Complementary and integrative approaches to dementia.

Abstract: This is a review that evaluates complementary and alternative approaches to dementia and places them into an integrative framework. While many therapies in popular use have yet to be supported by "best-evidence" trials or meta-analysis, conventional treatments for dementia are clearly suboptimal. This encourages both health care providers and patients' families to expand their search for options for this difficult condition. We provide an in-depth review of mind-body and biologic therapies that have been studied or are in use for Alzheimer disease to provide a context for the busy clinician along with levels of evidence supporting them. Several principles emerge: the need for holism of care, support for care providers, the importance of social engagement and behavioral interventions, and the limited role of medication, nutriceuticals, and botanicals. Without dramatic and well-proven therapies, we find there is hope for the future in clinical care and research advances based on a number of promising therapies we describe.

Key Words: alternative medicine, Alzheimer disease, complementary medicine, dementia, integrative medicine, mind-body therapies, multi-infarct dementia

**********

The rapid growth of the elderly population in our society, particularly those over 80 years of age, has been a bittersweet success for contemporary medicine and society. While people are living longer in good health, Alzheimer disease (AD) or multi-infarct dementia (MDI) significantly affects the quality of life and survival of many. It is estimated that in the United States alone, approximately four million people suffer with AD. This number is expected to double within 2 decades and reach 16 million by 2050. Although there are several other kinds of dementias, including Parkinson dementia, dementia with Lewy Bodies, Creutzfeldt-Jakob disease, and Huntington disease, (1) this review will focus solely on AD and MDI.

Unfortunately, in the face of this rising tide, contemporary medical practice often has little to offer. The title of a review article in a prominent neurology journal 5 years ago asked, "Do we have drugs for dementia? No." (2) That succinct summary, while bleak, continues to reflect the field of dementia care and research. The horizon may include vaccines or drugs directed against the amyloid plaque build-up found in AD patients, but this work is quite preliminary. (3)

Ginkgo biloba, an herbal product long used in traditional Chinese medicine, has been studied extensively and found to be well tolerated with mild benefit, approximating that of the 2nd generation cholinesterase inhibitors. (4) Many other herbs, antioxidants, and nutritional supplements have been offered to support health and delay the progression of dementia. Blueberries, for example, rich in antioxidants and proanthocyanidins, have been shown to be helpful to a healthy brain and perhaps delay dementia. (5) Many products are advocated as part of comprehensive "brain longevity" (6) or "anti-aging" (7) (Tables 1-3) programs. Their use is not generally buttressed by adequate prospective randomized controlled trials, though. Mind-body approaches are intrinsic to all such programs.

In the absence of pharmaceuticals, nutriceuticals, botanicals, or other substantially effective biologic medicines, prevention remains the first defense against dementia. Such measures as optimization of blood pressure, improving serum lipids, an anti-inflammatory diet rich in fruits and vegetables, regular exercise, avoidance of smoking, and reduction in alcohol consumption remain mainstays of prevention. Public health measures and a global biomedical ethic addressing the long-term impact of environmental degradation are essential in an integrally informed approach to dementia and other health problems of aging. Social interaction, stress reduction, biobehavioral, and psychosocial influences optimize functioning of the geriatric patient.

Indeed, in a thoughtful editorial, Whitehouse startlingly challenges the predominant biologic view of AD as myopic, culturally insensitive, and industry driven. (8) While many advances in functional genomics, proteonomics, pharmacology, and pathophysiology have helped in the understanding of dementia, Whitehouse argues that this is only part of the picture. In many societies, views of healthy aging, changing social roles in different life stages, specific cultural beliefs, and community practices significantly alter the way cognitive changes of aging are addressed. Tribal or village culture, unfettered by modern society's preoccupation with speed, innovation, and productivity, value the traits of long-term memory--precisely those elements of memory which are often well preserved in dementia. Ancient rituals and values, hunting and planting patterns, traditional healing lore, and archetypal stories are kept safe in the elders' minds. New roles and social expectations for elders in contemporary society can result from deconstructing the concept of cognitive loss as a pathologic state. Mental changes may be seen as a range from mild cognitive impairment, benign senile forgetfulness, aging-associated memory loss, to full-blown dementia. By re-valuing the contributions of elders in our society, much of the anxiety precipitated by the occasional "senior moment" can be alleviated. Indeed, stress about mildly failing abilities may precipitate a downward spiral in which the senior increasingly loses confidence and self-esteem, withdrawing into a more isolated world.

Since the current state of medical science provides few truly effective therapeutic options for dementia, creative complementary approaches are needed. These must be integrated with conventional care despite, or even because of its limitations. Mind-body and biobehavioral approaches are a subset of such therapies.

Mind-Body Therapies

First, let us define mind-body therapies (MBT). In a helpful review article, Astin describes the range of mind-body therapies and their definition. (9) (Table 1). He cites the National Institute of Health definition of MBTs as "interventions that use a variety of techniques designed to facilitate the mind's capacity to affect bodily function and symptoms." (9) He concludes his meta-analysis and systematic review stating that a stronger biopsychosocial, rather than an exclusively biologic and genetic approach to health is warranted by evidence. While his review did not report specific studies of MBTs and dementia, these therapies were found to be beneficial in many corollary and contributing conditions such as coronary artery disease, stroke, diabetes, and chronic obstructive pulmonary disease, perhaps prognosticating an ultimate effect in dementia as well.

Relaxation Therapies

Agitation, stress, and increased cortisol production further restrict the functional capacities of patients with dementia. As Khalsa notes, cortisol is secreted in a situation of stress in which the teleological benefit is survival, not acquiring or seeking memories. Immediate action is required in the classic flight-or-fight reaction in which stress hormones such as cortisol, epinephrine, and norepinephrine are secreted. Indeed, high levels of cortisol are neurotoxic, accelerating aging and degeneration of the brain. (6) One approach to relaxation therapies in dementia is to enhance the self-efficacy skills of caregivers through training in relaxation therapies. (10) This novel approach lessens the burden of care and risk of infectious anxiety to the patient as well as decreasing risk of elder abuse by overly stressed caregivers. While massage therapy is generally classified as a hands-on or manual alternative therapy rather than an MBT, the relaxation component it induces has been studied in AD, particularly in the nursing literature. (11) Trials of massage therapy for relaxation and reduction of agitation, wandering, and disruptive behaviors showed mixed results with three of six trials demonstrating positive effects. (12) Expressive physical touch and vocalization were found in one of these studies to be particularly effective in calming behaviors, by keeping patients feeling safe and calm and allaying anxiety and disruptive behavior after the intervention. (13) In a small trial of 10 subjects, therapeutic touch was found to decrease agitated behaviors such as vocalization and pacing and reduce markers of stress, including salivary and urine cortisol levels in persons with AD. (14) Autogenic training, while helpful in the general elderly population on several standardized neuropsychiatric measures, was not found to be useful for the cognitively impaired, demented, and frail elderly. (15)

Meditation

This age-old practice has been studied by many mind-body researchers as an aid to centering, calming, and being in the present moment. As lack of attention and concentration compound and are intrinsic to many dementias, the prospect of meditation reinforcing immediacy and "here and nowness" in the demented patient is highly intriguing. Tai Chi and yoga, both of which incorporate meditative aspects, are potentially useful in dementia. Anecdotal reports that Tai Chi training reduces agitated behavior in demented patients need further substantiation by clinical trials. Certainly, Tai Chi has been found to be useful in fall prevention, balance, physical functionality, mobility, and even in cardiovascular aerobic capacity. (16) Yoga is useful in improving mood states but not cognitive improvements in elders and can enhance physical function such as flexibility, breathing mechanics, balance, and body awareness. However, according to a recent textbook, "While yoga, Tai Chi, and meditation probably have some beneficial general health effects, there are no reliable data to suggest specific efficacy in dementia." (16)

Guided Imagery

This MBT has substantial benefits in cognitively intact individuals in allaying anxiety and down-regulating sympathetic tone. Is it useful in those with established dementia? Can a demented patient be entrained by inner words and images to achieve more stability in emotions and focus? We could find no clinical trials of guided imagery in dementia.

Hypnosis

Useful in many medical settings to allay fear, manage phobias, alter habitual dysfunctional behavior, and other areas of symptom reduction, we found no data on the use of hypnosis in dementia in our literature review other than a case report of its use in controlling lumbar puncture distress in a needle-phobic demented patient. (17)

Biofeedback 

Neurobiofeedback, also known as EEG-biofeedback (electroencephalogram), has been utilized to improve attention deficit disorder. (18,19) It has the potential in the elderly to alter physiologic parameters, improve attention, and enhance or preserve cognitive functioning but has not been studied in this population; therefore, clinical trials are warranted.

Cognitive Behavioral Therapies

Stopping faulty thinking patterns, rescripting, affirmations, and mental practice to replace thoughts that negatively impact the psyche by creating anxiety, depression, anger, etc. are a few of the techniques utilized by cognitive behavioral therapists. Can these be useful in a person with a substantial cognitive impairment? Again, little data is available. One study of cognitive retraining where reorientation information is rehearsed to improve reality orientation failed to show any improvement for patients with dementia in a psychogeriatric hospital. (20)

Psychoeducational Approaches

Helping caregivers of demented patients better cope with the responsibilities and frustrations of the 36-hour day, (21) to reduce risk of burnout and elder abuse, and maintain home care to forestall institutionalization has been utilized in multiple sites with good results. Combining patient exercise with caregiver teaching of behavioral management techniques improved physical health and decreased depression in AD patients. (22) Teaching relaxation therapies to caregivers has been found to improve self-efficacy, though does not improve behavioral problems of their AD patients. (10) Interventions with staff at institutional facilities for patients with dementia have also improved the quality of care and improved the morale of the caregivers. (23,24)

A novel program in Michigan has made an AD television channel available to the general public through a statewide kiosk project. Implications of this approach include enhanced public access to information about AD for caregivers and family members. Utilization and impact is under study. (25) Creating culturally and linguistically appropriate public information for ethnic groups such as Hispanics can help with the early identification and treatment of AD. (26)

While most psychoeducational studies addressed the needs of caregivers, the real question is: Can psychoeducational approaches be useful for the one with dementia? Limited short-term memory, distractibility, and attention deficits may prevent such therapies from being implemented. While small gains in some cognitive measures were found in a placebo-controlled trial, no overall impact on neuropsychologic functioning or patient quality of life was found in one study of this type of intervention. (27) So-called memory clinics have been established in Europe with the goals including early diagnosis and management of dementia in elderly outpatients, detecting reversible causes, providing psychosocial therapies and supportive activities including memory training, neuropsychological rehabilitation, caregiver groups, relaxation and biofeedback training, as well as performing research. (28)

In summary we cite Gurka: "Psychosocial therapies including cognitive training methods, behavior orientated concepts, emotion orientated approaches, and family interventions ... are poorly validated in randomized controlled trials. Nevertheless, they hold great promise to improve the quality of life well being of dementia patients and their caregivers ... [And] should be considered to be an integral part of a comprehensive therapeutic approach to dementia patients and their families." (29)

Lifestyle Changes/Social Support

Much research described here relates to caregivers of patients with AD, but one study of behavioral treatment looked at both patients and their caregivers. Behavioral treatment, such as increasing pleasant events, maximizing cognitive ability, and effective problem solving, reduced depression in both patients and caregivers. (30) When combining exercise with behavior management, behavioral impairments may diminish and frailty may decrease if caregivers receive training in these methods. (22)

Environment

In Israel, a controlled multisensory environment, known as a Snoezelen (SNOO-ze-len) room or sometimes Snoezelen therapy, developed in 1995, is now in use in three dozen settings in that country--residential care centers and the community. (31) The Alzheimer's Information Site describes the treatment as one that "evokes the sense of dozing and lazy relaxation." (32) With more than 500 now in use in the US, these rooms often simulate gentle music, appealing fragrances, sounds of a rainforest, waterfalls, star-filled skies, sunrises, and more. These peaceful settings can diminish dementia symptoms such as agitation and wandering.

Recreation/Education

One educational program that focuses on the patient rather than the caregiver has been implemented in Florida. (33) At the Center for Positive Aging at Florida Gulf Coast University, those in the early stages of dementia participate in a 10-week college-level course covering nutrition, cognitive fitness, stress reduction, communication, information about the course of the disease, and more. It provides knowledge and skills to empower participants with a greater measure of personal control. This program helps initiate behavior change early, while the patient is willing and capable of adapting to effective coping mechanisms.

A study using a glider swing demonstrates the range of interventions being implemented and at the same time the difficulties inherent in studying their efficacy. (34) The original goal was to investigate what effects such a modality might have on emotions, relaxation, and possible aggressive behavior.

Creative Expression

One storytelling technique for patients with dementia was developed at the Center for Twentieth Century Studies in the College of Letters and Science and the Graduate School at the University of Wisconsin by Anne Davis Basting, PhD. Called TimeSlips,[c] it has generated thousands of stories, an off-Broadway play, and art exhibits, while providing renewed mechanisms for human connection among people struggling with Alzheimer disease and related dementia. (35) This intervention enhances self-esteem and encourages self-expression, while measurably improving quality of life. Caregivers, visitors, and others also see seniors in a new, positive light. Those with Alzheimer disease and related dementias benefit from exercising creativity, initiating conversation more frequently, having more positive interactions, and being more expressive. Interestingly, Basting found that staff caring for those who participated in the TimeSlips[c] groups also benefited. Staff members reported higher satisfaction in working with those clients, even when the staff themselves had not been involved in the intervention. (36) The program also aims to deepen public awareness of the possibility of creativity among this group.

Music

Music therapy interventions show promise for patients with AD. A recent study in Spain suggests that such indicators as the Dementia Scale, Cohen-Mansfield Agitation Scale, Beck Depression Inventory, and others improve when patients in their 70s and 80s experienced music therapy. (37) Another earlier study found that just listening to music may improve attentiveness and social interactions with caregivers and others. Individuals who listened to preferred music while bathing exhibited decreases in 12 of 15 identified aggressive behaviors. (38)

Nutrients and Botanicals

Therapy for AD is aimed at ameliorating the symptoms of AD that result from neurochemical imbalances. (39) Cholinesterase inhibitors and N-methyl d-aspartate receptor antagonists are the primary conventional agents currently available for use in the treatment of AD in the USA. These agents increase the amount of acetylcholine available in neuronal synapses. (40) A variety of other enhancers of cognition have been used in the hope of slowing the cognitive decline associated with dementias, such as estrogen, nonsteroidal antiinflammatory agents, and antioxidants. See Table 3 for a summative listing of these natural biologicals that have been used in dementia.

Acetylcholinesterase Inhibitors

Huperzine A is a potent plant-based alkaloid with reversible acetylcholinesterase-inhibitory action isolated from the Chinese club moss. (41) Used extensively in China over the centuries to treat fever, inflammation, blood disorders, and schizophrenia, (42) it is now used to enhance memory. (43) Since FDA approval of pharmaceutical acetylcholinesterase inhibitors, huperzine A has gained attention in the research community both in China and the United States as a possible natural alternative to these prescription agents. In a Chinese placebo-controlled randomized trial, huperzine A was significantly better than placebo in improving memory. (44) Further studies demonstrated a significant improvement in the memory of Alzheimer patients. (45,46) Huperzine A appears to have an additional pharmacological property of providing some protection to neurons from glutamate toxicity (47) similar to the newly released conventional medication memantine. Numerous products containing huperzine A are sold in the United States. (48) Patients should not take products containing huperzine A while taking a conventional acetylcholinesterase inhibitor (donepezil, galantamine, rivastigmine, or tacrine). Reported side effects for huperzine A are similar to these conventional drugs. (46,49) Theoretically, huperzine A may exacerbate bradycardic heart arrhythmia, seizure disorder, chronic obstructive pulmonary disease, or peptic ulcer disease. (48)

Acetylcholine Precursors

Acetyl L-carnitine (ALc) is structurally similar to acetylcholine and acts as a weak postsynaptic cholinergic agonist by promoting acetylcholine release and increasing choline acetyltransferase activity. (50) Endogenously, it is an important natural scavenger of free radicals in mitochondria. It helps in cell membrane stabilization and stimulates nerve growth factor levels. (51) There have been several controlled clinical trials suggesting that ALc slows the progression of AD. (52-54) There also is a 1 year multicenter, placebo-controlled study with negative results. (55) Of interest is a post hoc subgroup analysis of one of the studies showing that the subjects with onset of AD before age 66 had a slowing in the progression of AD, but those with onset after age 66 declined faster than the placebo controls. The use of ALc in early onset and rapid progressive AD is still under investigation. Acetyl L-carnitine is sold in the United States as L-acetyl carnitine or a precursor, the amino acid L-carnitine. L-carnitine does not cross the blood-brain barrier until it has been converted to ALc. Acetyl L-carnitine is well tolerated in the majority but has been reported to cause nausea, vomiting, depression, mania, confusion, and aggression in AD patients. (52,54-59)

Attempts to augment acetylcholine levels with lecithin, choline, and phosphatidylcholine supplementation have not demonstrated increases in brain acetylcholine levels, (60) and there is no reliable evidence that it improves cognition or function. (61-64) A derivative of lecithin, phosphatidylserine, may provide some modest improvement in cognition and behavior, (65-68) but there is evidence that this positive effect is short term.

Antioxidants

Antioxidants alone or in dietary supplements are mentioned as potentially beneficial in AD (69,70) by counteracting the oxidative neuronal damage seen in AD. (71) AD exhibits a number of premortem and postmortem biochemical abnormalities that support effects of free radical injury and lipid peroxidation. (72) Thus, the interest in antioxidant therapy is spurring research into the use of vitamins to prevent and possibly treat this disease. Some studies (73,74) did not find a decreased risk of AD and no pathologic difference between AD and controls (75) with vitamin E, coenzyme Q10, and selegiline in AD patients. Some were stopped early because of lack of efficacy (76) while others reported benefit when comparing a coenzyme Q10 metabolite (77) and vitamin E (78) and selegiline (52) to placebo. However, most studies of antioxidants in AD vary significantly in methodology, measurements, and patient baseline AD cognitive status measurements.

Current thinking is that vitamin supplementation may enhance or protect cognitive function in people without pathologic cognitive defects. While vitamin deficiencies have been implicated in AD, it is essentially unstudied whether mega-doses of vitamins can be used as a treatment for the disease. Vitamin C and beta carotene are popular supplements used to stimulate the immune system. (48) No controlled trial for either of these supplements has been carried out to evaluate their effect as treatment for AD. Nonetheless, a few epidemiologic studies support positive benefits of dietary carotenoids and report mixed results for dietary vitamin C related to the preservation of memory.

Anti-inflammatory Therapy and Agents with Anti-inflammatory Effect

AD is associated with elevated levels of acute phase reactants, cytokines, tumor necrosis factor, and complement in the amyloid plaques. Use of NSAIDs in AD received scientific attention after an epidemiologic study, The Baltimore Longitudinal Study, identified a significant reduction in AD risk among elderly patients taking NSAIDs. (79) Double-blind, placebo-controlled studies with newer NSAIDs and selective cyclooxygenase-2 have not shown significant benefits in AD patients.

Numerous plant extracts have traditionally been used to treat cognitive disorders. Several new drugs used in allopathic medicine are direct isolates from plants or compounds from plant sources. None have received the attention that ginkgo biloba has in the last decade. Though in vitro experimental evidence shows that EGb761, an extract from the leaves of ginkgo biloba, seems to protect against neuronal damage with antioxidant (80) and anti-amyloid properties, so far randomized, double-blind, placebo-controlled studies have shown mixed or limited clinical benefits. (81) EGb761 extract contains several glycosides, terpene lactones, and various other compounds, (82) and research has not been able to determine which compound has the neuroprotective activity. Clinical studies (83,84) of gingko extract in AD treatment showed a trend but lacked significant clinical effect on AD patients. Several large randomized, double-blind, placebo-controlled studies are underway with high-dose ginkgo biloba in AD.

Hormonal Agents

Hormone levels change with aging and significant differences have been found in women with AD and in the control group. (85) These findings had been the basis for treating women with AD with estrogen. However, because of an increased risk of vascular events and cancer, (86) estrogen-based treatment for AD is not recommended. Several randomized, double-blind and placebo-controlled studies of estrogen effect on cognition in women with AD showed no significant benefit. Unopposed estrogen in females with a hysterectomy in the Women's Health Initiative Memory Study determined an increased risk of developing dementia in older women using estrogen plus progestin compared with those using a placebo. (87)

Dehydroepiandrosterone (DHEA) is an adrenal hormone that is a precursor to the sex hormones. DHEA levels peak at puberty and decline with aging. (88) Also, there appears to be an association between AD and low levels of DHEA. (89,90) But a randomized clinical trial did not show positive results in the treatment of AD. (91) Also, serious side effects can occur in patients taking DHEA due to potent steroid effects. DHEA supplements might increase the risk of hormone-sensitive cancers. (92,93) Other reported side effects are acne, male pattern baldness, insulin resistance, decreased high-density lipoprotein cholesterol, and hepatic dysfunction. Women are more sensitive to DHEA side effects, because their normal DHEA levels are a fraction of their male counterparts. (94)

Miscellaneous

Vinpocetine is an extract from the Vinca minor plant, a potent vasodilator that lowers blood viscosity. It appears to have some cholinergic activity (95,96) and may be able to protect neurons against oxidative stress. Because of these reported properties, vinpocetine looks promising as a possible treatment for AD. Small, short-term clinical trials are showing modest positive results. Patients taking vinpocetine are at increased risk of bleeding if it is taken with other antiplatelet or anticoagulant drugs.

The Framingham Study (72,97,98) found that elevated homocysteine doubled the risk of developing AD. (99) Homocysteine enhances amyloid B-peptide toxicity, (100) which appears to be an associated risk factor for AD. (101) Lowering homocysteine with cobalamin and folate therapy (102) seemed to improve cognition in people with mild dementia whose homocysteine levels were elevated. (103,104) This unique study links elevated serum homocysteine with AD. Since January of 1998, cereals and grains have been fortified in the US with 150 [micro]g of folic acid. Though to date no studies have looked at the effect this has had on homocysteine levels, physicians and a large sector of the US population have opted for polyvitamin therapy with folic acid, cobalamin, and pyridoxine to lower risk factors for AD and vascular medical disorders. (105) Cobalamin (vitamin [B.sub.12]) deficiency has no convincing evidence of an association with AD but is a known risk factor for neurologic and psychiatric disorders. The activity of ([B.sub.1]) thiamine-dependent enzymes is decreased in the brains of patients' with AD. (106) In addition, thiamine is involved in neurotransmission within the cholinergic system of animals. (107,108) Small clinical trials have shown some positive effects with high dose thiamine supplementation, (109) but the numbers of subjects in the trials are too small to allow a definitive interpretation of their results.

Conclusion: From Despair to Hope

In an era when the diagnosis of AD is often considered to be worse than a death sentence or a diagnosis of advanced cancer or heart disease, it is heartening to see so many paths of potential research toward effective and integrative models of care. Clearly, this is a disease in which the search for a silver bullet is unrealistic and inappropriate. We are however, intrigued by clues of evidence from approaches that are not yet adequately evidence-based to become the standard of care. Only by embracing a variety of approaches from the psychosocial, nutritional, biologic, and even the spiritual dimensions of human life can we help our AD patients and their families move from despair to hope and meaning.

Table 1. Mind-body therapies for dementia care (a)

Major Categories        Definitions

Relaxation techniques   Primary goal is elicitation of
                          psychophysiological state of relaxation
Meditation              Intentional self-regulation of attention
Guided Imagery          Individuals evoke images, usually sensory or
                          affective
Hypnosis                Natural state of arousal, coupled with
                          suspension of peripheral awareness
Biofeedback             Uses devices that amplify physiological
                          processes
Cognitive behavioral    Cognitive processes shape affective experiences
Psychoeducational       Combines psychological strategies with patient
                          Education

Other Categories        Examples

Lifestyle Changes       Nutrition, sleep, fitness, activity, alcohol
Social Support          Family, spiritual/community/cultural, group
                          quilting, public awareness, service
Movement                Walking, Tai Chi, yoga, exercise, dance
Environment             Lighting, sound, stimulation, glider swing, pets
Recreation/Education    College courses, therapeutic recreation, seminar
                          groups, sign language, patient as teacher
Creative Expression     Story, art, memory, theater, crafts
Music                   Listening, playing, movement, prescriptive,
                          singing
Music in Combination    Dance, touch, memory, caregivers, long term
                          care/adjustment
Other Combinations      Physical/cognitive, creativity/groups,
                          art/environment, exercise/caregiver,
                          relaxation/caregivers

(a) Adapted from Astin J, et al. (9)

Table 2. Popular systematic approaches to anti-aging and brain longevity

Khalsa's Brain Longevity (a)             Null's Ultimate Anti-Aging
                                         Program (b)

Diet, Nutrients, and Botanicals          Diet, Nutrients, and Botanicals
  * 15-20% fat and nutrient dense        * Low fat with essential fatty
  * Vitamins A, B, C, E                    acids, whole grain,
  * Ginkgo biloba                          organically grown fruits,
  * Huperzine A, Vinpocetine               vegetables, vegetarianism
  * Magnesium, selenium, zinc            * Vitamins A, [B.sub.1],
  * Nutriceuticals--phosphatidylserine,    [B.sub.12], C, E
    acetyl-L carnitine, coenzyme Q10,    * Ginkgo biloba
    DHA and other Omega 3 oils, green    * Acetyl-L carnitine,
    juice products                         alpha-lipoic acid,
                                           phosphatidylserine
                                         * Boron
                                         * Melatonin
                                         * Dehydroepiandrosterone

Stress Management                        Mental gymnastics
  * Meditation                           * Slow the mind to live in
  * Endogenous cortisol reduction          conscious intention
  * Balancing "control"/"release"        * Transform crises
    dynamics                             * Awareness of personal
  * Social support                         identity
                                         * Breaking the rules for a
                                           change

Mind-body exercises                      Making Conscious Choices
  * Memory and cognitive exercise        * Relationships, love,
  * Yoga, chanting, and other              health, security, appearance
      concentration techniques           * Recognize
                                           overgeneralizations,
                                           unquestioned beliefs, excess
                                           need for security
                                         * Choose to change or perhaps
                                           be forced to integral
                                           thinking
                                         * Identify sources of anger and
                                           denial, act--don't wait,
                                           learn
                                         * Surrender

Exercise and Physical Activity           Exercise
Medications. cholinesterase inhibitors,  Medications. Hydergine,
  NMDA receptor antagonists--others        deprenyl
                                         Reduction of free radicals to
                                           lessen degenerative changes
                                         Cardiovascular risk reduction
                                           to diminish risks of dementia
                                         Eliminate heavy metal burden
                                           (e.g., mercury amalgam
                                           fillings)
                                         Chelation therapy

(a) Adapted from Khalsa. (6)
(b) Adapted from Null. (7)

Table 3. Natural biologicals

                        Insufficient
                        evidence of
                        potential
Potential beneficial    beneficial effects
  effects (with a       (with a degree of
  degree of safety)     safety)              Proven ineffective

Acetylcholinesterase    Antioxidants         Aceytlcholine precursors
  inhibitors              * Beta carotene      * Choline
  * Huperzine A         Anti-inflammatory      * Lecithin
Aceytlcholine             agents             Hormonal agents
  precursors              * Evening            * Dehydroepiandroesterone
  * Acetyl-L-carnitine    primrose oil
  * Phosphatidylserine    * Cat's claw
Antioxidants              Miscellaneous
  * Vitamin E             * Folic acid
Anti-inflammatory         * Gota kola
  agents/vasodilators     * Vinpocetine
  * Ginkgo biloba         * Vitamin
                            [B.sub.6]
                          * Vitamin
                            [B.sub.12]

Support for this article was provided in part by the National Institutes of Health/National Center for Complementary and Alternative Medicine CAM Education Project #IR25AT00586-01, Mind Body Exploratory and Development grant 1 R2I AG023951-01 and Career Development Award with Minority Supplement, National Center for Complementary and Alternative Medicine (NIH) AT000722. The opinions expressed are the opinions of the authors and not of the NIH or NCCAM. Thanks to Diana De Los Santos and Belinda Iles for their invaluable assistance in manuscript preparation.

Accepted December 15, 2004.

References

1. Hamdy R. Featured CME topic: dementia. Fact sheets. South Med J 2001;94:673-677.

2. Pryse-Phillips W. Do we have drugs for dementia? No. Arch of Neurology 1999;56:735-737.

3. Hensley S. New hope seen for vaccine for Alzheimer's. Wall Street Journal July 22, 2004:B1-B2.

4. Sierpina V, Wollschlaeger B, Blumenthal M. Ginkgo biloba. Am Fam Physician 2003;68:923-926.

5. Joseph J, Denisova N, Arendash G, et al. Bluebery supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 2003;6:153-162.

6. Khalsa D. The Cortisol Connection, Healthy Aging, in: Brain Longevity. New York, Warner Books, 1997, pp 3-23.

7. Null G. Ultimate Anti-Aging Program. New York, Broadway Books, 1999.

8. Whitehouse P. The end of Alzheimer disease. Alzheimer Dis Assoc Disord 2001;15:59-62.

9. Astin J, Shapiro S, Eisenberg D. et al. Mind-body medicine: state of the science, implications for practice. J Am Bd Fam Prac 2003;16:131-147.

10. Fischer P, Laschinger H. A relaxation training program to increase self-efficacy for anxiety control in Alzheimer family caregivers. Holistic Nurs Prac 2001;15:47-58.

11. Rowe M, Alfred D. The effectiveness of slow stroke massage in diffusing agitated behavior in individuals with Alzheimer's disease. J Ger Nurs 1999;25:22-34.

12. Cohen-Mansfield J. Nonpharmacological interventions for inappropriate behaviors in dementia. Am J Psychiatr 2001;9:261-381.

13. Kim E, Buschmann M. The effect of expressive physical touch. Int J Nurs Studies 1999;36:235-243.

14. Woods D, Dimond M. The effect of therapeutic touch on agitated behavior and cortisol in persons with Alzheimer's disease. Biol Res Nursing 2002;4:104-114.

15. Kircher T, Teutsch E, Wormstall H. et al. Effects of autogenic training in elderly patients [article in German]. Z Gerontol Geriatr 2002;35:157-165.

16. Oken B. Complementary Therapies in Neurology: An Evidence-based Approach. New York, Parthenon Publishing, 2004.

17. Simon E, Canonico M. Use of hypnosis in controlling lumbar puncture distress in an adult needle-phoic dementia patient. Int J Clin Exp Hypn 2001;49:56-67.

18. Adams L, Gatchel R, Gentry C. CAM for cognitive functioning in the elderly. ATHM 2001;7:52-61.

19. Lubar J. Neocortical dynamics: implications for understanding the role of neurofeedback and related techniques for the enhancement of attention. Appl Psychophysiol Biofeedback 1997;22:111-126.

20. Hanley I, Mcguire R, Boyd W. Reality orientation and dementia: a controlled trial of two approaches. Br J Psychiatr 1981;138:10-14.

21. Mace N. The 36-Hour Day: A Family Guide to Caring for Persons with Alzheimer's Disease, Related Dementing Illnesses, and Memory Loss in Later Life. Baltimore, Johns Hopkins University Press, 1999, ed 3.

22. Teri L, Gibbons LE, McCurry SM, et al. Exercise plus behavior management in patients with Alzheimer's disease: a randomized controlled trial. JAMA 2003;290:2015-2022.

23. Heliker D. Transformation of story to practice: an innovative approach to long-term care. Issues in Mental Health Nursing 1999;20:513-525.

24. Heliker D, Brophy E, Naughton-Walsh M, et al. A study of professional health care students attitudes toward the elderly. J Nurs Educ 1993;32:370-373.

25. Connell C, Shaw B, Holmes S, et al. The development of an Alzheimer's disease channel for the Michigan Interactive Health Kiosk Project. Health Communication 2003;8:11-22.

26. Briones D, Ramirez A, Guerrero M, et al. Determining cultural and psychosocial factors in Alzheimer's disease among Hispanic populations. Alzheimer Dis Assoc Disord 2002;16(suppl 2):S86-S88.

27. Davis R, Massman P, Doody R. Cognitive intervention in Alzheimer disease: a randomized placebo controlled study. Alzheimer Dis Assoc Disord 2001;15:1-9.

28. Monsch A, Ermini-Funfschilling D, Mulligan R, et al. Memory Clinics in Switzerland. Collaborative group of Swiss Memory Clinics. Ann Med Interne. 1998;149:221-222.

29. Gurka P, Marksteiner J. Psychosocial therapy of patients with dementia [article in German]. Wien Med Wochenschr 2002;152102-106.

30. Teri L. Behavior treatment of depression in patients with dementia. Alzheimer's Disease Assoc Disord 1994;8(suppl 3):66-74.

31. Merrick J, Cahana C, Lotan M, et al. Snoezelen or controlled multisensory stimulation. Treatment aspects from Israel. Scientific World Journal 2004;4:307-314.

32. The Alzheimer's Information Site. Available at: http://www.alzinfo.org/news/1_5_04.aspx. Accessed October 21, 2004.

33. Fitzsimmons S, Buettner L. Health promotion for the mind, body, and spirit: a college course for older adults with dementia. Am J Alzheimers Dis Other Demen 2003;18:282-290.

34. Snyder M, Tseng Y, Brandt C, et. al. Challenges of implementing intervention research in persons with dementia: example of a glider swing intervention. Am J Alzheimers Dis Other Demen 2001;16:51-56.

35. Basting A. TimeSlips[c] Educational Guide. Milwaukee, University of Wisconsin Press, 2002.

36. Basting A. It's 1924 and Somewhere in Texas, Two Nuns Are Driving a Backwards Volkswagen: Storytelling with People with Dementia, in McFadden SH, Atchley RC (eds): Aging and the Meaning of Time. New York, Springer, 2001, pp 131-149.

37. Brotons M, Marti P. Music therapy with Alzheimer's patients and their family caregivers: a pilot project. Journal of Music Therapy 2003;40:138-150.

38. Clark ME, Lipe AW, Bilbrey M. Use of music to decrease aggressive behaviors in people with dementia. Journal of Gerontological Nursing 1998;24:7-10.

39. Lustbader J, Cirilli M, Lin C, et al. ABAD directly linked AB to mitochondrial toxicity in Alzheimer's Disease. Science 2004;304:448-452.

40. Masterson D. Cholinesterase inhibitors in the treatment of Alzheimer's disease and related dementias. Clin Geriatr Med 2004;20:59-68.

41. Budavari S. The Merck Index. Whitehouse Station, Merck & Co., 1996, ed 12.

42. Liu J, Zhu Y, Yu C, et al. The Structure of huperzine A and B, two new alkaloids exhibiting marked anticoholinesterase activity. Can J Chem 1986;64:837-839.

43. Skolnick AA. Old chinese herbal medicine used for fever yields possible new Alzheimer disease therapy. JAMA 1997;277:776.

44. Xu S, Gao Z, Weng Z, et al. Efficacy of tablet huperzine: a memory, congnition and behavior in Alzheimer's disease. Zhongguo Yao Li Xue Bao 1995;16:391-395.

45. Xu S, Cai Z, Qu Z, et al. Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Zhongguo Yao Li Xue Bao 1999;20:486-490.

46. Zhang R, Tang X, Han Y, et al. Drug evaluation of huperzine A in the treatment of senile memory disorders. Zhongguo Yao Li Xue Bao 1991;12:250-252.

47. Wang X, Zhang J, Yang H, et al. Modulation of NMDA receptor by huperzine A in rat cerebral cortex. Zhongguo Yao Li Xue Bao 1999;20:31-35.

48. Natural Medicines Comprehensive Database. Available at: http://www.naturaldatabase.com/(ydk2ga55h3zyw055dglukn55)/home.aspx?li=1&st=2&cs=&s=ND. Accessed October 21, 2004.

49. Pepping J. Huperzine A. Review. American Journal of Health System Pharmacy 2000;57:530,533-534.

50. Mayeux R, Sano M. Treatment of Alzheimer's disease. N Engl J Med 1999;341:1670-1679.

51. Ott B, Owens N. Complementary and alternative medicines for Alzheimer's disease. J Geriatr Psyciatry Neurol 1998;11:163-173.

52. Sano M, Ernest D, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer disease. The Alzheimer's Disease Cooperative Study. NEJM 1997;336:1216-1222.

53. Rai G, Wright G, Scott L, et al. Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimers dementia. Curr Med Res Opin 1990;11:638-647.

54. Pettegrew J, Klunk W, Panchalingam K, et al. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease. Neurobiol Aging 1995;16:1-4.

55. Thal L, Carta A, Clarke W, et al. 1-year muticenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology 1996;47:705-711.

56. Spagnoli A, Lucca U, Menasce G, et al. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology 1991;41:1726-1732.

57. Brooks Jr., Yesavage J, Carta A, et al. Acetyl L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double-blind, placebo-controlled study of the trilinear approach. Int Psychogeriatr 1998;10:193-203.

58. Montgomery S, Thal L, Amrein R. Meta-analysis of double blind randomized controlled clinical trials acetyl-L-carnitine versus placebo in treatment of mild cognitive impairment and mild Alzheimer's disease. Int Clin Psychopharmacol 2003;18:61-71.

59. Hudson S, Tabet N. Acetyl-L-carnitine for dementia. Cochrane Database Syst Rev 2003;2:CD003158.

60. Tan J, Bluml S, Hoang T, et al. Lack of effect of Oral choline supplement on the concentrations of choline metabolites in human brain. Magn Reson Med 1998;39:1005-1010.

61. Mohs R, Davis K, Tinklenberg J, et al. Choline chloride effects on memory in the elderly. Neurobiol Aging 1980;1:21-25.

62. Brinkman S, Smith R, Meyer J, et al. Lecithin and memory training in suspected Alzheimer's disease. J Gerontol 1982;37:4-9.

63. Pomara N, Domino E, Yoon H, et al. Failure of single-dose lecithin to alter aspects of central choliner activity in Alzheimer's disease. J Clin Psychiatry 1983;44:293-295.

64. Etienne P, Dastoor D, Gauthier S, et al. Alzheimer disease: lack of effect of lecithin treatment for 3 months. Neurology 1981;31:1552-1554.

65. Heiss W, Kessler J, Mielke R, et al. Long-term effects of phosphatidyslerine, pyritinol and cognitive training in Alzheimer's disease. A neuropsychological, EEG, and PET investigation. Dementia 1994;5:88-98.

66. Crook T, Petrie W, Wells C, et al. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull 1992;28:61-66.

67. Delwaide P, Gyselynck-Mambourg A, Hurlet A, et al. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand 1986;73:136-140.

68. Funfgeld E, Baggen M, Nedwidek P, et al. Double-blind study with phosphatidyslerine (PS) in Parkinsonian patients with senile dementia of Alzheimer's types (SDAT). Prog Clin Biol Res 1989;317:1235-1246.

69. Mecocci P, Polidori M, Cherubini A, et al. J. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer's Disease. Arch Neurol 2002;59:794-798.

70. Ishizuka K, Kimura T, Yoshitake J, et al. Possible assessment for antioxidant capacity in Alzheimer's disease by measuring lymphocyte heme-oxygenase-1 expression with real-time RT-PCR. Ann NY Acad Sci 2002;977:173-178.

71. Rinaldi P, Polidori M, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiology of Aging 2003;24:915-919.

72. Selley M, Close D, Stern S. The effect of increased concentrations

of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiology of Aging 2002;23:383-388.

73. Morris M, Evans D, Bienias J, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer's disease in a biracial community study. JAMA 2002;287:3230-3237.

74. Luchsinger J, Tang M, Shea S, et al. Antioxidant vitamin intake and risk of Alzheimer's disease. Arch Neurol 2003;60:203-208.

75. Williamson K, Gabbita S, Mou S, et al. The nitration product 5-nitrogamma-tocopherol is increased in the Alzheimer's brain. Nitric Oxide: Biology and Chemistry 2002;6:221-227.

76. Weyer G, Babej-Dolle R, Hadler D, et al. A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease. Neuropsychobiology 1997;36:73-82.

77. Gutzmann H, Hadler D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl 1998;54:301-310.

78. Chandra R. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 2001;17:709-712.

79. Stewart WF, Kawas C, Corrada M, et al. Risk of Alzheimer's disease and duration of NSAID use [see comment]. Neurology 1997;48:626-632.

80. Luo Y, Smith J, Burdick A, et al. Inhibition of amyloid-beta aggregation and caspase-3 activation by the gingko biloba extract EGb 761. Proc Natl Acad Sci USA 2004;99:12197-12202.

81. Le Bars P. Magnitude of effect and special approach to gingko biloba extract EGb 761 in cognitive disorders. Pharmacopsychiatry 2003; 36(suppl 1):S44-49.

82. Ahlemeyer B, Krieglstein J. Pharmacological studies supporting the therapeutic use of ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry. 2003;36(suppl 1):S8-14.

83. Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry 2003;36:297-303.

84. Kanowski S, Herrmann WM, Stephan K, et al. Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 1996;29:47-56.

85. Hoskin E, Tang M, Manly J, et al. Elevated sex-hormone binding globulin in elderly women with Alzheimer's disease. Neurobiology of Aging 2004;25:141-147.

86. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial [see comment]. JAMA 2003;289:2651-2662.

87. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study [see comment]. JAMA 2004;291:2947-2958.

88. Kroboth P, Salek F, Pittenger A, Fabian T, Frye R. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327-348.

89. Sunderland T, Merril C, Harrington M, et al. Reduced plasma dehydroepiandrosterone concentrations in Alzheimer's disease. Lancet 1989;2(8662):570.

90. Nasman B, Olsson T, Backstrom T, et al. Viitanene M Serum dehydroepiandrosterone sulfate in Alzheimer's disease and multi-infarct dementia. Biol Psychiatry 1991;30:684-690.

91. Wolkowitz O, Kramer J, Reus V, et al. DHEA treatment of Alzheimer's disease: a randomized, double-blind, placebo-controlled study [see comment]. Neurology 2003;60:1071-1076.

92. Kuritzky L. DHEA: science or wishful thinking? Hosp Pract (OffEd) 1998;33(5):85-86,92.

93. Stoll B. Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk. Eur J Clin Nutr 1999;53:771-775.

94. Morales A, Haubrich R, Hwang J, et al. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulationg sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf) 1998;49:421-432.

95. Pepeu G, Spignoli G. Nootropic drugs and brain cholinergic mechanics, Prog. Neuropsychopharmaol Biol Psychiatry 1989;1(supp 1):S77-88.

96. McDaniel M, Maier S, Einstein G. Brain-specific nutrients: a memory cure? Nutrition 2003;19:957-975.

97. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. NEJM 2002;346:476-483.

98. Mattson MP. Will caloric restriction and folate protect against AD and PD? Neurology 2003;60:690-695.

99. Miller J, Green R, Mungas D, et al. Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology 2002;58:1471-1475.

100. Zetterberg H, Nexo E, Regland B, et al. The transcobalamin (TC) codon 259 genetic polymorphism influences holo-TC concentration in cerebrospinal fluid from patients with Alzheimer's disease. Clinical Chemistry 2003;49:1195-1198.

101. Nilsson K, Gustafson L, Faldt R, et al. Hyperhomocysteinaemia--a common finding in a psychogeriatric population. Eur J Clin Invest 1996;26:853-859.

102. Wang H, Wahlin A, Basun H, et al. Vitamin [B.sub.12] and folate in relation to the development of Alzheimer's disease. Neurology 2001;56:1188-1194.

103. Nilsson K, Gustafson L, Hultberg B. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. Intl J Geriatr Psychiatry 2001;16:609-614.

104. Clarke R, Smith A, Jobst K, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer's disease. Arch Neurol 1998;55:1449-1455.

105. Diaz-Arrastia R. Hyperhomocysteinemia: a new risk factor for Alzheimer's disease? Arch Neurol 1988;55:1407-1408.

106. Gibson GE, Sheu KF, Blass JP, et al. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Archives of Neruology 1988;45:836-840.

107. Eder L, Hirt L, Dunant Y. Possible involvement of thiamine in acetylcholine release. Nature 1976;264:186-188.

108. Eder L, Dunant Y. Thiamine and cholinergic transmission in the electric organ of Torpedo. I. Cellular localization and functional changes of thiamine and thiamine phosphate esters. Journal of Neurochemistry 1980;35:1278-1286.

109. Nolan K, Black R, Sheu K, et al. A trial of thiamine in Alzheimer's disease. Archives of Neurology 1991;48:81-83.

RELATED ARTICLE: Key Points

* We describe several complementary and integrative programs which offer potential benefits to patients with dementia as well as their caregivers.

* Mind-body therapies are extremely safe in providing structure, support, and encouragement to patients and their families, though many need further research.

* Herbal medicines and nutritional supplements are widely recommended and used for the prevention and treatment of dementia, although many are supported by limited evidence.

* Psychosocial support, encouragement of cognitive activity, and offering opportunities for creative activities such as Time Slips[c], can offer an improved quality of life for patients with dementia.

Victor S. Sierpina, MD, Michelle Sierpina, MS, Jose A. Loera, MD, and Loretta Grumbles, MD

From the Departments of Family Medicine and Internal Medicine, University of Texas Medical Branch, Galveston, TX.

Reprint requests to Victor S. Sierpina, MD, WD and Laura Nell Nicholson Family Professor in Integrative Medicine, Associate Professor, UTMB, Family Medicine Department, 301 University Boulevard, Galveston, TX 77555. Email: [e-mail]