Malattia di Alzheimer: i pro e i contro delle terapie farmaceutiche, nutraceutiche, botaniche e stimolatorie

1. Review Article
amr
Alzheimer’s Disease: The Pros and Cons of
Pharmaceutical, Nutritional, Botanical, and
Stimulatory Therapies, with a Discussion of
Treatment Strategies from the Perspective of
Patients and Practitioners
Keith A. Wollen, PhD
Abstract emphasis has been on single-target approaches, AD
Alzheimer’s disease (AD) is characterized by dysfunctional is characterized by many different cellular dysfunc-
intracellular and extracellular biochemical processes that tions, suggesting that a multi-target approach may
result in neuron death. This article summarizes hypotheses provide more therapeutic value.
regarding cell dysfunction in AD and discusses the effective- The goal of this article is to present a current
ness of, and problems with, different therapies. Pharma- review of pharmaceutical, nutritional, botanical,
ceutical therapies discussed include cholinesterase inhibitors, and stimulatory therapies. Stimulatory therapies,
memantine, antihypertensive drugs, anti-inflammatory drugs, which include physical exercise, music, and
secretase inhibitors, insulin resistance drugs, etanercept, cognitive training, have received very little
brain-derived neurotrophic factor, and immunization. attention but may prove to be important adjuncts
Nutritional/botanical therapies included are huperzine A, to more traditional approaches. Since FDA-
polyphenols, Ginkgo, Panax ginseng, Withania somnifera, approved pharmaceuticals offer only modest
phosphatidylserine, alpha-lipoic acid, omega-3 fatty acids, short-term benefits, serious side effects, and high
acetyl L-carnitine, coenzyme Q10, various vitamins and cost, and nutrients and botanicals often have less
minerals, and melatonin. Stimulatory therapies discussed are research backing, practitioners must weigh the
physical exercise, cognitive training, music, and socialization. potential drawbacks of all therapies against the
Finally, treatment strategies are discussed in light of the certain consequences of AD progression.
benefits and drawbacks of different therapeutic approaches. It
is concluded that potential risks of both approved and AD Pathology
non-approved therapies should be weighed against the At the most basic level, AD results from cell
Keith A. Wollen, PhD – potential benefits and certain consequences of disease death that can result from many different factors.
Professor Emeritus, progression. Approaches that target several dysfunctions Alzheimer brains have low levels of acetylcholine
Psychology Department of
Washington State University; simultaneously and that emphasize nutritional, botanical, and (ACh), which can arise from the accumulation of
research area in learning stimulatory therapies may offer the most benefit at this time. beta amyloid (βA) protein fragments that form
and memory. (Altern Med Rev 2010;15(3):223-244) hard plaques that can in turn interfere with the
Correspondence address:
3203 South Maple Street, ability of ACh to effect synaptic transmission and
Port Angeles, WA 98362 Introduction initiate inflammatory processes that produce
Email: kfw@olypen.com Although there have been numerous reviews of reactive oxygen species. Research suggests that βA
therapies for Alzheimer’s disease (AD), most have opens channels in cell membranes, permitting
concentrated on either pharmaceuticals or natural calcium ions (Ca2+) to enter the cell and triggering
therapies, with only a few covering elements of several processes leading to mitochondrial dysfunc-
both. Many papers are oriented toward researchers tion, inflammation, and cell death.1 Some research
rather than practitioners. Although usually the suggests that, in the early stages of AD, βA has an
223 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

2. amr Review Article
Key words: Alzheimer,
antioxidant function so that efforts to reduce it Administration (FDA) for treating AD. Meta- huperzine, hupA, Ginkgo,
might be counterproductive. Other research has analyses have repeatedly found that AChEIs have a Virtiva, ginseng, Withania,
found only a weak relationship between the modest beneficial effect on cognition and memory.5 ashwagandha, lipoic,
phosphatidylserine,
amounts of βA and the severity of AD. βA may be Donepezil and rivastigmine are often regarded as omega, fish oil, EPA, DHA, ALA,
the end result of a destructive chain of events and providing only symptomatic relief without provid- acetyl-L-carnitine, ALC, ALCAR,
hence more symptomatic than problematic. ing neuroprotective effects. However, in vitro coenzyme, CoQ10, memory,
cognition, cognitive, brain,
Another possible cause of cell death in AD is a studies show that donepezil offers neuroprotection curcumin, resveratrol,
chemical change in a protein (tau) that keeps by reducing glutamate excitotoxicity, diminishing idebenone, lithium,
microtubules stable. This causes a neuron’s βA toxicity, and consequently increasing cell melatonin
microtubules to pair with other tubules producing longevity.6,7 Donepezil slowed atrophy of the
tau (neurofibrillary) tangles that result in tubule hippocampus in humans, which suggests a neuro-
disintegration and block neurotransmitters, protective effect.8 Data also suggest that cognitive
leading to cell death. benefits from donepezil after three years are
Reactive oxygen species (oxygen ions, peroxides, greater when treatment is started early rather than
and free radicals) can result in cell death by delayed one year.9
initiating a chain reaction that leads to damage of Galantamine, a natural AChEI (originally derived
cell membranes, mitochondria, lipids, and proteins. from the common snowdrop and other plants, but
Damage from toxic excitatory amino acid now synthesized), protects neurons and reduces
neurotransmitters, especially glutamate, can cell death by modulating nicotinic receptors, which
produce excitotoxicity and cell death. Excitotoxicity are significantly reduced in AD brains.10,11 In an
can occur even with normal glutamate levels if animal model, galantamine also increased dopami-
glutamate receptor sites become overstimulated.2 nergic neurotransmission in the hippocampus,10 a
The receptor most involved in excitotoxicity is brain area particularly important in memory.
N-methyl-D-aspartic acid (NMDA). If NMDA sites Galantamine does not result in tolerance and
are overactivated, high levels of Ca2+ can enter the only short-term efficacy characteristic of donepezil
cell, causing a permanent depolarization of the and rivastigmine.11 A meta-analysis of 10 random-
post-synaptic neuron and creating reactive oxygen ized, placebo-controlled, double-blind studies
species and other substances that cause cell death. concluded that galantamine either improved or
Potential mechanisms have also linked excitotoxic- prevented decline of cognition and activities of
ity to βA and tau tangles.2 daily living.12 Since galantamine can produce
Damage from toxins, chemicals, and trauma can gastrointestinal upset, researchers recommend
produce inflammation, another factor in AD. starting with a low dose and gradually increasing to
Inflammation often results from persistent 16-24 mg daily. The beneficial effects of galan-
oxidative stress, but other determinants include tamine have been found to persist for 36 months,
βA, protease inhibitors, pentraxins, inflammatory with 50-percent improvement over expected scores
cytokines, and prostaglandin-generating cyclooxy- of untreated mild-to-moderate AD subjects.13 The
genases. Unhealthy neurons contain low levels of magnitude of the benefit increases over time.
N-acetyl-aspartate (NAA), which may also be an Rivastigmine, which inhibits both butyrylcholin-
issue. Exposure to pollutants can make the esterase and AChE, provides two pathways for
blood-brain barrier permeable to toxins, thus prolonging ACh and so might be expected to be
causing oxidative stress, inflammation, and βA more effective than donepezil or galantamine. Such
accumulation.3,4 an outcome, along with less cortical atrophy in the
temporal parietal area, was observed in mild AD
Pharmaceutical Therapies patients over a 20-week period.14 A post hoc
Acetylcholinesterase Inhibitors (AChEIs) analysis of several studies suggests that rivastig-
AChEIs inhibit the action of acetylcholinesterase mine slows the rate of decline as long as five
(AChE), thereby enabling ACh to work for a longer years.15
period of time, interact with cholinergic receptors AChEIs have several limitations; they are
and potassium ion channels, and affect the uptake, expensive, provide modest benefits, and usually
synthesis, and release of neurotransmitters. have a brief period of effectiveness (sometimes
AChEIs include donepezil (Aricept®), rivastigmine partially resolved by switching to a different
(Exelon®), galantamine (Razadyne®), and tacrine AChEI). AChEIs have short half-lives and may have
(Cognex®) – all approved by the U.S. Food and Drug considerable side effects (especially tacrine),
Volume 15, Number 3 Alternative Medicine Review 224
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

3. Review Article
amr
resulting from activation of peripheral cholinergic less cognitive decline when given an ACE inhibitor
systems.16 More emphasis is needed on clinical that crossed the blood-brain barrier (perindopril or
significance rather than statistical significance. captopril) than when given an ACE inhibitor that
did not (enalapril or imidapril) or a calcium
NMDA Antagonists channel blocker (nifedipine or nilvadipine).30 A
Memantine is thought to reduce cell damage by recent study confirmed that ACE inhibitors slow
decreasing excitotoxicity resulting from overactiva- the progression of AD.31 A potential downside of
tion of NMDA glutamate receptors during synaptic ACE inhibitors is that they may block ACE from
transmission. Memantine stops overstimulation by converting βA1-42 to less damaging βA1-40, thereby
binding to NMDA receptors, which inhibits the reducing its protective function.32
influx of Ca2+ and results in a small improvement in Possible mechanisms by which ACE inhibitors
cognition and behavior.17 Although memantine has work include reducing angiotensin II (a substance
been FDA approved only for more severe AD, it has that interferes with memory formation by reducing
been found effective in phase III trials for both ACh),33 increasing an enzyme that breaks down βA,
moderate-to-severe18,19 and mild-to-moderate and increasing acetylcholine. Another possibility is
cases.20,21 Nevertheless, the overall data suggest that angiotensin II is converted to angiotensin III
that clinically significant effects on cognition, and then to angiotensin IV. Angiotensin IV binds at
mood, and performance of daily activities are seen AT4 receptor sites, which are most prevalent in the
primarily with more severe cases of AD.22 neocortex, hippocampus, and other areas impor-
It is important not to completely block all tant in cognition and memory. This counteracts a
glutamate-mediated synaptic transmission since dysfunctional cholinergic system, resulting in more
cells must have some NMDA activity to function ACh and improved learning and memory.34
properly. Memantine meets this criterion since it Angiotensin receptor blockers are antihyperten-
selectively blocks only excessive stimulation.2,23 sive drugs that block the action of angiotensin II by
In a small study of 11 AD patients, memantine binding at AT1 receptor sites. They have been
was shown to reduce tau phosphorylation, which reported to reduce AD risk and slow its progres-
would be expected to reduce tau tangles.24 Other sion.35,36 These drugs include telmisartan, valsartan,
neuroprotective effects have been summarized in a losartan, and candesartan. Potential mechanisms
recent review.25 Memantine appears to be well of action include reducing angiotensin II and
tolerated.26 increasing the activation of AT4 receptors.
NMDA antagonists, such as memantine, have Calcium channel blockers are another category
generally been regarded as neuroprotective,2 but of antihypertensive drugs. It may be that βA,
they have also demonstrated neurotoxic properties mutations in presenilin proteins, or other factors
that diminish memory, incite neuron death, and open channels that permit Ca2+ to enter and
even produce psychotic episodes in humans.27 damage cells.37 If so, calcium channel blockers
Memantine’s neurotoxicity may be increased by might be expected to benefit AD patients.
AChEIs. Such an effect has been demonstrated in Although some research has shown that people
an animal model where the concurrent use of taking calcium channel blockers were less likely to
donepezil and memantine produced a substantial develop dementia,38 other studies have been
increase in neurotoxic reactions.27 Although the negative.39 Since most research has been on
clinical relevance of this in humans is unknown, hypertensive individuals, the effects of calcium
the simultaneous use of both drugs merits caution. channel blockers on nonhypertensive subjects are
On the other hand, recent research shows that such unknown.
combinations slow cognitive decline more than
memantine or AChEIs alone and that the benefit of Anti-Inflammatory Drugs
combination therapy increases over time and Most research on nonsteroidal anti-inflamma-
persists for years.28 tory drugs (NSAIDs) has focused on prevention
rather than treatment of AD. One study that
Antihypertensive Drugs examined 49,349 NSAID users for five years found
Antihypertensive drugs have potential for AD the risk of acquiring AD was clearly reduced by
therapy. Angiotensin converting enzyme (ACE) ibuprofen and less so by indomethacin, while
inhibitors reduced inflammation and mental celecoxib and the salicylates offered no protec-
decline in AD patients by 50 percent.29 Mild-to- tion.40 It was not possible to determine AD risk for
moderate AD subjects with high blood pressure had many NSAIDs because of small numbers of users.
225 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

4. amr Review Article
NSAIDs that reduced βA1-42 were no more likely to Insulin
be effective than those that did not. Studies of risk Insulin has many roles in normal cell function-
have been inconsistent and correlational in nature, ing. Nasal administration of insulin improved
making it impossible to conclude causation. several cognitive measures in subjects with early
Moreover, other studies have reported that NSAID AD or mild cognitive impairment.51 Nasal adminis-
use can actually increase the risk of developing tration allows insulin to reach the brain quickly
dementia.41 NSAIDs are well known for producing without affecting insulin levels elsewhere in the
gastrointestinal symptoms as well as liver and body. Nasal administration has also improved
kidney toxicity. verbal memory but only for persons with a specific
Research on the use of NSAIDs for the treatment genetic makeup (the apolipoprotein E4 [APOE ε4]
of AD patients has also been disappointing.42 A allele).52 The latter study used only three doses of
randomized, placebo-controlled study of people insulin (versus 42 in the previous study) and tested
with mild-to-moderate AD found no cognitive 15 minutes after administration (versus after 21
benefit from NSAIDs.43 days).
Animal models have demonstrated that anti- Insulin resistance can affect the brain as well as
inflammatory cyclooxygenase-2 (COX-2) inhibitors other organs, making it difficult for the brain cells
(rofecoxib) reduced oxidative stress but non-spe- to acquire energy for cell maintenance and synaptic
cific COX inhibitors (flurbiprofen and ibuprofen) connections; thus, cell death can occur.53 Also,
did not.44 An animal model revealed that ibuprofen, hyperinsulinemia has been found to increase
naproxen, and a COX-2 inhibitor (MF-tricyclic) inflammation and βA1-42 in healthy adults.54
each restored memory, but only MF-tricyclic A possible mechanism underlying insulin
blocked the suppressive effects of βA on synaptic resistance in the central nervous system is the
plasticity.45 In an 18-month human trial, celecoxib, formation of toxic protein fragments called
a COX-2 inhibitor, improved memory and cogni- beta-amyloid derived diffusible ligands (ADDLs).
tion in individuals with mild cognitive According to this view, ADDLs bind to synaptic
impairment.46 receptor sites, where they prevent insulin from
working, causing synaptic dysfunction and
Secretase Inhibitors eventual dementia. Other possible mechanisms of
Secretases are enzymes that break amyloid action are described elsewhere.55
precursor protein (APP), found in cell membranes,
into βA fragments that form plaques. Consequently, Etanercept (Enbrel®)
secretase inhibitors should slow the production of Etanercept has recently generated interest
βA. Human research is very limited, but a gamma- because it produced dramatic cognitive improve-
secretase inhibitor has been shown to reduce ment. AD brains have elevated levels of the
plasma βA by about 60 percent in a small 14-week cytokine tumor necrosis factor-alpha (TNF-α).
study of mild-to-moderate AD patients; however, Since TNF-α regulates neural transmission,
no significant differences in cognition were found.47 lowering it by spinal injections of etanercept might
Conclusions that the treatment was well tolerated restore the brain to more normal functioning. A
seem false, given hair color changes, skin rashes, a dramatic cognitive improvement was evidenced in
bowel obstruction, nausea, vomiting, diarrhea, and one moderate-to-severe AD subject within min-
more in just 36 treated subjects. utes.56 The author reported this finding was
Beta-secretase inhibitors have been shown to commonly observed on multiple patients over
reduce βA in animal models and may have fewer three years of clinical practice. An open-label pilot
adverse effects.48,49 Memoquin is a beta-secretase study with mild-to-severe AD found once weekly
inhibitor that also inhibits AChE, reduces βA treatments of 25-50 mg etanercept produced
production, limits tau hyperphosphorylation, and improvement over a six-month period.57 Etanercept
fights oxidation, but it is early in the developmen- is FDA approved for immune disorders but not for
50
tal stage. Presently, most research involves develop- AD.
ing secretase inhibitor molecules that will pen-
etrate the blood-brain barrier, produce beneficial Brain Derived Neurotrophic Factor (BDNF)
results, and not produce adverse effects. BDNF is a protein produced in the brain that
helps existing neurons survive, facilitates the
growth of new neurons and synapses, and reverses
neuronal atrophy and behavior deficits;
Volume 15, Number 3 Alternative Medicine Review 226
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

5. Review Article
amr
intracellular signaling is also facilitated. BDNF is Flavonoids and other Novel Plant
active in the hippocampus and cortex and low Constituents
levels of it are associated with poor memory. In HuperzineA (HupA)
some areas of the brain, BDNF stimulates neuro- HupA is an extract from the Chinese moss
genesis. BDNF levels decline with age and are lower Huperzia serrata that has been used for centuries in
in AD brains than in those without dementia.58 Chinese folk medicine to treat a wide range of
In various mouse, rat, and primate models, diseases. A review of in vitro and animal studies
BDNF has reversed synaptic damage, partially found HupA preserves ACh longer than tacrine,
normalized genetic errors, improved cell signaling, galantamine, or donepezil.69 HupA reduces
reversed learning and memory deficits, reversed βA-induced neuronal degeneration in the hippo-
cognitive decline, and reduced oxidative stress and campus and cortex, decreases oxidative damage
cell death.59 These changes did not result from from free-radical induced βA plaques, protects
changes in βA. neurons from cytotoxins and apoptosis induced by
A major problem is that the BDNF molecule is βA and free radicals, and inhibits glutamate
too large to penetrate the blood-brain barrier. toxicity. The research and potential mechanisms of
Human trials, mostly investigating Parkinson’s action underlying these effects have been reviewed
disease, have used a micro pump to directly infuse in detail.69,70
BDNF into the brain through a cannula inserted Acetylcholinesterase exists in different molecular
into the skull. This risky procedure accounts for the forms referred to as G1, G2, G3, and G4. Human
lack of human trials.60 In addition, too large a dose brains have mostly the G4 form with a smaller
can produce serious side effects. Although in vitro amount of G1. Hence, inhibition of G4 is more
and animal data are promising, it is unlikely that germane in terms of prolonging ACh and facilitat-
BDNF therapy will be in use anytime soon. ing synaptic transmission in humans. In the
However, physical exercise and diets rich in striatum and hippocampus (areas important in
omega-3 fatty acids have been found to normalize learning and memory), HupA primarily inhibits G4,
BDNF without the difficulties associated with brain whereas donepezil primarily inhibits G1. HupA
infusions.61,62 penetrates the blood-brain barrier better than
donepezil, rivastigmine, or tacrine.70
Immunization Two Chinese randomized, double-blind, placebo-
βA has been reduced by injecting AD patients controlled trials with 103 AD patients for eight
with a synthetic form of βA called AN1792. weeks71 and 202 mild-to-moderate AD patients for
Although this reduces βA, the effect on AD is 12 weeks72 used 400 mcg HupA daily. In both cases,
unclear. Some people respond to immunization there was statistically and clinically more improve-
with a slowing of disease progression even after 4.6 ment in several measures of cognition, memory,
years,63 but other studies have found a clearing of and activities of daily living in the HupA group
βA without any cognitive benefit.64 It may be that than in placebo controls. A recent meta-analysis of
βA accumulation starts a chain of events that four Chinese studies found 300-500 mcg HupA
cannot be stopped by merely clearing βA depos- produced a marked improvement in cognition.73
its.65 Three phase II studies have been reviewed A U.S. phase II clinical trial of 210 mild-to-mod-
elsewhere.66 It is unlikely that immunization erate AD patients over 16 weeks found 800 mcg of
therapy will be practical for some time. HupA, but not 400 mcg, resulted in cognitive
The advantages and disadvantages of pharma- enhancement.74 A Cochrane review concluded that,
ceutical therapies are summarized in Table 1. although HupA improves cognition, there are too
few studies of sufficient quality to recommend its
Antipsychotics and Sedatives Warning use.75 Similar conclusions were reached in another
Antipsychotics and sedatives have accelerated the review.76 At this point, HupA appears to be
progression of AD, defined as an increase of one effective and better tolerated than FDA-approved
or more points in the Global Deterioration Scale,67 AChEIs, but larger studies with longer treatment
and produced a 50-percent decrease in cortical periods would be desirable.
plasticity in cats.68 Thus, care should be exercised in
using such drugs for AD patients. Polyphenols
Polyphenols are a group of plant-derived
chemical substances with more than one phenol
unit. They protect plants from stress induced by
227 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

6. amr Review Article
Table 1. Advantages and Disadvantages of Pharmaceuticals for AD
Pharmaceutical Advantages Disadvantages
Acetylcholinesterase inhibitors* Prolong ACh; some Often short-term e cacy; severe
evidence for neuroprotec- side e ects; high costs; modest
tion; FDA approved bene ts
Memantine* Decreases glutamate Possible neurotoxicity; some
excitotoxicity; possible severe adverse e ects; primarily
other neuroprotective recommended for moderate-
e ects; well tolerated; FDA to-severe AD; high cost
approved for moderate-to-
severe AD, but also helps
mild-to-moderate AD
Antihypertensive drugs Reduce in ammation; may Most human research on
block Ca2+; may reduce βA hypertensive individuals and
and increase ACh animals
Anti-in ammatory drugs May reduce neural in am- Most research focused on risk of
mation acquiring AD and not on
treatment; human research
correlational in nature, making
causation impossible to deter-
mine; e ects on intestinal tract,
liver, and kidneys; therapeutic
bene t questionable
Secretase inhibitors May reduce βA and inhibit Little human research; severe
AChE adverse e ects; insu cient data
Insulin drugs Improve energy production Must be administered nasally to
and cellular functions; may prevent insulin changes in
reduce ADDLs and oxidative non-brain areas; little human
stress; reduce cell death data
Etanercept Produces dramatic improve- Little research; risky spinal
ment within minutes injections required
BDNF Stimulates neurogenesis; Molecule too large to penetrate
reverses synaptic damage; blood-brain barrier; risky
improves signaling; reduces administration via a cannula in
oxidative stress and cell the skull; can produce serious
death side e ects; little human
research.
Immunization Reduces βA Often ine ective; clearing of βA
not always accompanied by
symptom reduction; early in the
development stage
*Denotes therapies with the most research backing and therapeutic potential for AD
Volume 15, Number 3 Alternative Medicine Review 228
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

7. Review Article
amr
ultraviolet radiation, disease, pests, and physical systems that protect cells.77,89 Animal models
damage. Polyphenols also protect animals by suggest that resveratrol mimics the effects of
activating a number of intracellular processes that caloric restriction on longevity and negates the
preserve neurons. harmful effects of a high-fat diet,90 doubles
resistance to muscle fatigue,91 reduces neurotoxic-
Curcumin ity, decreases cell death, reduces degeneration of
Curcumin is extracted from the plant Curcuma the hippocampus, and prevents learning impair-
longa (turmeric). Reviewers suggest curcumin may ment.92 Several studies have shown that moderate
be a promising therapy for AD because it has at consumption of red wine reduces the risk of
least 10 neuroprotective properties, including developing AD.93
anti-inflammatory, antioxidant, inhibition of βA Resveratrol is similar to curcumin in that oral
formation, clearance of existing βA, and copper bioavailability is low because it is quickly metabo-
and iron chelation. 42,77,78 lized and excreted. Attempts have been made to
Curcumin readily penetrates the blood-brain increase bioavailability by the use of quercetin,
barrier, but oral administration may produce barely catechin, apigenin, fisetin, myricetin, and kaemp-
detectable blood levels at doses of 2 g and low ferol.94 Whether resveratrol will slow the progres-
levels at 8 g.79 The reasons for bioavailability sion of AD awaits the outcome of trials currently
problems appear to be low absorption, rapid underway.95
metabolism, quick elimination, and the inherent
instability and hydrophobic nature of curcumin. Herbal Supplements
Efforts to increase bioavailability have been Ginkgo biloba
covered in an extensive review.80 One approach is Ginkgo biloba contains compounds that have
to use adjuvants, such as piperine, that increase antioxidant and anti-inflammatory properties that
bioavailability by blocking metabolic pathways. protect neuron membranes, regulate neurotrans-
Adding 20 mg of piperine to 2 g of curcumin mitters, and retard cell degeneration. It is sold as a
increased bioavailability by a factor of 20 in supplement in the United States, dispensed as a
humans.81 Quercetin may also enhance bioavail- pharmaceutical in Europe, and has been used for
ability.82 Bioavailability has been significantly centuries in traditional Chinese medicine. In vitro
enhanced by combining curcumin with phosphati- data show that Ginkgo biloba extract EGb 761
dylcholine or other lipophilic formulations.83 Other reduces βA and neuron death.96,97 Elderly mice fed
approaches combine curcumin with turmeric oil or EGb 761 exhibit hippocampal neurogenesis.98
use nanoparticles.84 Numerous other animal and in vitro studies
Turmeric is a widely used spice in India, which support Ginkgo’s neuroprotective benefits.
may explain why India has a much lower incidence Many early human studies found that Ginkgo
of AD than the United States.85,86 Bioavailability improved cognition in AD patients. However, these
may not be a problem for Indians because it is studies often used few subjects and had method-
combined with oil in cooking. A randomized, ological problems. More recently, a number of
double-blind, placebo-controlled clinical trial tested randomized, double-blind, placebo-controlled trials
nine subjects from old-age homes and 24 from have produced positive results. Ginkgo produced
dementia clinics over six months. A daily dose of 1 more cognitive benefits than placebo for 156 AD
g or 4 g curcumin without bioavailability enhancers patients receiving 240 mg daily for 24 weeks,99 for
produced no cognitive benefit relative to a pla- 202 AD patients receiving 120 mg daily over 52
cebo.87 No significant effects were found on several weeks,100 in a 2003 re-analysis of Kanowski et al
cognitive tests in another randomized, double- 1999 data using previously unpublished data,101 for
blind, placebo-controlled trial that used 2 g or 4 g 214 patients with probable AD given 240 mg
curcumin enhanced by piperine and green tea Ginkgo daily for 22 weeks,102 and for a post hoc
extract (Curcumin C3 Complex®) in 36 mild-to- analysis of LeBars et al showing that Ginkgo
moderate AD patients.88 improved cognition for mild to very mild impair-
ment and reduced deterioration in subjects with
Resveratrol more severe dementia.103
Resveratrol, a polyphenol found in red wine, In contrast, recent randomized, double-blind,
peanuts, and other plants, reduces oxidative stress, controlled studies, using subjects without demen-
decreases inflammation, reduces βA, protects DNA, tia, concluded that Ginkgo did not slow dementia
decreases cell death, and modulates various other onset. One study gave 120 mg Ginkgo twice daily
229 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

8. amr Review Article
to 2,587 healthy subjects and 482 subjects with another study of 96 subjects with probable AD over
mild cognitive impairment over a period of 6.1 22 weeks, comparing daily doses of 240 mg Ginkgo,
years, with testing at six-month intervals. Ginkgo 5 mg donepezil increasing to 10 mg after four
was no better than placebo at preventing the onset weeks, or placebo. Although the groups did not
of dementia or AD.104 A second study examined differ significantly, there was a suggestion that a
3,069 healthy individuals given 120 mg Ginkgo combination of the two might be better than either
twice daily for 6.1 years. There was no effect on alone.112
cognitive decline.105 Another study of 240 mg There are indications from a small placebo-
Ginkgo daily to 118 subjects with no cognitive controlled, double-blind study of 28 healthy young
impairment for 42 months found no effect on adults that 120 mg Ginkgo is more effective when
cognitive decline.106 Thus, it appears that Ginkgo combined with 360 mg phosphatidylserine (PS) as
aids cognition when subjects have AD but does not a phytosome (Virtiva®). Subjects were given
prevent the onset of AD. cognitive tests at intervals of from 1-6 hours after
A study that is an exception to this conclusion dosing and were tested every seventh day for five
failed to find benefit from 120 mg Ginkgo daily for sessions. Ginkgo improved performance from
six months.107 This study recruited 176 partici- baseline when complexed with phosphatidylserine,
pants with mild-to-moderate dementia by ads and but not as a standardized extract alone or com-
by a clinical diagnosis of dementia from the plexed with phosphatidylcholine.113 Whether this
individuals’ physicians rather than by uniform, outcome would apply for AD patients is unknown.
objective criteria. Although individuals were Although concern has been raised about
excluded if they admitted taking AChEIs, the increased bleeding with Ginkgo, a review of the
authors mentioned there was some noncompliance. clinical-trial literature lends no credence to this
Other interventions were allowed, which could hypothesis.114
have masked the effect of Ginkgo. A final study
found a benefit for Ginkgo only for a subset of AD Panax ginseng
patients who also had behavioral disturbances.108 Panax ginseng (Chinese, Asian, or Korean
As the authors concluded, this outcome can be ginseng) has been studied for its effects on
questioned because the placebo group failed to cognition. Although an early review of randomized,
decline over the course of the study, as would have placebo-controlled clinical trials on ginseng found
been expected, thereby potentially masking any three of four studies produced cognitive benefits,
effect of Ginkgo. the reviewers nevertheless concluded that its
A Cochrane review of 36 trials concluded that effectiveness was in doubt because of methodologi-
the effect of Ginkgo is inconsistent, except in cal deficiencies.115 In a placebo-controlled, double-
subjects having dementia with neuropsychiatric blind, crossover design, a single dose of 200, 400,
features, and that further clinical trials are unwar- or 600 mg Panax ginseng enhanced memory in 20
ranted.109 This meta-analysis combined studies on young healthy adults, with 400 mg providing the
dementia patients with studies of subjects with most benefit.116 Subjects were tested at intervals
little cognitive impairment or just age-related from 1-6 hours following dosing.
cognitive decline. A subsequent meta-analysis The active components in ginseng are thought to
avoided such confounding by including only be steroid-like compounds called ginsenosides.
studies with a diagnosis of mild-to-moderate AD or Ginsenoside Rg3 reduced βA1-42 by 84 percent in
AD plus vascular dementia, including several more vitro and by 31 percent in vivo.117
recent studies and excluding older, methodologi- Despite promising results, there have been few
cally problematic studies.110 The screening yielded studies on AD. A recent review found only two
nine randomized, double-blind trials ranging from studies that met the inclusion criteria. Although
12-52 weeks and totaling 2,372 subjects; all but those studies found significant cognitive benefits,
one study was placebo-controlled. Ginkgo was the authors concluded that methodological
moderately more effective than placebo and the shortcomings rendered the evidence inconclu-
difference was statistically significant. sive.118 A recent trial examined the effect of 4.5 g
Ginkgo and donepezil appeared equally effective Panax ginseng powder daily for 12 weeks on 58
in a 24-week, randomized, placebo-controlled, patients with probable AD, with 39 patients
double-blind study of 76 mild-to-moderate AD serving as controls. The ginseng group gradually
subjects given 160 mg Ginkgo, 5 mg donepezil, or a improved over the 12 weeks of treatment, whereas
placebo daily.111 Similar results were obtained in the placebo group gradually declined.119 During a
Volume 15, Number 3 Alternative Medicine Review 230
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

9. Review Article
amr
12-week follow-up period without treatment, the bovine PS is no longer available.
ginseng group gradually declined to the level of the There is very little research on soy-based PS for
control group. AD. An open study found cognitive benefit for 18
healthy elderly subjects with age-associated
Withania somnifera memory impairment treated with 100 mg soy-
Withania somnifera, a small evergreen shrub based PS three times daily for 12 weeks. Testing at
commonly called ashwagandha or Indian ginseng, six and 12 weeks showed cognitive gains relative to
has been used in India for thousands of years to baseline performance (there was no control
treat many different diseases. A recent review group).129 In a second randomized study, 120
enumerated many neuroprotective properties of elderly subjects with age-associated memory
ashwagandha, including anti-inflammatory, impairment received 300 mg or 600 mg soy PS or
antioxidant, inhibition of βA, inhibition of calcium, placebo daily for 12 weeks. Various cognitive tests
inhibition of AChE, and reduction of cell death.120 were given after six, 12, and 15 weeks. No signifi-
In vitro research has demonstrated that ashwa- cant effects or interactions were found.130 The lack
gandha regenerates damaged axons, dendrites, and of recent research and convincing data on soy-
synapses.121,122 Oral administration of ashwa- based phosphatidylserine presents a confusing
gandha to mice reversed damage to the hippocam- picture requiring more research.
pus and cortex by decreasing neurite atrophy,
restoring synapses, and improving memory.122 At alpha-Lipoic acid (ALA)
least 18 withanolides, the active components in ALA, a fatty acid found in all cells and in some
ashwagandha, have been identified. Withanolides foods, is manufactured in the body. It is a powerful
have different neuroprotective properties; for antioxidant that readily penetrates the blood-brain
example, withanolide-A preserves axons whereas barrier, chelates metals, reduces inflammation, and
withanolides IV and VI preserve dendrites.123 increases ACh. The potential mechanisms underly-
There is no published research on possible ing these and other neuroprotective effects are
therapeutic effects of ashwagandha on AD. reviewed elsewhere.131-133
However, a recent double-blind, randomized, Despite potential benefits, there has been a
placebo-controlled study of the effects of ashwa- paucity of human studies. In one open study, nine
gandha on stress found that it reduced symptoms patients with AD and similar dementias were given
of stress, including forgetfulness and inability to 600 mg ALA daily for an average of 337 days.
concentrate, in a dose-dependent manner, with Before ALA supplementation, cognitive test scores
500 mg/day more effective than 250 mg/day. No had continuously declined; however, after onset
adverse effects were found.124 the scores remained constant.134 This study was
extended to 48 months for 43 subjects with the
Nutrients same result.135 Although promising, these studies
Phosphatidylserine had few subjects, no control group, were not
Phosphatidylserine is important in neurotrans- double-blind, and came from only one lab.
mission, mitochondria function, and cell metabo-
lism. It has also been implicated in the enhance- Omega-3 Fatty Acids
ment of nerve growth factor. In vitro research Omega-3 fatty acids have many beneficial effects
demonstrates PS increases ACh125 and provides that make them investigative prospects for AD. A
neuroprotection by inhibiting βA and recent study followed 5,395 healthy adults for an
inflammation.126 average of 9.6 years to assess the relationship
Supplemental PS was originally derived from between dietary omega-3 intake and risk of
bovine brains, and research using bovine PS developing AD. Dietary intake of omega-3s was the
typically found cognitive benefits. The largest same for the 365 subjects who developed AD as for
double-blind, multi-center, placebo-controlled those who did not.136
study investigated 494 patients with moderate-to- Another study showed no effect of 2 g/day
severe cognitive decline, 69 of whom dropped out. docosahexaenoic acid (DHA) on 402 subjects with
They were given a placebo or 300 mg bovine PS mild-to-moderate AD, but there was a slower rate
daily for six months. The PS groups showed of cognitive decline among those without the
cognitive improvement relative to the placebo.127 APOE ε4 allele.137 Although 1.7 g DHA plus 0.6 g of
Other early positive studies have been reviewed EPA did not slow the rate of cognitive decline in
elsewhere128 and will not be covered here because 204 mild-to-moderate AD patients, a subset with
231 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

10. amr Review Article
very mild AD did benefit.138 A randomized, double- protection against ischemia, as reviewed.151-153 Data
blind, six-month study of 485 subjects with on CoQ10 have been obtained from in vitro studies,
age-related cognitive decline found 900 mg algal animal models, and human research on neurode-
DHA daily improved performance on learning and generative diseases other than AD. The one trial to
memory tests relative to a placebo.139 These data examine the effect of CoQ10 on AD has not yet
suggest that the benefits of omega-3 fatty acids are been published.154 CoQ10 has been found to be safe
limited to those with very mild cognitive and well tolerated at doses as high as 3,600 mg/day,
impairment. although maximum plasma levels are reached at a
dose of 2,400 mg/day.153
Acetyl L-Carnitine (ALCAR) Idebenone is a synthetic variant of CoQ10 that
ALCAR, derived from the amino acid L-carnitine, protects cell membranes and mitochondria from
works synergistically with ALA to transport acetyl oxidative stress, preserves adenosine-triphosphate,
groups and fatty acids into the mitochondria for stimulates nerve growth factor,155 and protects
energy production. ALCAR is a small molecule that from βA toxicity.156 A two-year, randomized,
readily penetrates the blood-brain barrier and double-blind study with 450 mild-to-moderate AD
promotes biosynthesis of ACh while clearing subjects found that each of two idebenone groups
mitochondria of toxic fatty-acid metabolites.140 Its (90 and 120 mg three times daily) scored signifi-
effect on APP helps prevent the buildup of amyloid cantly better than the placebo group in several
plaque and preserves synaptic function.141 ALCAR cognitive measures, with the 120-mg group scoring
also increases nerve growth factor.142 better than the 90-mg group.157 A six-month,
ALCAR has been found to produce cognitive randomized, double-blind, placebo-controlled
benefits for AD patients. A small double-blind study of 300 mild-to-moderate AD patients
study of seven probable AD patients and five compared idebenone (30 or 90 mg three times
placebo controls found that 3 g ALCAR daily daily) with placebo. At the end of six months, only
resulted in less cognitive decline over the course of the 90-mg group performed better than the
one year.143 A meta-analysis of 21 double-blind, placebo on several cognitive tests.158 However, not
randomized, placebo-controlled studies lasting all studies have been positive. A randomized,
from three months to one year showed that ALCAR double-blind, one-year study of 536 subjects with
either improved cognitive deficits or delayed the probable AD compared idebenone (120, 240, or
progression of cognitive decline.144 These effects 360 mg three times daily) with placebo. There were
were both statistically and clinically significant no significant differences among the four groups,
with the magnitude of the effects increasing over although one cognitive test showed a small but
time. Most studies used daily doses from 1.5-2 g, significant difference between the placebo and the
which were well tolerated. three idebenone groups combined. The authors
concluded that the difference was too small to be of
Coenzyme Q10 (CoQ10; Ubiquinone)/Idebenone practical import.159
Coenzyme Q10 is essential for mitochondrial
energy production. Mitochondrial dysfunction can Vitamins and Minerals
result in generation of reactive oxygen species and B Vitamins
oxidative stress.145 Many mitochondrial dysfunc- Low levels of vitamin B12 and folate appear to be
tions occur in AD brains, including disruption of associated with an increased rate of cognitive
energy production, apoptosis deregulation, altered decline.160,161 Also, in a study of 107 normal elderly
calcium homeostasis, and others (reviewed individuals, those with low-normal vitamin B12 had
elsewhere).146 For these reasons, mitochondria are the greatest five-year loss of brain volume.162 Since
viewed as promising therapeutic targets.147 AD patients typically have high levels of homocys-
CoQ10 reduced oxidative stress and tau pathol- teine,163 researchers have examined the possibility
ogy in mice,148 and metabolized βA and inhibited that lowering homocysteine would be therapeutic.
its formation in vitro.149 The reduction of βA found A combination of vitamins B12 and B6 and folate
in a mouse model was attributed to the antioxidant lowered homocysteine both in normal seniors164
properties of CoQ10.150 and in those with mild-to-moderate AD,165,166 but
CoQ10 has other neuroprotective virtues, had no effect on cognition. Homocysteine levels
including protection of mitochondria, reduction of appear to correlate with aging but not with
apoptosis, extension of life, reduction of brain cognition.167
atrophy, promotion of energy production, and
Volume 15, Number 3 Alternative Medicine Review 232
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

11. Review Article
amr
Vitamin A Lithium
Vitamin A has received attention because it is Lithium is a naturally occurring mineral found in
essential for learning, memory, and cognition, and small amounts in many foods. Lithium got a bad
because vitamin A levels in the brain decline with reputation in the 1940s when its use as a salt
age and are lower still in individuals with AD.168 A substitute produced toxicity and even fatalities.
metabolic product of vitamin A, retinoic acid, is The lithium salts orotate and aspartate are some-
known to slow cell death and offer protection from times recommended for neurogenerative disorders.
βA.169 Lithium increases the level of a neuroprotective
protein called bcl-2 in the rat hippocampus and
Vitamin E frontal cortex and inhibits glycogen synthase
Antioxidants have been examined extensively as kinase 3β (GSK-3), which is implicated in increas-
therapeutic possibilities, although questions exist ing levels of phosphorylated tau176 and is thought
regarding whether oxidative stress produces AD or to be a factor leading to βA plaques and cell
vice versa. Vitamin E is low in AD patients.170 death.177 There is also human evidence that lithium
Although in vitro and animal data have been increases N-acetyl-aspartate (NAA) which protects
encouraging, human trials have produced conflict- cells from dysfunction and death.178 An in vitro
ing results.171 The reason for this may be that most study found lithium’s neuroprotection resulted
studies have used only α-tocopherol. A study that from inhibiting Ca2+ influx mediated by NMDA
followed 3,718 individuals over six years examined receptors.179
dietary consumption (excluding vitamin E supple- Increases in grey matter were found for 8 of 10
ment intake, which showed no effect) of all four bipolar subjects given four weeks of lithium.180
tocopherols (α, β, γ, and δ) as determined by These neuroprotective effects have led some to
questionnaires. The authors concluded that suggest that lithium may have been overlooked as
α-tocopherol alone may not be as protective as the a therapy for dementia.181
combined tocopherols.172 In addition, the risk of No human trials have been published, but some
AD was inversely related to the intake of α, γ, and δ data are relevant. One study found only five
but not β tocopherol. In general, higher levels of percent of bipolar patients treated with lithium
dietary vitamin E lowered the risk of AD and had AD compared with 33 percent of untreated
slowed cognitive decline over the six-year course of patients.182 Anecdotal evidence comes from
the investigation. Jonathan V. Wright, MD, who claims he has used
10-20 mg lithium aspartate or orotate for over 30
Multiple Nutrients years and found it effective for AD.183 Human trials
Since AD patients often have multiple deficien- are sorely needed.
cies, it makes sense to use multiple supplements. A
mixture of alpha-lipoic acid, acetyl-L-carnitine, Hormones
DHA, phosphatidylserine, and glycerophosphocho- Melatonin
line prevented cognitive decline in aged mice.173 A Melatonin is a naturally occurring hormone that
recent study found long-lasting cognitive improve- is produced in decreasing amounts with age.
ment in elderly beagles with the daily use of one Melatonin is a powerful antioxidant, provides
capsule/5 kg body weight of a complex with 25 mg mitochondrial support, protects against tau
phosphatidylserine, 50 mg Ginkgo biloba, 33.5 mg tangles, and reduces βA toxicity.184 Melatonin
d-alpha tocopherol, and 20.5 mg pyridoxine.174 readily crosses the blood-brain barrier and enters
A study of 14 individuals with early AD found all cell structures. A case study in which one
that a multiple formulation (400 mcg folic acid, 6 identical twin was given 6 mg melatonin daily,
mcg vitamin B12, 30 IU vitamin E, 400 mg whereas the other was not, revealed that the
S-adenosylmethionine, 600 mg N-acetylcysteine, melatonin-treated twin had less memory loss over
and 500 mg acetyl-L-carnitine per tablet, with a 36 months.185 Another small study showed 6 mg
daily dose of two tablets) improved all measures of melatonin daily improved mood and memory over
cognition, although the increase in memory was six days for 10 patients with mild cognitive
not statistically significant. The improvement impairment.186 In another study, melatonin (9 mg/
persisted throughout the 12-month study.175 day) was given to 14 sleep-disordered AD patients
over 22-35 months. In the authors’ judgment, the
subjects did not show typical cognitive decline over
the course of this experiment,187 or in a similar
233 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

12. amr Review Article
Table 2. Summary of Botanicals and Nutrients for AD
Nutrient or Botanical Advantages Disadvantages
Huperzine A Prolongs ACh; reduces oxidative damage; excitotox- Not many studies
icity & apoptosis; penetrates the blood-brain barrier
better than cholinesterase inhibitors; well tolerated;
bene ts cognition
Polyphenols Curcumin has at least 10 neuroprotective properties Curcumin has low bioavailability unless
including inhibition of oxidative stress, in amma- accompanied by bioavailability enhancers;
tion, and βA; bene ts cognition; resveratrol has need more human trials; little human
similar bene ts; both are well tolerated research on resveratrol therapy for AD
Ginkgo biloba* Has antioxidant and anti-in ammatory properties; Appears to work for AD but not mild
retards cell death; well tolerated; considerable cognitive impairment; does not reduce risk
research backing cognitive bene t of getting AD
Panax ginseng Has neuroprotective e ects, including reduction of Human studies few in number and weak in
βA, but mechanisms are largely unknown; cognitive methodology
bene ts have been reported; well tolerated
Withania somnifera Many neuroprotective properties, including reduc- No research on humans with AD
ing in ammation, oxidation, Ca2+, βA, AChE, and cell
death; restores synapses
Phosphatidylserine Important in neurotransmission, mitochondria Most positive research used bovine-
function, and cell metabolism; may enhance nerve derived PS now unavailable; the studies
growth factor; increases ACh and inhibits βA; well using soy-derived PS equivocal
tolerated
alpha-Lipoic acid Increases ACh and glucose; easily penetrates the Limited AD research; none without serious
blood-brain barrier; powerful antioxidant inside and shortcomings
outside cells; regenerates itself; reduces in amma-
tion; well tolerated
omega-3 Fatty acids Many bene cial e ects, but not speci c to AD; well Limited research; little bene t except in
tolerated mild impairment
Acetyl L-carnitine* Readily penetrates the blood-brain barrier; promotes More research would be welcome, but
ACh and clears mitochondria of toxic metabolites; reasonable current body of literature
inhibits free radicals; increases NGF; preserves
synaptic function; reduces βA production; consider-
able evidence of bene t; well tolerated
Coenzyme Q10 Protects mitochondria and promotes energy Research has been on neurodegenerative
production; reduces oxidative stress, βA, apoptosis, diseases other than AD except for one
and brain atrophy. The synthetic variant, idebenone, unpublished study; not all idebenone
more readily penetrates the blood-brain barrier; all studies have shown cognitive bene ts
forms well tolerated
Vitamins & minerals AD patients typically have low levels; supplementa- Although reasonable to supplement when
tion has shown bene t for E, lithium, and some de ciencies exist, insu cient research to
nutrient combinations draw conclusions in most cases
Melatonin Antioxidant, protects mitochondria, reduces tau Few studies on AD subjects and those are
tangles and βA toxicity; readily penetrates the small and poor in quality
blood-brain barrier; enters all cell structures;
cognitive bene ts in several studies; well tolerated
*Denotes therapies with the most research backing and therapeutic potential for AD
Volume 15, Number 3 Alternative Medicine Review 234
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

13. Review Article
amr
study using 6 mg/day for four months to 45 AD interventions for more than two semesters showed
patients with sleep disturbances.188 One study no year-to-year decline in various measures of
failed to find cognitive benefits from 3 mg melato- cognitive functioning.199 In another study, 37
nin, which is a lower dose than others typically adults were divided into placebo versus treatment
used.189 groups. The treatment group, given a variety of
Despite numerous studies, few have examined cognitive tasks to work on at home, showed
its effect on AD and the ones that did were small modest gains in recall and face name recall (tasks
and of poor quality. Since melatonin improves on which they were trained), although the training
sleep, it might help memory by facilitating memory did not generalize to other cognitive measures.200
consolidation. Another study with mild-to-moderate AD
The advantages and disadvantages of nutritional patients demonstrated that the benefits of
and botanical therapies are summarized in Table 2. memory training lasted months after the training
ended.201 Even longer-term benefits have been
Stimulatory Therapies observed. A total of 2,832 elderly (mean age 73.6)
Physical exercise, cognitive training, and normal adults were randomly assigned to placebo
socialization are generally thought to facilitate or training on memory, reasoning, or processing
cognitive functioning.190,191 Physical exercise speed. Training resulted in improved cognitive
increases the blood supply to the brain and scores specific to the area in which they were
regulates chemicals such as insulin that are trained that lasted five years after the first treat-
necessary for a healthy brain. Recent reviews of ment.202 In all such studies, it would be desirable to
studies on exercise indicate that exercise may examine the amount of sleep subjects got since
facilitate learning and memory, improve vascular that is when memories are consolidated.
function, reduce inflammation, improve metabo- Unfortunately, sleep quality and quantity, which
lism, elevate mood, delay age-related memory loss, are commonly poor in the elderly, are generally
speed information processing, increase brain overlooked.
volume, aid hippocampal neurogenesis, increase Brain exercises can improve function in those
synaptic plasticity, increase brain-derived neuro- suffering from mild cognitive impairment. A
trophic factor, increase dendritic spines, enhance randomized, controlled, double-blind study on 487
the glutamatergic system, and reduce cell elderly subjects without significant cognitive
death.192,193 impairment was conducted using Posit Science’s
A meta-analysis of 18 studies examined the Brain Fitness Program, a series of computer-based
effect of exercise on healthy but sedentary older exercises that target different areas of the brain
adults. Exercise had the largest effect on executive (visual, auditory, speech, motor, etc.).203 Cognitive
function (planning, coordination, working memory, training was conducted for one hour daily, five days
abstract thinking, initiating appropriate actions, per week, for eight weeks. The control group
and inhibiting inappropriate ones), with lesser viewed educational videos, after which they were
effects on skill acquisition and visuospatial tasks.194 tested for memory of the content. For all measures,
Executive functioning requires the greatest level of cognitive training produced higher scores than
cognitive function and suffers significantly in AD. educational videos; the training generalized to
Patients with early AD who exercised showed non-trained tasks. Other companies are pursuing
less brain atrophy than those who did not.195 similar approaches but have less research backing.
Another study of people with mild cognitive Most studies of music stimulation have exam-
impairment found exercise (mostly walking) led to ined it as a way to moderate problematic behavior
significantly better performance than control in cases of moderate-to-severe AD,204 and to reduce
subjects on some, but not all, cognitive mea- levels of stress, anxiety, and depression in mild-to-
sures.196 Actual changes in the brain have also been moderate AD.205 However, a few studies have
found. Aerobically fit individuals had larger focused on cognitive changes. One study compared
hippocampi and better spatial memory than those the effects of music with controls shown a movie.
who were less fit.197 On the other hand, sedentary Once a week for eight weeks, 17 dementia subjects
elderly adults showed more memory decline over were randomly assigned to music or movie groups.
the course of a day than those more active.198 Cognitive testing immediately after the interven-
Brain stimulation and socialization are impor- tion and the next morning showed superiority for
tant in brain plasticity. Mild-to-moderate AD the subjects given music; however, the effect did
patients who engaged in socialization not last until the next week’s session.206
235 Alternative Medicine Review Volume 15, Number 3
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.

14. amr Review Article
Mechanisms that might underlie such benefits positive attitudes by the way they interact with
include increased natural killer cells that destroy patients, instilling confidence and a positive
dysfunctional cells207 and increased serum melato- attitude.
nin levels.208 A recent paper hypothesized that The advantages and disadvantages of stimulatory
music increases steroid production that facilitates therapies are summarized in Table 3.
neurogenesis, repairs cells, and increases neural
plasticity.209 Notwithstanding these studies, Therapeutic Strategies
music’s potential for AD therapy remains largely One therapeutic strategy is to use only FDA-
uninvestigated. approved pharmaceuticals for AD. However, it has
Psychological factors that might either amelio- been estimated that less than 20 percent of AD
rate or exacerbate AD have generally been over- patients have even a moderate response to
looked because the emphasis has been on medica- approved drugs.210 Also, approved drugs offer little
tions to treat the problem. The patient’s attitude or no neuroprotection, are effective for only a short
could play a key role in retarding or accelerating duration, often produce serious side effects, and
progression of the disease. A patient who views all are expensive. Another option is to use FDA-
as lost will likely unknowingly contribute to approved drugs off label, such as rosiglitazone and
making that view a self-fulfilling prophecy. On the ACE inhibitors. This approach also has risks of
other hand, patients who have a positive attitude adverse effects and no conclusive evidence of
and engage in activities they enjoy may experience benefit.
a slowing of AD progression. Such people are likely Some nutritional and botanical therapies,
to eat better, exercise more, be more positive about although not FDA approved, have been approved
life, and engage in other activities that could for AD in Europe and other countries.
enhance brain function. Therapists can encourage
Table 3. Stimulatory Therapies for AD
Activity Advantages Disadvantages
Physical exercise Increases blood to brain; improves None if done within one's
vascular function; aids sleep; reduces physical capabilities; little
in ammation; elevates mood; increases research speci cally on AD
brain volume; increases synaptic patients
plasticity; aids neurogenesis; reduces
cell death; bene ts some cognitive
processes
Cognitive training Improves many cognitive functions More research indicated
Socialization Preserves cognitive functioning; may Little research
improve mood
Music Reduces stress and depression; Little research
improves cognition, perhaps by aiding
the destruction of dysfunctional cells,
increasing melatonin levels, facilitating
neurogenesis, and increasing plasticity
Psychological A positive attitude may stimulate No research speci c
factors patients to exercise and engage in to AD
activities that are bene cial
Volume 15, Number 3 Alternative Medicine Review 236
Copyright © 2010 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.