Alzheimer's disease: new perspectives on integration of multidisciplinary and multidimensional approaches.

BACKGROUND

Aging is one of the most significant social phenomena of the twenty-first century. A recent demographic projection estimates that approximately 20% of the United States population, or 72 million people, will be aged 65 years or older by the year 2030. The U.S. is a relatively young country in terms of population age compared with others such as China or India; it has been projected that 70% of the world's older population by 2030 will be living in what are now called developing countries. (1) As average life expectancies in most populations increase, so do the problems associated with age-related dementias such as Alzheimer's disease (AD). A recent study by Brookmeyer et al (2) forecast a fourfold increase in the prevalence of AD by 2050 to 106.8 million cases. This translates into a prevalence ratio of 1.2% of the world population if nothing is done to curb either the onset or the gradual deterioration associated with the disease. The magnitude, both from a population-level but also an interpersonal perspective, is sizable, making this disorder a priority health issue worldwide.

AD is one of two main types of dementia, the other being vascular dementia, and accounts for over 60% of all incident dementia cases. (3) The onset and cognitive decline for dementia of the Alzheimer's type is gradual, which distinguishes AD from other dementias. It is difficult to obtain direct pathological evidence for this disorder, as there is not yet an understood etiology, so the diagnosis is made conditionally on the exclusion of other dementias. This difficulty presents challenges in diagnosis. Despite these challenges, based on a combination of psychiatric and neurological signs and symptoms, some studies suggest that an AD diagnosis can be made with 90% reliability. (4) According to the American Psychiatric Association's DSM-IV, the diagnostic features of AD include impairment in memory, aphasia, apraxia, agnosia, and a disturbance in executive function. AD's etiology is unknown but probably multifactorial in nature, so the challenges for prevention are immense. (5) Despite our current lack of understanding about the etiology, studies of AD can be compared because it is well-defined by widely accepted clinical criteria that show remarkable reliability across time and among different clinicians.

AD and all the issues related to it are becoming one of the greatest challenges facing public health, various medical disciplines such as gerontology and neuroscience, and society at large. It is a progressive, debilitating disorder with severe consequences not only for the patient and society but also for caregivers, family members, and friends. Early intervention and prevention using integrated multidisciplinary approaches embracing the biological, psychosocial, and spiritual dimensions is a next logical step for controlling the onset and progression of this complex disorder through prevention efforts. Several different prevention strategies will be discussed here, using the terminology of universal, selective, and indicated preventions, proposed for mental health disorders in a 1994 Institute of Medicine report. (6) A universal preventive intervention is a prevention strategy that may be applied to everyone in a population-based setting. Selective preventions are for subgroups of a population, those with a higher risk for developing AD. Most of the interventions discussed in this review are universal, but may be applied selectively depending on financial and logistical realities. Finally, indicated preventions are those applied to persons with prodromal signs and symptoms for the disorder but who do not yet meet DSM-IV diagnostic criteria for it. In taking a prevention approach, we imply that there are risk and protective factors for AD that are malleable with intervention. Several such interventions will be discussed throughout this review.

EPIDEMIOLOGY

Alzheimer's disease and the aging phenomenon

Age is the most significant risk factor for AD. In the Canadian Study of Health and Aging in adults aged 65 and older, the overall prevalence of dementia was 8%, and progressively increased from 2.4% among those 65 to 74 to 34.5% among those 85 and older. (7) Another study reported a similar prevalence of 3% among those aged 65-74, and the proportion doubled approximately every 5 years. (8) Data from the Framingham Study found that the five-year incidence of AD ranged from 3.5 per 1,000 persons between ages 65 and 69 to 72.8 per 1,000 between ages 85 and 89 years. (9) According to Glenner (10), by the time AD is diagnosed, most patients already have a 50% reduction in life expectancy. Several longitudinal studies of cohorts of demented and non-demented patients confirm that AD is a risk factor for early death. (11)

Public health issues and holistic approaches

The care and coping for the elderly population suffering from AD is a major challenge facing health care and public health worldwide and will only worsen with time. Patients who suffer from this disorder experience cognitive impairments and progressively more problems carrying out activities of daily living. (12) AD received little attention as a public health issue until several years ago for largely logistical and economic reasons; because it is a disease among the elderly, the impact of AD on total life expectancy and health was assumed to be minimal. Additionally, since older adults who develop AD are generally retired, it was believed that they do not generate enough income to impact the economy to a significant degree. Finally, until the past few years there was no knowledge base of preventive strategies that could combat the disease anyway,. (5) Growing awareness of AD as a problem for public health resulted not only from a realization of astronomically high costs to society, the direct and indirect costs together estimated to be $100 billion annually in the United States, but also because of the increased longevity derived largely from improved medical care and decreased mortality at younger ages. (4,5) AD, therefore, has potential to become a burden for families, society, and the medical field globally.

Holistic approaches to treatment stress the importance of a multidisciplinary team of medical professionals to handle AD alongside comorbid medical conditions. (13) Psychiatric and behavioral symptoms, which are common and include hallucinations, delusions, agitation, depression, aggression, etc., should be managed by minimizing environmental triggers, properly educating and training caregivers, and accounting for side effects and interactive effects of prescribed medications. In addition to caregiver education and support, integrative public health approaches also stress utilization of advocacy services and involvement of community supports. (14)

Despite the rapid growth in the elderly population and advancements in medical science and technology, the specific etiology for AD remains undetermined. Data supporting preventive interventions for AD come from epidemiological observational studies, animal studies, laboratory analyses, and clinical trials, and they range from mechanisms involving diet and nutrition to lifestyle and psychosocial elements. (15) Although a variety of preventive approaches to AD have been proposed, few randomized controlled trials have been undertaken because of the need for large sample sizes, among other considerations. (16) Some potential risk factors that have been associated with cognitive decline in AD include vascular risks such as high blood pressure and coronary artery disease, diabetes mellitus, white matter lesions due to brain injury, and the possession of Apolipoprotein E (APOE) [epsilon]4 allele and other possible candidate genes. (17) Additionally, a multitude of confounding factors also exist, including age, gender, education, environmental factors, and medications. (14,18)

BIOLOGICAL DIMENSION OF PREVENTION

There have been several biological theories of possible causes of AD that entail genetic factors, vascular factors, cerebrovascular amyloidosis, viral infection, environmental neurotoxicity, immunological deficits and cholinergic abnormalities in the brain. However, few theoretical explanations have been widely accepted. It is likely that the disease, as mentioned previously, is not caused by a single factor, but by multiple factors or an accumulation of insults to the brain. (7) Most recent studies of prevention have focused on early pharmacological interventions and genetic therapies for AD. We will explore these and other alternatives for approaching and studying AD from multidisciplinary perspectives.

Genomic Interventions

AD, as a progressive neurodegenerative disease, has been linked with several candidate genes. For the rare familial, early-onset AD, mutations in three genes inherited in an autosomal dominant fashion have been implicated. These genes are those encoding amyloid precursor protein (APP), presenilin 1, and presenilin 2. (19) The [epsilon]4 allele of the APOE gene has been associated with an increased risk for early-onset AD (3), whereas presence of the APOE [epsilon]2 allele appears to be protective against AD, which persists even in the presence of APOE [epsilon]4 allele. (20) However, the APOE [epsilon]4 allele is neither necessary nor sufficient to cause the disease, indicating epistatic or epigenetic mechanisms.

Additionally, many other genes have been tested for involvement with the onset or development of AD, with varying results. (21) Many potential candidates identified through linkage analysis include angiotensin I converting enzyme (ACE), catechol-O-methyltransferase (COMT), and others. (22) Conflicting evidence exists for each of these genes and gene systems, though, and is probably reflective of the fact that many genes contribute to the dementia phenotype, such that any single gene's contribution is probably rather small. (22) The population attributable risk of a gene as prevalent as APOE [epsilon]4 allele, though, is probably large.

An indicated prevention strategy for those with an increased genetic risk lies in gene therapy. Growth factors, such as nerve growth factor (NGF), have been shown to improve memory in animal models and avert neuronal death. NGF targets basal forebrain neurons that have cholinergic receptors, the deterioration of which is associated strongly with cognitive decline and AD progression. In a recently reported phase 1 clinical trial utilizing a unique ex vivo gene therapy approach to deliver nerve growth factor (NGF) directly to the basal forebrain of probable AD patients, a mild but significant therapeutic benefit of NGF for the treatment of AD was reported. (23) Participants did not yet have a diagnosis of AD, and so this offers important evidence concerning the safety and efficacy of NGF ex vivo gene therapy as a helpful indicated prevention for AD in humans.

Neuroimaging Evidence as a Screening Tool

In terms of early detection of preclinical stages of AD, the construct of mild cognitive impairment (MCI) has received significant attention, but the relationship between MCI and AD remains unclear. Not all MCI cases convert to AD, and some get better after one year. Neuropsychological tests may be utilized in conjunction with other tools such as neuroimaging, cerebrospinal fluid (CSF) analysis, and other biomarkers to predict AD with better accuracy. (24) Human and nonhuman primate data suggest that beginning in midlife, the structural integrity of myelin sheaths begins to deteriorate. This demyelination results in a progressive deterioration of distributed neural networks over time, and may be the reason why age is a risk factor for AD. In myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE genotypic status. Therefore, taking into consideration APOE status also with results from neuropsychological tests and measures of myelin breakdown involving brain-imaging techniques may be helpful in assessing the efficacy of proposed AD preventions and interventions. (25) PET scans show that glucose metabolic rates in areas of the brain affected by AD are substantially lower in APOE [epsilon]4 carriers during periods of mental rest. Similarly, fMRIs show amplified brain activation during certain memory tasks among APOE [epsilon]4 carriers in brain regions affected by AD. An integration of these brain-imaging techniques with genetic markers can enable more advanced and specific measures of AD disease progression that can inform selective prevention efforts by identifying susceptible populations. (26)

Pharmacotherapeutic Preventions

There are a variety of pharmacotherapeutic prevention strategies available for AD; however, for the sake of time and space we mention in detail only a few here. Such pharmacological regimens as HRT and NSAIDs are some proposed approaches to AD intervention and prevention. An example of HRT is estrogen replacement therapy which may have potential for protection against AD and cognitive decline if undertaken early enough before AD onset. Several biological mechanisms have been proposed to explain this effect, such as modulation of APOE [epsilon]4 expression and neurotransmitter levels. (18) Meta-analysis studies of AD have found NSAIDs to be related to lower AD incidence. (27) Studies of biological mechanisms suggests that development of the neuritic plaques associated with AD pathology can be prevented by NSAIDs, although this effect is only found given an intact brain with no cognitive decline, and there is a lag of several years in their physiological effect. (5) A recent longitudinal observational study reported an inverse association between NSAID use and AD onset, with APOE status as a modifier. (28)

Other recent findings have established that cyclooxygenase-2 (COX-2) is important in the inflammatory response and may be a significant factor in neuronal degeneration. Selective COX-2 inhibitors may then be beneficial as therapeutic agents for AD, perhaps moreso than traditional NSAIDs. (29) Another possible drug for indicated prevention that may have a protective role for persons in early stages of AD or with MCI is acetylcholinesterase (ACEI). Four of the five FDA approved medications for AD are cholinesterase inhibitors, although these medications are more helpful in offering symptomatic relief than changes in the rates of cognitive decline. Some have challenged the validity of the cholinergic hypothesis that justifies these drugs because not all brains of those with MCI or AD have impaired acetylcholine neuronal receptors. (30)

More recent findings indicate that cholesterol can increase levels of toxic [beta]-amyloid seen in AD. Consequently, cholesterol-reducing drugs are being assessed for AD prevention. (31) Because AD shares common risk factors with cardiovascular disease, it is often considered to have vascular components. (32) Statins, which are the primary treatment option for hypercholesterolemia, might be considered a candidate for prevention of AD. Results from observational studies suggest that statin therapy, if initiated in midlife long before disease onset, reduces risk for AD and would therefore make a decent selective prevention strategy. Proposed mechanisms for this effect involve statin's known anti-inflammatory effects as well as their ability to reduce [beta]-amyloid levels. (33) Beneficial effects of the antihypertensive drug nitrendipine further suggest AD has a cardiovascular component. Evidence from a follow-up of the Sys-Eur study in which older hypertensive participants randomized to receive a placebo or nitrendipine showed a 62% decrease in AD incidence among those receiving the antihypertensive medication. (34)

Dietary Supplements

There is some evidence that oxidative mechanisms, vitamins, supplements, and fats have a role in the pathogenesis of AD. Antioxidants that scavenge for free radicals have been proposed as prevention options for the development of several vascular conditions recognized as risk factors for AD. Given this, it has been suggested that adequate consumption of antioxidants from sources like green tea might directly or indirectly prevent AD. (35) Consumption of homocysteine-related vitamins such as vitamin C together with E, B6, B12, niacin, folate, and unsaturated fatty acids have been found to be associated with lower risk for AD. (36) Regarding vitamins C and E, one study found in a large sample of community-dwelling elderly residents that their anti-oxidative effects were associated with reduced rates of cognitive decline and AD incidence. (37) In addition, dietary supplements containing Ginkgo biloba have been investigated on theoretical grounds for their free radical scavenging ability (38), although randomized trials have been unable to find protective effects against AD. (39)

Dietary omega-3 fatty acids are involved in brain biochemistry and physiology, and have also been implicated as protective agents against cognitive decline and AD. (40) They are prevalent in components of what has been termed the Mediterranean diet, such as fish and fish oil supplements, flax seed oil, and vegetables. (41) However, further research is necessary before policy recommendations should be confidently made regarding the health effect of omega-3 fatty acids. (42) Luchsinger et al (43) cautioned that with regard to each of the aforementioned dietary supplements, epidemiological reports are inconsistent and no randomized trials have yielded promising results to date.

Other Physiologically-based Preventions

Vascular risk factors have been associated with cognitive decline and impairment. (44) There are conflicting reports of associations between modifiable cardiovascular risk factors and AD, and the distinction between vascular dementia and AD is often difficult. Hyperhomocysteinemia, hyperlipidemia, hypertension, and smoking have been identified as possible AD risk factors. (45) Mechanisms for these associations are uncertain, but they are likely the result of a combination of direct as well as indirect cerebrovascular disease-related mechanisms.

Various metals have also been implicated as risk factors for AD. Some studies have shown that metals such as aluminum and zinc affect the toxicity and development of [beta]-amyloid protein, the aggregation of which is a hallmark of AD. (46) Other studies have found elevated concentrations of mercury in brains of dead and living AD patients' blood. Even miniscule doses of mercury can lead to morphological neuronal modifications typical of AD, and APOE genotypic status has been identified as a potential moderator. (47) Reduction of aluminum and mercury intake from food and the environment, and maintenance of normal zinc serum levels in older individuals may be helpful universal preventive strategies against AD.

Finally, immunization against [beta]-amyloid peptides has been proposed as a universal prevention for AD. (48) Evidence for immunotherapy in AD has been supported with animal models using transgenic mice. Anti [beta]-amyloid antibodies dissolve [beta]-amyloid plaques by reaching the central nervous system, thereby protecting mice from age-related memory deficits.

PSYCHOSOCIAL DIMENSION OF PREVENTION

It appears that contemporary technology and science paved the way for a dramatically expanding elderly population before the human mind and society at large was prepared to cope with the phenomenon's psychological and social dynamics. Psychosocial preventions exist for AD.

Cognitive Activities and Cognitive Training

Several epidemiological studies have suggested that factors such as life experiences and lifestyle factors such as occupational attainment and education provide a cognitive reserve that buffers against the clinical manifestations of neuropathological changes in AD and cognitive decline generally. The theoretical construct of cognitive reserve holds that the brain is able to compensate for damage, such as that seen in AD pathology, by using pre-existing or compensatory approaches to maintain and build cognitive networks. Higher education and occupational achievement are ways to increase one's cognitive reserve, and have been associated with a reduced risk for AD. (15,18) Mnemonic and other cognitive training efforts have also been studied extensively over the past several decades as ways to help older adults continue to function in the community by modifying neurological and behavioral outcomes associated with dementia. The ACTIVE intervention trial found that cognitive training at older ages can improve long-term memory performance, presumably by bolstering cognitive reserve. (49) One recent longitudinal study of aging found evidence suggesting that higher cognitive reserve, here operationalized as a latent construct measured by education and occupational status, postponed AD onset but was associated with more rapid cognitive decline after clinical diagnosis. (50) Also, functional and structural imaging studies suggest that individuals with anatomical features of AD but a higher cognitive reserve might tolerate more of the neuritic plaques and neurofibrillary tangles characteristic of AD before exhibiting clinical dementia, characterized by performance on neuropsychological test batteries. (51)

Cognitively stimulating activities such as music, prayer, and meditation are also approaches that could be considered as primary preventive efforts for AD. (15) In a longitudinal study, cognitive activities such as reading magazines were associated with reduced cognitive decline over time; increased cognitive activity was significantly associated with a decreased annual rate of cognitive decline. (52) In a case-control study, persons with more complex work roles as measured by occupational complexity scores, particularly those involving interactions with people, showed a lower prevalence of AD. (50) A randomized prevention trial, the Baltimore Experience Corps study, is currently underway to investigate the cognitive, physical, and psychosocial effects of volunteering in elementary schools among older adults. Preliminary pilot data suggests that this universal social intervention strategy increased cognitive activity levels of participating volunteers. (54)

Physical Activity Preventions

Physical activity has also been suggested as a protective factor against cognitive decline associated with Alzheimer's disease. (54) Much of this evidence comes from animal studies involving a voluntary exercise design, though observational studies in humans have shown that aerobic activity in young, middle-aged, and older adults improves neuronal plasticity through increased levels of neurotransmitters in the brain. (55) Verghese et al (56) reported that engagement in leisure activities was associated with reduced risk for dementia even when baseline cognitive status was accounted for. The specific biological mechanisms by which physical activity, aerobic or anaerobic, lead to improved cognitive outcomes are not known for certain. Anaerobic exercise does produce increases in IGF-1, a neurotransmitter associated with improved neuronal plasticity. Moderate aerobic exercise improves circulatory and respiratory function, but there is no clear explanation for why it is as beneficial to cognition as it has been shown to be in human and animal research. (57)

Several lines of investigation are being conducted in the areas of learning and memory using animal behavioral models of both lesioned and intact rats combined with electrophysiological techniques. There is evidence that physical exercise on a regular basis is associated with reduced risk of cognitive decline associated with AD through activation of memory stimulating factors in the rat hippocampus. (57) In a transgenic animal model, transgenic mice with an amyloid precursor protein (APP) mutation in the hippocampal area of the brain displayed significant deficits in memory and general cognitive behavioral aspects resembling AD in humans. (58) After a lengthy period of voluntary exercise in a cage, this study reported significant decreases in extra-cellular [beta]-amyloid plaques in the neurons found in the frontal cortex, the cortex around the hippocampus, and in the hippocampus. These results suggest that exercise modifies how APP is processed and increases the rate of learning among mice, and so a lesson from this animal model is that indicated behavioral interventions to change exercise routines in humans might slow down the development of AD. (58)

Social Engagement Preventions

Social engagement is a construct involving size and quality of social networks, feelings of self-efficacy, and feelings of self-worth. Many believe that social activity affords older adults opportunities to cognitively engage themselves in stimulating activities, and this construct may be a modifier between AD and cognition that is amenable to prevention efforts. (59) Both observational epidemiologic and animal studies contribute to this knowledge base. Animal models have found reduced memory performance in physically restrained animals, presumably a result of increased neurological glucocorticoid levels. (59) Additionally, in the Seattle Longitudinal Study, Schooler and Mulatu (60) offered evidence that complex leisure activities throughout life increased intellectual functioning. Other intervention efforts, notably the Baltimore Experience Corps study and Senior Odyssey, are currently underway to test this hypothesis in randomized trials. (54,61)

SPIRITUAL DIMENSION OF PREVENTION

One aspect of Alzheimer's disease that has not received a great deal of prior attention is the effect of spirituality on patients and their families. Although patients with AD lose their intellectual faculties and memory, they often will retain a capacity for spiritual awareness and intuition. (62) In spiritual writings, special emphasis has been put on the human spirit as a "divine trust". The Baha'i World Faith explains that the "temple of man is like unto a mirror, his soul is as the sun, and his mental faculties even as the rays that emanate from that source of light. The ray may cease to fall upon the mirror, but it can in no wise be dissociated from the sun." Even if mental faculties such as intelligence and memory become impaired, this by no means indicates that the soul has ceased to function. Rather, it means that the instrument, the brain or the mirror, is unable to reflect the power of those faculties.

In the spiritual dimension of AD, there is a small but growing body of research about how AD patients are affected spiritually, and the application of spirituality to the care of Alzheimer's patients. (63) Engaging adults with AD in activities such as prayer and meditation may alleviate anxiety associated with AD, and may therefore be a potential indicated intervention strategy that may reduce negative symptoms and behaviors. Prior research has documented the potential for chronic disease patients in general to enhance their quality of life through spirituality. (64) A recent longitudinal study measured religiosity and spirituality in AD patients using standardized instruments and followed them over time to assess levels of cognitive decline, and found that higher levels of spirituality were associated with less cognitive decline. (65)

Most spiritual traditions involve a meditation or prayer component in their daily rituals. Meditation is a calming behavior that relieves stress. Little research has been done regarding specific effects of meditation behaviors on cortisol levels and other physiological and neuropsychological processes associated with anxiety and stress levels. Such spiritual activities involving procedural memory and limbic system aspects of attachment have been associated with a reduction in anxiety and also improved memory performance among AD patients. (66) It is theoretically plausible that a calmer disposition conferred by spirituality through meditation habits might enhance one's cognitive reserve against the pathological damage described earlier that is characteristic of AD. There is evidence using both electrophysiological and neuroimaging techniques that AD patients with a comorbid mental disorder who engage in regular meditation, yoga, or prayer are able to better handle stress and daily life events. (67,68) The University of Pennsylvania Health System's Center for Spirituality and the Mind is currently focusing on this and other mind-body issues. (69)

CONCLUSION

This review article aims to be a guide to those preventive intervention approaches to AD that are most promising given contemporary research. The review highlights the vast richness and diversity of the strategies used in the early prevention and detection of AD. It is our hope that this interdisciplinary review, divided into biological, psychosocial, and spiritual dimensions of prevention, will contribute in a holistic way to early intervention or prevention of AD. The population of older adults in the U.S. and worldwide is one of the few growing natural resources in the world today. The quality of health for this growing population is of significant importance.

List of abbreviations

ACEI     Acetylcholinesterase Inhibitor
AD       Alzheimer's Disease
APOE     Apolipoprotein E
APP      Amyloid Precursor Protein
CAT      Computerized Axial Tomography
COX-2    Cyclooxygenase-2
CSF      Cerebrospinal Fluid
DSM-IV   Diagnostic and Statistical Manual of Mental
         Disorder-IV
fMRI     Functional Magnetic Resonance Imaging
HRT      Hormone Replacement Therapy
MCI      Mild Cognitive Impairment
NGF      Nerve Growth Factor
NSAID    Non-Steroid Anti-Inflammatory Drug
PET      Positron-emission Tomography
TNFa     Tumor Necrosis Factor Alpha

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Mojdeh Moghaddam, Yung-Chieh Yen, Alden L. Gross, and George W Rebok

Department of Mental Health Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, U.S.A.

Address for correspondence: George W. Rebok

Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, 8th Floor Hampton House, 624 North Broadway, Baltimore, MD 21205, U.S.A.

Phone: [phone], Fax: [phone]

e-mail: grebok@)jhsph.edu