Alzheimer’s Disease: What the Primary Care Physician Needs to Know

EXECUTIVE SUMMARY

The term neurocognitive disorders largely has replaced the stigmatized label of dementia, but the latter is still commonly used.

• Although there is evidence for a decreased incidence of dementia in specific geographical populations in the United States and Europe, the current epidemic of dementia affected 46 million people worldwide in 2015, and is projected to affect 131 million by 2050.
• Multiple subtypes of dementia include Alzheimer’s disease, vascular dementia, mixed dementia, Lewy body dementia, and frontotemporal lobar degeneration.
• In 2015, a Gerontological Society of America working group reported that older adults are inadequately assessed for cognitive impairment during routine visits with their primary care providers.
• The Centers for Medicare and Medicaid Services includes a cognitive exam or evaluation in the annual wellness visit.
• Genetic factors, especially the APOE4 allele, increase the incidence of Alzheimer's disease by three-fold to eight-fold.
• Medications, while not curative, may offer modest improvement in cognitive function.
• Prevention interactions emphasize lifestyle modifications by encouraging middle-aged persons to stop smoking; exercise; eat diets rich in fruits, vegetables, and fish; avoid obesity, diabetes, and excessive alcohol intake; and treat hypertension.

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Dementia: stemming from the Latin demens or mad

In May 2013, “dementia” disappeared — at least according to the American Psychiatric Association (APA). In an effort to avoid the stigma of the word “dementia,” the 2013 updated edition of the APA’s Diagnostic and Statistical Manuel introduced the term “neurocognitive disorders.” This category encompasses the spectrum of mild to severe conditions involving deterioration in memory, thinking, and reasoning. Yet, despite the change in terminology, the term dementia (and perhaps the associated stigma) remains in common use — at least for the immediate future.

This article explores current medical approaches to Alzheimer’s dementia, the most common subtype of the known dementias or neurocognitive disorders. Preventive treatment is at the forefront of efforts to defeat this progressively impairing disorder; but to be effective, intervention must start well before symptoms begin. The role of the primary care provider in initiating vigorous and early preventive measures and applying appropriate pharmacologic and non-pharmacologic interventions at each stage of disease progression is reviewed and discussed.

Introduction

The medical community had warning. “Dementia in the Elderly: The Silent Epidemic,” a 1982 Annals of Internal Medicine landmark article, looked at the “greying of America” and noted one natural consequence of longer life span would be an explosive impact on the prevalence of dementia.¹ Indeed, the epidemic has come — not only in the United States, but also globally, with dementia affecting an estimated 46 million people worldwide in 2015 and projected to affect 131 million by 2050.²

Despite these daunting numbers, more recent investigations have revealed promising news. Although there is still no cure for dementia, prevention efforts seem to be making an impact. Although dementia remains a substantial health burden with risk increasing with age, the incidence of this progressively impairing disorder is on a downward trend. First noted in 1988, subsequent studies have been consistent in finding a decreased incidence of dementia in specific geographical populations in the United States and Europe.^3,4

Perhaps the most convincing evidence of this trend comes from a recently published analysis of Framingham Heart Study data.⁵ These findings show a significant and steady decrease in the incidence of dementia progressively in each of the three decades since the study began in 1975. It is important to understand that despite this decreasing trend, given the continued growth of the elderly population, sheer numbers of those affected by dementia are still projected to boom.⁴

The Framingham Study data investigators noted that the specific lifestyle changes and/or advancement in treatment of disease states contributing to the decline in incidence of dementia among the study population are not completely understood. However, several factors are thought to be important, including progress in control of cardiovascular risk factors (including blood pressure and lipid status) and attainment of higher educational level. Interestingly, the downward trend of the incidence of new dementia diagnosis in the population investigated was found only in those with at least a high school education, leading to speculation and investigation into the impact of cognitive stimulation on prevention of dementia.⁵

Medical professionals providing primary care for elderly patients, their families, and/or their caregivers are in a unique position to observe, diagnose, and provide guidance to those affected by dementia. At this point, the medical system remains without a definitive cure for dementia. The decrease in incidence of dementia has served to strengthen the shift toward prevention, risk reduction, and early intervention, making a holistic and comprehensive approach to patient care the goal in effective treatment and management.^6,7

Dementia

The multiple subtypes of dementia, in order of prevalence, include Alzheimer’s disease (AD), vascular dementia, mixed dementia, Lewy body dementia, and frontotemporal lobar degeneration. All have a progressive, irreversible, and deteriorating effect on independent functioning.² Less common causes of dementia include Creutzfeldt-Jakob disease and normal-pressure hydrocephalus.

AD, estimated to occur in 60-80% of all dementia cases, is the most common form of dementia. About 50% of AD cases are termed “mixed dementia,” having symptoms or clinical evidence of pathology related to another dementia as well.² Table 1 delineates these dementias and gives some clinical information relevant to each diagnosis.

This article examines current medical recommendations and the relevant evidence for these recommendations for treatment and prevention of AD. Specific approaches during each stage of AD are discussed.

Historic and Recent Findings (1901-2016)

Alzheimer’s disease bears the name of the early 20th century physician Dr. Alois Alzheimer, who described this disorder in a 51-year-old woman and subsequently isolated neurofibrillary tangles (NFTs) and amyloid plaques (senile plaques [SP]) in sections of his patient’s brain. Dr. Alzheimer published these findings in 1907, and they remain a hallmark of what is now known as Alzheimer’s disease.⁸

Advances in imaging techniques have since revealed evidence that the presence of SPs and NFTs is not specific to AD; NFTs are found in other types of dementias and SPs may be found in adults with near-normal cognition. It appears that the quantity and distribution of the lesions are the more significant finding in making or confirming a diagnosis.⁹

Currently, there are several hypotheses under investigation regarding the pathophysiology of AD. Most prominent are the amyloid hypothesis and the tau hypothesis, although the tau theories seem to be gaining in traction with new imaging techniques.^10,11

Tau protein helps support healthy neurons. In AD, tau protein is hyperphosphorylated, contributing to the development of NFTs, which negatively affects communication between neurons and eventually leads to cell death.

Beta-amyloids are protein fragments that appear to be the main constituent of SPs. It is known that SP accumulation precedes clinical signs in AD and that accumulation of NFTs and cell death more closely correlate with progressive clinical decline.¹¹

As research progresses, the role of each of these in the development of AD and eventually in the prevention and/or treatment of this disorder should become more apparent and useful in clinical practice. Tau positron emission tomography (PET) and other advanced techniques are opening the door to a better understanding of the pathogenesis, the clinical course, and the development of screening tools for AD. The linear causality once thought to be an underlying mechanism in the amyloid hypothesis has shifted to a multi-causality, more nuanced understanding of development of this neurodegenerative disorder; with this shift has come an increased emphasis on preventive screening and intervention.^12,13

Screening for AD: Annual Wellness Visit

The Centers for Medicare and Medicaid Services include a cognitive exam or evaluation in the annual wellness visit (AWV).¹⁴ Noting that a timely and accurate diagnosis of AD is essential to initiate early treatment and help families and patients plan for the future, a Gerontological Society of America working group reported a concern in 2015 that “older adults are inadequately assessed for cognitive impairment during routine visits with their primary care providers.”¹⁵ All too often, primary care providers have neither the time nor the resources to conduct a full cognitive evaluation and collect collateral information essential for early diagnosis. Recognizing these factors, researchers are pursuing screening tests appropriate for the primary care office.

It is conceivable that in the near future a serum blood test or another fairly specific tool to rule out and/or screen for AD will be in common use. Currently, however, the American Alzheimer’s Association recommends the following screens for use during an AWV to detect the presence of cognitive impairment and identify those patients in need of further screening or diagnostic evaluation. The entire packet is presented as a “cognitive assessment toolkit” for primary care and can be reviewed and downloaded from the Alzheimer’s Association site.¹⁶ Although all are copyrighted, the owners allow free use as clinical tools. Notably, all are validated screening tools that can be administered by non-physicians.

General Practitioner Assessment of Cognition (GPCOG): Brief patient exam accompanied by informant portion if informant is available during screen (increases detection power if used together).¹⁶

Memory impairment screen: Examines word retrieval and basic ability to sort and code; verbal only (best to use if motor impairments limit ability to use writing tools).¹⁶

Mini-Cog: Less language, less educational and cultural bias; three word recall and clock drawing in a standardized format.¹⁶

Informant questionnaires: Several are recommended including the GPCOG informant portion.¹⁶

The following are several newer screens in development.

Dementia Risk Score: Using routinely collected data, including age, body mass index, blood pressure status, mental health, and smoking habits, this UK group developed a risk score with especially good negative predictive value for those 60-79 years of age. This is a straightforward algorithm that can be used clinically to help rule out those not needing further testing or screening for AD. It is not valid for persons older than 80 years of age.¹⁷

Informant-based screens: Several studies have looked at the validity and utility of informant (family or caregiver) based screens. Most investigations are finding that simple informant-based questionnaires are more specific and useful to detect need for further studies than the more complex and traditional patient-based screens. These are highly dependent on having a reliable caregiver or informant available at the time of the screen.¹⁸

Blood Screen: Several groups of investigators are looking at a simple blood test that can identify patients who would benefit most from in-depth evaluation. A recent publication by O’Bryant and colleagues describes progress on a 21-protein AD algorithm now validated across ethnic and racial groups. The screen is still in experimental stages but appears to be moving rapidly toward clinical implementation. The impressive predictive powers (negative higher than positive) of this blood screen have potential for cost-effective use in the primary care office.¹⁹

Differential Diagnosis

Differential diagnosis of AD includes treatable and reversible conditions such as depression, delirium, medication side effects, substance use (alcohol as well as pain medication and other substances of abuse), vitamin deficiencies (folate and B12), thyroid abnormalities, chronic subdural hematoma, and normal pressure hydrocephalus.⁶ A careful and complete history with collateral information from family or caregivers, appropriate lab tests, and imaging studies are used to distinguish conditions and determine diagnosis. Although not required for diagnosis, neuropsychological testing often is useful to better understand the degree and extent of cognitive impairment, the level of impairment of judgment, and impulse control, and to aid in determination of specific type of dementia.^20,21

Neuroimaging Studies

Magnetic resonance imaging (MRI) and computed tomography (CT) scan are important to diagnosis, if only to rule out other causes of dementia, as noted in earlier sections (see Table 1), and more acute processes, such as subdural hematomas or brain tumors. Advances in this field have led to the ability to extract more specific inclusionary (not just exclusionary) information from MRI, including precise measurements of atrophy in specific regions known to be linked with AD pathology. Specialized PET scans are sensitive to synaptic destruction and can be diagnostic (depending on the pattern of destruction). Combining cerebrospinal fluid biomarkers with the PET scans can aid early diagnosis and tracking of disease progression.²²

Genetic Factors in AD

Genetic factors influencing the development of AD have grown to be a promising area of research. Researchers now know there are at least two forms of AD with different genetic patterns of inheritance and risk. The early-onset form, occurring in less than 5% of all AD patients, is almost always inherited and has onset between the ages of 30 and 60 years. In contrast, the more common late-onset AD is multi-factorial in origin; the genetic risk here is related to carriers of the apolipoprotein (APOE4) allele.^22,23

APOE4 allele is found in 10-15% of the general population. It appears that the number of copies of this allele increase the risk of AD by three-fold to eight-fold. However, the presence or absence of this allele does not correlate 1:1 with disease occurrence. Thus, it is known as a “risk-factor” gene.²³

For APOE4 homozygotes, the lifetime risk for development of AD is 50%, which is clearly significant when compared with a lifetime risk of AD in women of 14% and in men of 11% (regardless of genotype).²² (See Table 2.)

Screens for Cognitive Staging

There are several stages of AD. These stages may be distinguished by scores on the Mini-Mental State Exam (MMSE) commonly used in general medical practice. The MMSE is an office-administered standard scoring tool with a maximum score of 30.²⁴ Scores of 21-25 are generally found in early-stage AD; scores of 11-20 imply a progression to mid-stage, and scores of ≤ 10 are indicative of severe or late-stage AD.²⁵ Note: The MMSE is not diagnostic of AD and is more often used to track progression than to screen or diagnose.

Mild cognitive impairment (MCI) is a term used to indicate a stage in the “grey area between intact cognitive functioning and clinical dementia.”²⁶ This time period has evolved into a rich area of investigation for AD prevention. There are efforts in progress to subtype MCI and clarify risk for progression to specific types of full-blown dementia, including AD. A 2015 review article looked at promising results from 23 randomized, controlled trials involving nonpharmacological interventions aimed at delaying progression to AD; cognitive training and exercise figure most prominently here.²⁷

The Montreal Cognitive Assessment (MoCA) is an office-based screen with specific utility in differentiating the early stages of AD from MCI.²⁸ This may be especially useful in clinical situations when tracking disease progression is a priority, such as when discussing placement options or prognosis.

Several studies, including a 2015 Cochrane analysis, concluded that no one screen is sufficiently reliable and specific enough to track disease progression or conversion from MCI to AD. Current recommendations are to use several screens or use several measures of the MMSE over time.²⁹

A recent publication looked carefully at delineating disease progression specifically in an effort to assist the primary care practitioner in explaining evolution of the disease and thereby to help patients and caregivers prepare for and predict the future. Although there are many individual variations, probability indicates that word recall, general orientation, and immediate memory are typically affected during the first stages of AD; attention and concentration, language, and executive function begin to deteriorate in mid-stage AD; and more global memory problems emerge at progression to the more severe stage of the disease. An animation explaining this progression is available for download and distribution to patients and family members: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad150852.

Medications

There are several FDA-approved medications for AD. Cholinesterase inhibitors used during early-mid stages include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne.) These work to increase availability of acetylcholine, a neurotransmitter crucial in memory and learning.

Studies show cholinesterase inhibitors lend a modest but significant benefit in slowing cognitive and functional decline in early stages of AD. It is important to understand and convey to patients and families that these agents neither target nor reverse the ongoing destructive progression of the disease, but may delay this process.^30,31

As AD progresses, memantine (Namenda), an N-methyl-D-aspartate antagonist or glutamate regulator, may be used to attempt to preserve functioning as long as possible. The newest agent, Namzaric, combines donepezil and memantine, both of which are approved individually for treatment at this stage. Clinical studies with all of these agents indicate responses tend to vary in individuals.³² (See Table 3.)

Approaches to Treatment of AD

As noted, there remains no known agent to definitively treat and cure AD. The decreasing incidence of dementia of all types in the elderly suggests efforts toward prevention and early intervention have been successful.

A thoughtful holistic approach to the patient with AD involves consideration of multiple dimensions. A recognition of the role and health of not only the identified patient but also the caregiver becomes important, especially as the disease progresses.

Given the limited efficacy and impact on the progression of AD from available pharmacotherapy, many patients, families, and practitioners look to adjunct or alternative treatments. Although limited information is available regarding specific numbers of patients with AD seeking such treatments, several studies note the use of integrative therapies among elderly patients in general reaches 40-45% in the United States.³³ A strategy combining conventional medication and treatment with less conventional approaches, including nutritional, behavioral, and other non-pharmacologic interventions, is useful. Informing a patient (to the extent he/she can understand) and caregiver about the medical evidence supporting such treatments — or the lack of evidence in some cases — helps create a cohesive treatment team and allows the patient and/or caregiver a degree of autonomy at a time when fears of loss of control and decision-making ability typically rise to the forefront.

In discussing treatment, it is helpful to distinguish interventions during each of several stages of disease progression. Treatment approaches for at-risk populations, including those with MCI (prevention), early- to mid-stage AD, and late- or end-stage AD, are described below. Although the most robust evidence points to the value of preventive interventions, emerging studies and evidence for useful interventions are available to affect the course of AD at all stages.³⁴

Prevention

Age remains the most significant risk factor for development of late-onset AD. The expected incidence rate in the United States ranges from 0.2% among people 65-74 years of age to 1.3% among people 75-84 years of age and finally to 3.9 % among those > 85 years of age. Second to age, genotype (APOE4) is the next most significant risk factor in the development of AD.²

Little can be done in the way of prevention regarding the above unmodifiable risk factors; prevention work revolves around the known modifiable risk factors. At the London G8 summit in December 2013, an international group of scientists presented conclusions that AD can be prevented and recommended the following:

“Public health policies should encourage middle-aged people to stop smoking; exercise; eat diets rich in fruit and vegetables and fish (and other “Mediterranean foods”); avoid becoming obese nor diabetic; avoid excessive alcohol intake; and treat high blood pressure. In other words — counsel people that adopting a healthy lifestyle may help to ward off Alzheimer’s dementia as it does for other diseases.”³⁵

Physical activity: Studies suggest the impact of exercise and physical activity goes beyond mitigation of cardiovascular risk. A 2011 meta-analysis of studies looking at physical activity and cognitive decline suggests a decline in risk of cognitive deterioration of
> 30% through moderate- to high-intensity exercise.³⁶

Diet/nutrition: This is a very active and exciting area of investigation and research. Data from observational studies suggest a role for specific heart-healthy diets, while randomized, controlled trials fail to show a consistent impact for nutritional intervention. There is no evidence that omega-3 fatty acids directly help cognition in the elderly, but there is evidence that control of cardiac risk factors in mid-life aids AD prevention. Promising results from a 2015 observational study of a hybrid diet are noted below.^37,38

Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND diet)³⁹: Developed and investigated by researchers from Rush University Medical Center, the MIND diet combines elements of two heart-healthy diets with neuroprotective foods. Results from a large observational study are encouraging and point to a delay in cognitive decline in adults who follow this modification of the Mediterranean and DASH diets. Evidence suggests a preventive effect even with only moderate adherence and further suggests the preventive impact may mirror the length of time adhering to the dietary pattern.

Components of MIND diet include:

• Whole grains, three times daily
• Green leafy vegetables daily
• Other vegetables daily
• Berries (strawberries and blueberries)
• Nuts
• Beans
• Fish
• Poultry
• Olive oil
• Wine

Eliminate or significantly reduce:

• Red meats
• Butter
• Cheese
• Sweets/pastries
• Fast food/fried food

Hypertension control: This is important in mid-life, with some emerging evidence that hypotension becomes a risk factor in the elderly.⁴⁰

Obesity: Longitudinal studies have identified mid-life obesity as a risk factor for AD.⁴¹

Hypercholesterolemia: There appears to be a link between cholesterol, plaque formation, and hyperphosphorylation of tau protein. A recent randomized, controlled trial involving almost 1,000 elderly males during an eight-year period found convincing evidence that consistent statin use reduced AD risk.⁴²

Cardiovascular risk factors: Better control of diabetes, heart disease, and metabolic syndrome is associated with AD risk reduction, although studies are not clear regarding cause and effect.⁴³

Cognitive training and social engagement: Multiple randomized, controlled trials have tried to measure the effect of cognitive stimulation programs on persons with and without cognitive impairment; results have been mixed. Researchers who performed a robust study with 2,832 randomized participants and multiple intervention arms published a 10-year follow-up of their patients in 2014. These results point to a positive effect of cognitive intervention on reasoning, speed of processing, and self-reported activities of daily living, but no effect on memory.⁴⁴

Sleep: This is an active area of investigation, as it is thought that sleep disturbances during midlife may affect amyloid deposits in the brain. Improvement of sleep during midlife may help prevention of AD.⁴⁵ Interestingly, obstructive sleep apnea is thought to be a stand-alone risk factor for development of cognitive impairment, especially in older women.⁴⁶

Relevant Negatives

Ginkgo evaluation of memory study: More than 3,000 community volunteers with normal cognition or early changes were involved in a prospective study (2000-2008); median follow-up was six years. Ginkgo biloba, at 120 mg twice daily, was not effective in reducing the rate of development of dementia or AD.⁴⁷

Vitamin B12: This trial of 201 participants, which looked at correction of moderate vitamin B12 deficiency (no anemia; serum level 107-210 pmol/L), found no evidence of improved cognitive functioning in AD.⁴⁸

Take-home Message for Those at Risk (the biggest single risk factor for AD is age)

• Increase physical movement.
• Eat more whole grains, berries, vegetables, nuts, and beans while decreasing red meat.
• Control weight.
• Address and correct cardiovascular risk factors in midlife.
• Keep brain active and stimulated.
• Watch for and correct sleep disturbances in midlife.

Early to Mid-Stage Alzheimer’s

Look Carefully at Complete Picture

Evaluate and simplify a medication list: Many older patients are on anticholinergic agents (i.e., diphenhydramine, oxybutynin), which contribute to confusion and counteract the impact and action of cholinesterase inhibitors. Carefully evaluate a patient’s medication list and eliminate or minimize such agents when possible.⁴⁹

Polypharmacy in older adults may be a risk factor itself. A recent Northern Ireland study, including almost 7,000 community-dwelling patients with dementia, identified more than 80% prevalence of polypharmacy with potentially inappropriate prescribing in more than 60% of this population. In the United States, we can claim no better results — a 2016 descriptive study published in the Journal of the American Medical Association identified climbing rates of polypharmacy among older adults in America, with a potential 15% of these adults at risk for major drug-drug interactions.⁵⁰

Treat comorbid illnesses, which are common in this population of elderly patients. Look particularly for signs and symptoms of depression, anxiety, and psychosis. As AD progresses, it is likely that neuropsychiatric symptoms will emerge. There is good evidence that treatment of these symptoms can help with disease management, but little evidence that pharmacologic intervention is the best or even the most helpful option. The first line of management is to address any underlying causes, such as an untreated urinary tract infection, thyroid abnormality, or medication side effect. The next step is to look toward non-pharmacologic treatment (such as increase in outside stimulation or correction of a sleep disturbance.) When pharmacologic intervention is necessary for depression or anxiety, a low-dose selective serotonin re-uptake inhibitor is usually well tolerated. Antipsychotic treatment also should be kept at a low dose, with a full understanding of the risks involved in using these agents in older patients.⁴⁶

As noted above, obstructive sleep apnea should be corrected to minimize this risk factor, especially for older women.⁴⁶ Correction of cardiovascular abnormalities, and especially sugar control in diabetics, can help with prolongation of stable functioning and memory during this stage of AD.^46,51

Discuss medication adherence and compliance with the patient and caregiver, recognizing that as cognitive deterioration progresses, old strategies for managing medications may no longer work. This often is the ideal time to plan for future needs since the patient is still able to express preferences. Make sure to explain expected progression of the disease as well as strategies to preserve current level of functioning.⁵¹

Reveal Diagnosis

Revealing a diagnosis to patients and/or caregivers is an important, difficult, and often neglected step in management of this disorder. A large-scale analysis of Medicare records from 2008, 2009, and 2010 found diagnosis disclosure rate of 45% among persons diagnosed with AD (and even lower for other forms of dementia). Multiple studies explore the benefits of disclosing a diagnosis early and clearly. These point to implicit advantages for patients, including having the time to plan for the future financially and legally while still cognitively able; being able to provide informed consent for treatment options; providing a sense of autonomy and control; and allowing patients and families the time to develop positive coping strategies by putting a name to the changes they are experiencing or noticing. Contrary to many providers’ beliefs, there is little evidence that revealing this diagnosis increases the likelihood of depression or suicide.⁵¹

Exercise

Exercise has long been thought to be important in treatment, with few evidence-based studies backing up clinical impression. A recent Danish randomized, controlled trial involving 200 community-dwelling patients with mild Alzheimer’s (mean MMSE score of 24 and all scores > 19) is considered the first “rigorously conducted study of moderate-to-high intensity aerobic exercise in mild AD.” Findings from this study are promising but mixed, pointing to a need to conduct more studies and to differentiate the effect of socialization from the effect of exercise. In this study, high-intensity exercise seemed most effective in leading to measurable improvements in cognition.⁵²

Stress Management

Promising results from several studies have looked at the effect of meditation, yoga, sleep quality and quantity, and control of depression symptoms in early AD. Music may have a neuroprotective effect; participation in music-related activities may help with short-term recall in early-stage AD.^53,54

Selected Supplements with Potential for AD

Ginkgo biloba: Plant extract; antioxidant and anti-inflammatory

A 2015 meta-analysis looked at results from nine adequately sized randomized, controlled trials investigating the use of Ginkgo biloba in dementia. All studies used standardized G. biloba extract EGb761 at varying doses; dementia was subtyped to AD and/or vascular dementia. Safety, in terms of side effects, did not differ markedly from placebo. G. biloba at 240 mg daily outperformed placebo in specific measures of cognitive improvement in most of the studies but had no effect on prevention.⁵⁵

Huperzine A: Chinese herb extract; acetylcholinesterase inhibitor

A 2013 review article looked at results of 20 randomized, controlled trials and concluded that there may be evidence of efficacy in AD, but methodology of studies does not allow clear recommendations or conclusions. There were no serious adverse effects noted in the studies.⁵⁶

Vinpocetine: Semi-synthetic ester of a compound obtained from the leaves of the vinca plant (lesser periwinkle)

Vinpocetine’s theoretical efficacy in AD derives from its action as a phosphodiesterase inhibitor. It has been used as a folk remedy around the world in a variety of disorders, including treatment of diabetes in Europe and use as a diuretic in Asia. There have been limited studies in AD, although the basic science is starting to drive investigation. A 2003 Cochrane analysis showed limited beneficial effect in dementia at doses of 30-60 mg/day and no adverse effects, and recommended larger well-designed studies moving forward.⁵⁷

Phosphatidylserine (PS): Phospholipid contributing to integrity of cell membranes

Promising studies were conducted with bovine-derived PS, which is no longer available because of safety concerns regarding the risk of bovine spongiform encephalopathy. Soybean-derived PS represents a safer alternative and is being actively investigated for efficacy and safety in humans.

A promising exploratory study in 2013 gave soybean-derived PS to 30 volunteers with memory impairment at a dose of 300 mg/day. Recommendations are to move forward with more broad-based robust studies.⁵⁸

Selected Investigational Studies in AD

Acupuncture: A meta-analysis published in June 2015 looked at 10 randomized, controlled trials (585 patients; all studies were published in Chinese).

Results: Acupuncture alone (six trials) showed greater improvement on MMSE scores than acetylcholinesterase inhibitors alone. Acupuncture in addition to donepezil (three trials) showed greater improvement on MMSE than donepezil alone. There were few reported adverse side effects related to acupuncture. Limitations of the studies include no follow-up, moderate sample sizes, and unclear diagnostic criteria.⁵⁹

Cognitive training/cognitive rehabilitation: These consist of specific, usually individualized, approaches to address impairments in cognition. A review article in 2013 looked at 11 randomized, controlled trials.

Cumulative Results: The authors found no association with positive or negative outcomes in AD. Limitations of the studies included design and methodology.⁶⁰

Multi-pronged, individualized approach with diet, exercise, and stress reduction: Reversal of cognitive decline was reported in a series of case studies in the September 2014 issue of Aging. The authors reported reversal of cognitive decline in nine out of 10 patients using dietary changes (elimination of simple carbohydrates and processed foods and increased fruit and vegetables), vitamin supplementation, stress reduction, hormone replacement, and exercise.⁶¹

Limitation: This was not a randomized, controlled trial. Individualized approach makes replication difficult.

Anti-tau vaccine⁶²: Phase I trial with 30 patients (early to moderate Alzheimer’s with mean MMSE = 20); stable cognition over six months

Limitation: clearly investigational, limited subjects, limited follow-up, no statistical analysis, some adverse effects.

Take-home Message for Early-mid Alzheimer’s

• Keep up or increase physical activity.
• Address medication compliance strategies.
• Consider cholinesterase inhibitors early to delay progression.
• Simplify medication regimen and look for interactions.
• Treat comorbidities including stress and anxiety.
• Consider dietary changes and vitamin supplementation.
• Plan for future needs.

Middle-Late-Stage AD

Manage secondary symptoms: Delusions or hallucinations may emerge now or at earlier stages and interfere with functioning and autonomy. Treatment with pharmacologic agents must be balanced with understanding of side effects. There is a black box warning from the FDA that treatment with atypical antipsychotics (as well as with many of the older neuroleptics) increases the risk of stroke or death in this population. The consensus is that it is best to use these agents in low doses and only as needed to improve or maintain level of functioning.⁵³

Consider behavioral interventions: Look at manipulation of environment (i.e., assistive devices, door alarms, electronic monitoring, and pill dispensers) and behavioral plans within nursing homes or as developed with a caregiver. These can address behavioral concerns without the risk associated with pharmacologic interventions, or can be used in combination with agents as clinically indicated.⁵³

Attend to the emotional needs of the caregiver: Educate him/her about signs and symptoms of burnout; refer to support groups or community agencies; and reinforce the need for self-care. At this stage, a caregiver is most likely the providers’ main source of information regarding functional impairments, decline, and unmet needs; whenever possible, include the caregiver at visits and examinations. Keep in mind that the caregiver may not be a family member or may not have the ability to make decisions for the patient, but still may have the most accurate source of information for the provider.^2,51

Take-home Message for Middle-late stage AD:

• Consider appropriate pharmacologic intervention for primary or secondary symptoms and behaviors that impair functioning.
• Consider changing or modifying environment to manage these same behaviors with less pharmacologic agents.
• Manage comorbidities.
• Address self-care of the caregiver and include the caregiver at appointments.

CONCLUSION

Advances in our understanding of the development and multifactorial nature of AD has led to a more sophisticated approach to address cognitive deterioration in patients. We know that the deteriorating processes leading to clinical manifestations of AD begin before dysfunction is apparent. We know preventive efforts in controlling risk factors, such as hypertension, weight, and lipid status, can help delay or prevent AD. We know that active, healthy habits developed in mid-life adulthood can be protective as well. We are gaining in knowledge about genetic risk factors in AD. Additionally, we have increasingly more accurate tools to diagnose and track disease progression.

However, there is a lot we do not know. In many cases, the primary care practitioner holds the unenviable role of revealing a diagnosis without being able to offer a cure. With this disorder, management of symptoms, education regarding disease progression, and support of the patient and caregiver in efforts to devise a safe and secure environment may be the most important tools modern science can offer at this point.

Integrative and non-pharmacologic approaches to AD are gaining traction in the treatment of this devastating and progressive disorder. It is conceivable that treatment of AD in coming years will have an individualized approach with lifestyle modification at the forefront. As new imaging techniques are developed and validated, the modifications may be able to be combined with new targeted medications and specific tracking mechanisms monitoring the impact on tau and beta-amyloid.

Given our current state of knowledge, screening and preventive efforts have a unique importance in the fight against AD. The primary care provider remains in the best position to administer the screens, refer for further testing if necessary, and provide anticipatory guidance to all at risk for AD. Recalling that the largest risk factor for AD is age, it is clear that most aging patients can benefit from the preventive efforts and healthy lifestyle believed to be essential in prevention of development of AD.

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