol/l) with AD examined the effect of treatment with intramuscular testosterone, 200 mg every two weeks for up to a year compared with placebo. Benefits on global cognitive measures were seen on the ADAS cog and the Mini-Mental State Exam. Prostate-specific antigen levels were also elevated (Tan and Pu, 2003).

Although the focus of this chapter is treatments for dementia and Alzheimer’s disease, there have been several studies to assess the value of estrogen and testosterone in non-demented males to protect against cognitive decline or to enhance cognitive function. Several reviews are recommended (Wharton et al., 2011; Yamada et al., 2010) ; most report little evidence of a benefit in cognition or dementia prevention.

MODIFICATION OF CARDIOVASCULAR RISK FACTORS AS A TREATMENT
OF DEMENTIA

Traditionally, AD has been thought to be a primary neurodegenerative disorder and not of vascular origin. However, many discussions of AD incidence and prevalence have included references to the vascular contributions to the symptoms of dementia (e.g., Barnes and Yaffe, 2011; Schrijvers et al., 2012). Cardiovascular risk factors are highly prevalent in the elderly population and rarely exist in isolation. Diabetes mellitus, hypertension, hyperlipidemia, and coronary artery disease often coexist, and this constellation of cardiovascular risk factors has been found to increase the risk for cognitive decline, vascular dementia, and AD (Luchsinger and Mayeux, 2004). The risk of AD has been found to increase with the number of vascular risk factors present in an individual (Luchsinger et al., 2005). However, many randomized clinical trials have been conducted to capture this benefit but to date few have succeeded in demonstrating that treatments for hypertension, hyperlipidemia, or diabetes can modify cognitive decline, incident dementia, or the trajectory of AD. These approaches are summarized as follows.

CHOLESTEROL LOWERING

A 2009 Cochrane review of two randomized trials of cholesterol lowering agents in adults with cardiovascular risks, with primary outcomes for reducing cardiovascular events, described the absence of benefit on cognition and dementia prevention (McGuinness, Craig et al., 2009). In the most recent trial with pravastatin (PROPSER), there was no effect on cognition or incident dementia despite robust assessment (Trompet et al., 2010), despite the fact that cognitive tests showed a significant decline over time, confirming sensitivity to cognitive deterioration with age. The review concludes that despite biological feasibility, there is good evidence from RCTs that statins given in late life to individuals at risk of vascular disease have no effect in preventing AD or dementia.

Another series of studies examined the effect of statins on improving the cognitive deterioration of individuals with AD who did not have cardiovascular risk factors. A study using atorvastatin, which does not have CNS penetration (Feldman et al., 2010) as well as a study with simvastatin, which does (Sano et al., 2011), had similarly negative results. Both showed no benefit on any cognitive, functional, or clinical outcome, despite evidence of significant lipid lowering, although both studies demonstrated acceptable safety. The efficacy of statins for preventing cardiovascular events prevents the ethical conduct of studies to assess the effects of these agents on cognition among individuals with AD who do have cardiovascular risks. Although these agents have efficacy for reducing events that are associated with cognitive impairment, there is no evidence of direct clinical or cognitive benefit in AD.

ANTIHYPERTENSIVES

Hypertension is a well-known risk factor for cardiovascular disease and stroke, and thus for vascular dementia. Vascular contribution to AD has been proposed and neuropathological studies suggest that these are independent and additive (Launer et al., 2008). However, the treatment of hypertension is not so clearly associated with a reduction in risk of dementia or a benefit in cognition. Treatment trials usually use a combination of agents from several classes to achieve maximum control of hypertension, including diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers. In a comprehensive review of antihypertensive treatment trials, four were identified that assessed incident dementia as an outcome (McGuinness, Todd et al., 2009). This metaanalysis found no treatment-related differences in incident dementia, despite a trend in that direction in three of the four trials. Three of the four also assessed cognitive change as an outcome, with only one trial, Hypertension in the Very Elderly Trial (HYVET-COG), showing a trend in the positive direction (Peters et al., 2008). A recent report, modeling the effect over longer intervals indicated persistence of the small benefit with treatment (Peters et al., 2010).

In a recent metaanalysis of more than 60,000 cases, vascular dementia was considered separately from all other dementias and the results detected a benefit of antihypertensive treatment on vascular dementia but not on other dementias (Chang-Quan et al., 2011). It is important to note that in these large-scale trials the dementia diagnosis is a clinical one and seldom includes technologies that assess the underlying pathology of amyloid, tau, or synaptic loss and dysfunction. Thus these trials might have yielded different results in subsets of individuals with specific AD pathology.

While the direct benefit of medications to lower cardiovascular risk on cognitive outcomes does not support its use to prevent or treat AD, evidence-based medicine indicates these agents should be used to treat cardiovascular disease. Yet there is evidence that patients with AD and related disorders are undertreated with these agents (Rattinger et al., 2012).

TREATMENTS FOR DIABETES MELLITUS

The association between cognitive impairment and dementia and diabetes has been supported by many epidemiological studies. In type II diabetes, cognitive impairment mainly affects learning and memory, mental speed, and flexibility (Allen et al., 2004). The association between diabetes mellitus and AD is particularly strong among carriers of the apolipoprotein ε4 (ApoE4) allele (Peila et al., 2002). Treatments for diabetes, including insulin, have been studied in large and small randomized clinical trials with mixed results. Two categories of studies are of note: one includes the treatment of individuals with diabetes with antidiabetic agents and assesses the impact on cognition and dementia. Sato et al. described a six-month, randomized trial in patients with AD and type II diabetes mellitus treated with 15–30 mg pioglitazone daily (N = 21) or not (N = 21) (Sato et al., 2011). While cognitive improvement over baseline was reported in the treated group but not the placebo group, no drug placebo comparison was conducted. A secondary analysis, comparing diabetic and non-diabetic patients with The ACCORD-MIND study examined the cognitive effect of intensive versus standard glucose lowering of individuals with type II diabetes, aged 49–79. No benefit on memory, attention, or executive function was observed (Launer et al., 2011). The authors indicate that intensive antidiabetic therapy is not recommended to reduce the adverse effects of diabetes on the brain.

The other category of studies assesses individuals with AD to determine if typical antidiabetic drugs can improve symptoms or modify disease course. Two phase 3 studies evaluated the safety and efficacy of the peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, in nondiabetic patients with AD. More than 2,000 subjects were enrolled, with one cohort receiving concomitant AD medications and the other not. There was no effect on cognition or other clinical measures and no interaction with ApoEε4 (Harrington et al., 2011). Studies with Piaglitazone, though smaller and fewer, show comparable results (Geldmacher et al., 2011). Small single site studies have indicated that insulin, administered by infusion or intranasally, may have some cogntive benefits. One study found a benefit with infused insulin in individuals with mild cognitive impairment who were ApoE ε4 carriers (Watson et al., 2009). Another larger study (N = 100) of individuals with MCI found better scores on memory with a low dose (20/mg) of intranasal insulin but poorer performance at a higher dose (Craft et al., 2012). This result will be explored in a larger trial in AD which was recently funded.

CONCLUSIONS

Although there are few currently FDA-approved treatments for AD, the data on the cholinesterase inhibitors consistently show robust although modest effect on cognitive improvement across disease severity. Some data suggest that higher doses provide greater effect, though this is limited by side effects. Memantine has shown less robust effects and primarily in moderate to severely impaired populations, but not in more mild individuals. A large current trial is again looking at effects in milder disease stages.

Despite the very significant need, no novel treatments have been approved over the past nine years. Although future research is likely aiming at prevention strategies, the challenge of treating symptomatic AD will continue to persist, given increased longevity. Novel approaches that target hallmark pathology may or may not have an effect at the fully symptomatic stage. New approaches may include addressing synaptic dysfunction and cell death, which should be relevant at a wide range of disease severity.

Future development of therapeutics for AD will undoubtedly include treatments for symptomatic individuals who are considered to have prodromal AD, and later trials will probably turn to those with no symptoms but who have imaging biomarkers that may prove to be associated with AD development later in life.

Although risk reduction of competing conditions has been proposed as an effective approach for the treatment and prevention of AD (Barnes and Yaffe, 2011), population-based studies suggest that these risks may already be well managed (Schrijvers et al., 2012), mitigating (Langa et al., 2008) the expectation of further benefit. Thus only new therapeutics hold a hope for true improvement.

DISCLOSURES

Dr. Sano reports that she has been a paid advisor/consultant to Eli Lilly, Esai, Medivation, Medpace, Nutricia, Sanofi-Aventis, and Takeda. Dr. Sano reports she has been an unpaid advisor to Merck.

Dr. Neugroschl has no conflicts of interest to disclose.

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