AUTHORS
K. Doug Pugar, DO, Dayton Center for Neurological Disorders, Dayton OH
Kenneth B. Pugar, DO, FACN, Dayton Center for Neurological Disorders, Dayton OH
PEER REVIEWER
Makoto Ishii, MD, PhD, Assistant Professor of Neuroscience and Neurology, Weill Cornell Medical College, New York
EXECUTIVE SUMMARY
Alzheimer’s disease affects more than 5 million Americans, is the sixth leading cause of death, and has a projected national cost of nearly $260 billion.
- Establishing a diagnosis of Alzheimer’s disease can be challenging, with only 80% correctly diagnosed based on clinical grounds alone.
- The preclinical stage of Alzheimer’s disease represents a new entity of patients with confirmed biomarkers who have not yet developed outward cognitive manifestations.
- The pathologic biomarkers are amyloid-β and markers of neuronal injury, such as phosphorylated tau; the presence of both biomarkers confers the highest risk of Alzheimer’s disease.
- Treatment includes cholinesterase inhibitors and the NMDA receptor antagonist memantine. A recent study has shown benefit from multi-domain interventions on diet, exercise, cognitive training, and vascular risk monitoring.
Definitions and Diagnostic Criteria
The diagnostic criteria for Alzheimer’s disease (AD) have changed in recent years, with a growing focus on pathologic and genetic biomarkers.1 The diagnosis itself now is divided into three distinct stages: the preclinical stage, mild cognitive impairment, and clinical AD. The preclinical stage has emerged as a new entity, representing patients with confirmed biomarkers who have not yet developed any outward cognitive manifestations of the disease.2 (See Tables 1 and 2.)
It is important to note that any of the major cognitive domains (memory, language, executive function, attention, perceptual-motor, and social cognition) can be affected to varying degrees in AD patients, but memory specifically must be affected to make this diagnosis. In fact, memory is typically by far the most prominent feature early in the course of the illness. Impairments in the other cognitive domains may be more prominent in atypical presentations of AD or in some of the other forms of dementia, which will be discussed later in this article.
Table 1. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Criteria1 |
|
Minor Neurocognitive Disorder
|
|
Major Neurocognitive Disorder
|
|
Major Neurocognitive Disorder Due to Alzheimer’s Disease
|
Table 2. Stages of Alzheimer’s Disease |
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Preclinical No outward cognitive signs or symptoms, but imaging and/or biomarker studies identify early neuropathological changes |
|
Mild Cognitive Impairment Some noticeable memory loss, but the patient is still able to live independently |
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Alzheimer’s Disease Patient meets the DSM-V criteria for AD |
Pathologic and Genetic Biomarkers
The pathologic biomarkers for AD currently are divided into two broad categories: markers of amyloid-β and markers of neuronal injury (i.e., phosphorylated tau). These are based on the pathologic hallmarks of the disease, namely amyloid plaques and neurofibrillary tau tangles. The presence of both biomarkers conveys the highest risk for the development of dementia. Deposition of amyloid-β is thought to begin up to 20 years prior to the development of clinically recognizable symptoms.3,4 The cerebrospinal fluid (CSF) profile with the strongest predictive value for AD would include elevated levels of tau with reduced levels of amyloid-β-42.5 Amyloid-β-42 levels are reduced in the CSF of AD patients because the protein is forming insoluble deposits within the brain (plaques) leading to decreased clearance, whereas tau, a relatively nonspecific marker of neuronal injury, increases along with progressive brain atrophy.6
A new imaging modality, the amyloid positron emission tomography (PET) scan, currently is being studied as a potential modality to aid in the diagnosis of AD and in distinguishing it from other forms of dementia. This technology uses the compound florbetapir (or a similar radioligand), which binds to amyloid-β within the brain, allowing it to be detected on PET scan. Postmortem study has shown that this modality is effective and correlates well with autopsy-confirmed amyloid burden.7 Another study currently is underway to evaluate the effect of amyloid PET data on patient outcomes. More recently, tau PET scans are being developed to identify tau pathology in vivo as well.8
There are some gaps in the current understanding as to the precise role of the above biomarkers on the pathogenesis of AD. For instance, multiple pharmacologic agents have been shown to effectively reduce amyloid-β levels within the central nervous system, but these agents failed to show any benefit on disease progression in clinical trials.9,10,11 Similar failures have been seen for agents that target tau. A recent Phase III clinical trial of a potent tau aggregation inhibitor failed to slow the rate of cognitive decline in patients with AD.12 One possible reason for these recent clinical trial failures is that the studies largely were targeting individuals who were already in the later stages of the disease, after extensive neurodegeneration already has occurred. Ongoing clinical trials are investigating the efficacy of these pharmacologic agents when initiated in earlier (even preclinical) stages of AD.
Although Mendelian inherited cases of AD are extremely rare (about 1% of all cases), multiple genes have been identified as causative. These include amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). All are inherited in an autosomal dominant fashion with full penetrance.6 The most common cause of familial AD is mutation of the PSEN1 gene, and this also is associated with the youngest age of onset. Mutations in each of these genes result in altered APP metabolism and increased production of amyloid-β.6,13 (See Table 3.)
Table 3. Genes Associated with Early-Onset Familial Alzheimer’s Disease |
|
|
Gene |
Chromosome |
|
APP |
21 |
|
PSEN1 |
14 |
|
PSEN2 |
1 |
Other genes have been identified as risk factors for the later-onset sporadic from of AD. Apolipoprotein E (APOE), and more specifically the *E4 allele, has been shown to confer the greatest risk for developing sporadic AD. Carrying one copy of the allele is associated with an up to fourfold risk for AD compared to non-carriers. Half of all patients carrying the APOE*E4 polymorphism will develop AD if they live to be 80 years of age. Homozygous carriers of the *E4 allele carry both an increased risk for AD and earlier onset of AD.6
Non-Alzheimer’s Dementias
There are several other forms of dementia, each with their own unique presentations and pathologic findings. AD is by far the most common, but Table 4 outlines three other common forms of dementia. Establishing a precise diagnosis within the realm of dementia can be difficult, as there is often significant overlap between these conditions, both clinically and pathologically. It is not uncommon for a variety of different proteinopathies to coexist within one patient, even in cases in which the clinical diagnosis seems clear.
Table 4. Other Common Forms of Dementia14,15,16 |
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|
Disease |
Primary Proteinopathy |
Distinct Features |
|
Dementia with Lewy Bodies |
Alpha-synuclein Amyloid |
|
|
Frontotemporal Lobar Degeneration |
Tau |
|
|
Vascular Dementia |
None |
|
In recent years, there has been growing evidence surrounding the effect of repeated head trauma on the development of dementia in later life. Chronic traumatic encephalopathy (CTE) is a relatively new diagnostic entity that is characterized by long-term neurologic impairment secondary to repetitive mild traumatic brain injury. The exact mechanism of this illness remains unclear, but it is thought to be a progressive tauopathy. Behavioral disturbances are common and often are among the earliest manifestations of the disease. It is important to discuss any history of head trauma when evaluating a patient for dementia, but definitive diagnosis of CTE currently can be achieved only at autopsy.17
Epidemiology and Effect of Dementia
Dementia is a significant and growing problem throughout the world. Currently, there are more than 5 million patients living with dementia in America alone, and it is estimated that by the year 2050, this number could be as high as 16 million. One in three seniors dies with some form of dementia, and it is the sixth leading cause of death overall. The economic burden of this illness is significant as well. An individual family spends (on average) more than $5,000 per year caring for a patient with dementia. Beyond this direct cost, it is estimated that in 2016, there were more than 18 billion hours of unpaid patient care, valued at more than $230 billion. The national cost related to AD alone is estimated to be $259 billion, and is projected to reach $1.1 trillion by the year 2050.18 (See Table 5.)
Table 5. Dementia By the Numbers18,19 |
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The disease appears to affect women in greater proportions than men, at a nearly 2:1 ratio.3 The reason for this discrepancy likely is multifactorial. Certainly, because age is the single greatest risk factor for dementia, the longer average life expectancy for women is likely one factor, but it probably is not the only one. However, it has been shown that men may be more likely to be misdiagnosed or underdiagnosed, so this discrepancy between the sexes may not be as robust as was once thought.20 African Americans and Hispanics have a higher prevalence of AD than age-matched white Americans. Other factors, such as education levels and the prevalence of cardiovascular comorbidities and depression, etc., undoubtedly play major roles in this discrepancy.3
Establishing a Diagnosis
Establishing a diagnosis of AD is not without its challenges. One study comparing clinical and neuropathologic diagnoses found that only 78.4-83.5% of cases were diagnosed correctly based on clinical grounds alone. There were equal rates of false positives and false negatives, with the most common cause of a false positive being vascular dementia and the most common cause of a false negative being dementia with Lewy bodies.21
Dementia diagnoses typically are made purely on clinical grounds, as definitive pathologic confirmation rarely is pursued and is achievable only postmortem. A thorough and detailed history, including family history, is critical. It is usually helpful and often essential to have a cognitively intact family member present during the interview, as patient insight into his or her own limitations often is quite poor (significant anosognosia is common in AD). Not uncommonly, the patient will deny any concern for memory impairment but his or her family will be the ones to “insist” on an evaluation. Having these family members present during the visit can provide valuable insight regarding the overall clinical picture.
Office-based assessment should include a full physical examination, including a thorough neurologic examination. Mental status testing should include evaluation of several different cognitive domains, including orientation, memory and recall, language, attention, concentration, and visual-spatial reasoning. The Mini-Mental State Examination (MMSE) is one well-known means of cognitive testing and is relatively easy to administer, but it should be noted that this assessment currently is under copyright by Psychology Assessment Resources, Inc. Additionally, the MMSE is not particularly sensitive for detecting milder cases of dementia, and there is a tendency for high test-retest variability. Also, it is highly reliant on patient effort and, therefore, is subject to a high likelihood of false positives for cases of conversion disorder or malingering. One attractive alternative to the MMSE is the freely available Montreal Cognitive Assessment (MoCA), which tests a wider range of cognitive domains and is more sensitive in detecting mild cognitive impairment than the MMSE. These and all other in-office cognitive assessments should be used purely as screening tools, and not as the sole means with which to establish a diagnosis.22
The initial workup typically includes screening for potentially reversible causes of memory impairment. The basic recommended workup is listed in Table 6. All patients with objective memory loss should have a brain imaging study, preferably a non-contrast MRI. MRI alone rarely will lead to a definitive diagnosis. Often, findings such as atrophy or chronic white matter changes can be suggestive of AD but are non-diagnostic. Furthermore, a normal-appearing MRI does not rule out a diagnosis of dementia. The primary role of neuroimaging in this context is to rule out potential structural etiologies. One study found that 5% of all patients presenting with cognitive decline had a causative structural brain lesion, such as a chronic subdural hematoma, neoplasm, or normal pressure hydrocephalus.23 Formal neuropsychometric testing can be very helpful, especially in cases in which suspicion for “pseudodementia” (a form of conversion disorder in which patients experience memory impairment as a result of depression, anxiety, or other psychiatric ailments) exists. This also can be beneficial if performed early on as a baseline for comparison for future studies in monitoring disease progression.
Table 6. American Academy of Neurology Recommended Workup for Patients Presenting with Memory Impairment22 |
||
|
Recommended for All Patients |
Others to Consider |
Only if Clinical Suspicion Exists |
|
|
|
Tests for specific biomarkers within the CSF are commercially available but they are not pursued routinely because of the invasiveness of lumbar punctures and often are reserved for more challenging cases.24 The amyloid PET scan (as discussed above) is not expected to become part of the routine workup for all cases of dementia, but it may be useful in ruling out mimickers. A positive result does not necessarily confirm that a patient has AD, but a complete absence of amyloid-β deposition would strongly suggest an alternative diagnosis.
Genetic testing is available for each of the genes listed in Table 3, but the utility of these studies is limited. A positive test is considered confirmatory only in patients who are symptomatic (and thus likely already meeting diagnostic criteria on clinical grounds), and a negative test does not necessarily rule out the disease. Furthermore, there is currently no proven therapeutic benefit to be obtained from genetic testing.13 Both the testing process as well as receiving results can be a highly distressing experience for patients and their families, so many question whether this is ever worthwhile since the results are not expected to help guide clinical management.25,26 When testing is pursued, genetic counseling always should be arranged as well. It is important to discuss all of the above considerations with patients, as it is not uncommon for those with a family history of AD to request genetic testing from their primary care physicians.
Several new diagnostic modalities for AD currently are being investigated. A noninvasive retinal amyloid fluorescence study has been shown to be 100% sensitive and 80.6% specific for differentiating AD from non-AD in preliminary studies.27 A panel of five specific plasma proteins has been identified and it showed a sensitivity and specificity of 89.36% and 79.17%, respectively.28 Tests of olfaction, specifically the UPSIT (University of Pennsylvania Smell Identification Test), have been shown to be predictive of cognitive impairment, amyloid burden, brain atrophy, and even behavioral symptoms in some studies, but the clinical applicability of these tests is currently unclear.29,30
Can Dementia Be Prevented?
The most significant risk factor for the development of dementia (by far) is age, but several other risk factors have been identified as well. Vascular risk factors, in particular, seem to be strongly implicated. An autopsy study of 1,143 patients showed that increased severity of atherosclerosis and arteriosclerosis were associated with significantly greater odds of dementia, as well as with decreased scores of cognition.31 Hypertension, smoking, hyperlipidemia, and diabetes each have been shown to carry a 20-40% increased risk of dementia in one study. Having any one of these risk factors is associated with a hazard ratio of 1.27 compared to patients with none, and this increases to 2.37 if all four risk factors are present.32 Another study found diabetes to convey a 56% increased risk of AD and a 127% increased risk for vascular dementia.33 Obesity in midlife has been shown to confer an increased risk as well.34
Heavy alcohol consumption and cigarette smoking are other significant modifiable risk factors. One study found patients who were heavy drinkers (defined as more than two drinks per day) or heavy smokers (defined as greater than or equal to one pack per day) developed dementia two to three years sooner than non-drinkers and non-smokers. This increased to nearly 10 years if patients were both drinkers and smokers, and also had the APOE*E4 allele.35 Another study found that overall cognitive decline was 36% faster in patients who were both smokers and heavy alcohol drinkers compared to those who were not.36 Other factors that have been shown to be associated with increased risk for dementia include unmarried relationship status, depression, and lower level of education.37,38 History of repetitive head injuries may increase the risk of all forms of dementia, but particularly CTE, as discussed earlier.
Some behavioral syndromes may convey an increased risk for dementia as well. The syndrome of “mild behavioral impairment,” characterized by prominent psychiatric and behavioral symptoms without significant evidence of cognitive decline, appears to carry an even greater risk for the eventual development of dementia than does a diagnosis of mild cognitive impairment. It is thought that this actually may be a dementia prodrome in some cases, particularly for frontotemporal dementia.39
Increased physical, cognitive, and social activity have been shown to be protective against dementia.40 Higher fitness levels in midlife are associated with lower risk for dementia, and this finding seems to be independent of the presence of cerebrovascular disease.41 One study showed that patients who participated in vigorous exercise at least three to four times per week were 34% less likely to develop dementia compared to those who did not.42 Patients with depression appear to be at increased risk for dementia, so early recognition and treatment are critical.43
Reviews of some specific medications, drug classes, and supplements are discussed in greater detail below.
Antihypertensives
Specific antihypertensive medications with evidence for reduced risk of dementia include calcium channel blockers and renin-angiotensin system blockers, but more study is needed to confirm these findings.44,45
Statins
In February 2012, the Food and Drug Administration (FDA) issued a statement based on anecdotal reports warning of possible adverse cognitive effects with statin use; however, several subsequent reviews and meta-analyses have refuted this association.46,47 In fact, there are data to support that statins actually may be protective against the development of dementia, regardless of lipophilicity, and this association was not seen for other cholesterol-lowering agents.48
Metformin
Long-term metformin use has been shown to have an inverse association with cognitive impairment, even when controlling for other factors such as age, diabetes duration, fasting blood glucose, and other risk factors.49
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs), particularly citalopram, have been shown to reduce amyloid-β burden in the brain.50,51 The clinical relevance of this finding remains unclear at this time.
Supplements and Nutrition
There is no evidence to suggest that Gingko biloba may have protective properties against dementia.52 Evidence regarding omega-3 supplementation is mixed.53, 54 A Mediterranean diet may have protective benefits.54
Management of risk factors early in life may help to delay or even prevent the onset of disease. Since age is the number one risk factor for dementia, it is estimated that delaying the onset by even five years may prevent up to 50% of all cases.55,56 Therefore, early education and intervention are crucial to curb the progression of this health crisis.
Dementia Management
Medications
Unfortunately, recent advances in the treatment of AD have been lacking. No new therapies for dementia have been FDA-approved since 2003. The mainstays of therapy continue to be acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Currently, the three acetylcholinesterase inhibitors approved for the treatment of dementia in the United States are donepezil, rivastigmine, and galantamine. Of these, donepezil has been studied the most extensively. Both donepezil and memantine have been proven to be effective as monotherapy for dementia, but evidence has shown that these two medications in combination are more efficacious than either agent alone.57,58,59,60,61 Early cognitive improvement may be seen after initiation of these medications, but it is important to remind patients and their caregivers that the goal of these medications is to retard the rate of disease progression. None have been shown to halt the progression of the disease entirely. For this reason, it is recommended that these agents be continued regardless of apparent clinical benefit, unless significant side effects develop.62 (See Table 7.)
Table 7. Recommended Dosages and Potential Side Effects of Dementia Medications63 |
||
|
Medication |
Recommended Dose |
Potential Side Effects |
|
Donepezil |
5 mg PO daily for 1 month, then increase to 10 mg PO daily In patients who tolerate the 10 mg dose, a 23 mg sustained-release formulation is also available |
Nausea, diarrhea, vomiting, abdominal pain, insomnia, dizziness, rhinitis, weight loss, anxiety, syncope There is an increased rate of adverse effects with the |
|
Rivastigmine |
1.5 mg twice daily, then increase every 4.6 mg/24 hr transdermal patch initially, may titrate every 4 weeks to 9.5 mg/ |
Nausea, vomiting, anorexia, abdominal pain, weight loss, dizziness, somnolence, syncope, headache, sweating Adverse effects tend to be less frequent and less severe with the transdermal formulation, especially with regard to GI side effects (which can be quite pronounced with the PO form) |
|
Galantamine |
4 mg PO twice daily, then increase every 4 weeks to target dose of 8 mg to 12 mg PO twice daily 8 mg extended-release tablet daily, then increase every 4 weeks to target dose of 16 mg to 24 mg daily |
Nausea, vomiting, diarrhea, abdominal pain, weight loss, syncope, dizziness |
|
Memantine |
5 mg PO daily for 1 week, then increase weekly by 5 mg/day to a target dose of 10 mg PO twice daily A sustained-release formulation is also available; 7 mg PO daily for 1 week, then increase weekly by 7 mg/day to a target dose of 28 mg daily |
Headache, somnolence, dizziness, confusion, hallucinations |
Medical Foods and Intranasal Insulin
The ketogenic agent AC1202 has been shown to improve scores of cognition in some patients, specifically those who are APOE*E4 negative. Unfortunately, this product did not meet statistical significance for the overall population, and the discontinuation rate was relatively high because of a propensity for gastrointestinal side effects.64 Studies for intranasal insulin currently are underway, and results from a small preliminary trial appear promising.65
Activity and Diet
Interventions focused on increasing cognitive and physical activity have been shown to slow cognitive decline.43 A two-year study of multi-domain interventions on diet, exercise, cognitive training, and vascular risk monitoring showed that patients who received these interventions performed significantly better than controls on tests of cognition.66 Physical activity should include both cardiovascular and weight training exercises, and diet should be high in fish, fruits, and vegetables and low in saturated fats. All patients should be encouraged to remain cognitively, physically, socially, and spiritually active. It is common for demented patients to become increasingly isolated and withdrawn as the disease progresses, so adult day care and senior living environments can be invaluable tools to promote socialization.
Safety and Supervision
It is important to address the social implications of the disease early. By definition, dementia will get worse over time, and the level of supervision a patient requires undoubtedly will increase. Family members should be questioned as to how the patient’s medications are monitored and administered. Safety concerns, such as tendency to leave on stove top burners, allowing food to spoil, or wandering outside of the home should be addressed. Responses to these questions may help determine whether the patient is able to live safely in the home environment or if placement into an assisted living or nursing home facility is necessary. Many patients may be able to remain safely in their homes (with proper supervision) for several years after a diagnosis is made, but doctors and caregivers should be proactive about developing plans for eventual institutionalization early, before this becomes a more urgent problem. If the patient still drives, an independent driving evaluation should be obtained to ensure that he or she is capable of safely operating a vehicle. If the patient has ever become lost while driving and was unable to reorient, driving privileges likely should be revoked. Unsurprisingly, these conversations often are met with a great deal of resistance on the part of the patient (and occasionally even their families), but it is a critical element to dementia care.
Mood and Behavioral Symptoms
One of the more challenging aspects of dementia treatment is management of mood and behavioral symptoms. Medications always should be used judiciously when managing behavioral manifestations, and should not be continued indefinitely. Non-pharmacologic interventions are preferred wherever possible. For acute behavioral changes or agitation, an underlying infection (particularly a urinary tract infection) always should be ruled out. The patient’s environment also should be analyzed for possible inciting factors, as he or she may not be able to adequately verbalize the underlying problem.
Music therapy has shown promise in management of neuropsychiatric symptoms, including agitation, depression, and anxiety.67,68,69 Other studies have disputed music therapy’s efficacy, but since this is an inexpensive and noninvasive measure that poses no significant risk to the patient, this may be an excellent initial option in many cases.70,71
Depression is common and generally is best managed with SSRIs, as these have a relatively low propensity for anticholinergic side effects. These also may be beneficial in treating anxiety, irritability, and agitation. When agitation becomes severe, neuroleptic agents sometimes are required, although it should be noted that these agents are not FDA-approved for management of psychiatric symptoms in dementia. In fact, these agents actually carry a “black box” warning for increased morbidity and mortality in elderly demented patients. The newer “atypical” antipsychotics (particularly quetiapine) generally are preferred when needed, and always at the lowest possible effective dose with a goal of eventually discontinuing the agent.3 Donepezil, aside from its benefits on cognition, actually has been shown to reduce behavioral symptoms, particularly mood disturbances and delusions, in AD patients as well.72
Reasons for Optimism?
Despite early grim predictions regarding the growing problem of dementia, a review of data from the Framingham Heart Study has shown that the incidence of new dementia diagnoses actually has declined over the course of three decades.73 A study of the U.K. population came to a similar conclusion.74 This is despite the fact that the medical community as a whole is likely better at diagnosing dementia than it was several decades ago. (See Table 8.)
Table 8. Dementia Incidence Changes as Seen in the Framingham Heart Study73 |
|
|
Years |
Incidence |
|
1978-1982 |
Baseline |
|
1986-1993 |
22% decline in new cases |
|
1996-2000 |
38% decline in new cases |
|
2006-2009 |
44% decline in new cases |
CONCLUSION
Dementia is a common and growing problem that is associated with significant caregiver burden and immense cost. Very few advances have been made in the treatment of AD, despite extensive research. A growing focus on disease prevention and management of risk factors in mid-life is vital to attempt to mitigate the daunting impact of this illness on patients, caregivers, and the healthcare system as a whole.
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The diagnostic criteria for Alzheimer’s disease (AD) have changed in recent years, with a growing focus on pathologic and genetic biomarkers. The diagnosis itself now is divided into three distinct stages: the preclinical stage, mild cognitive impairment, and clinical AD. Dementia is a common and growing problem that is associated with significant caregiver burden and immense cost. A growing focus on disease prevention and management of risk factors in mid-life is vital to attempt to mitigate the daunting impact of this illness on patients, caregivers, and the healthcare system as a whole.
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