Alzheimer's Disease: Diagnosis, Treatment, and Research

3.0 Contact Hours

Syllabus

At the conclusion of this module, the learner should be equipped to:

  • Cite the national and international statistics regarding Alzheimer's disease
  • Review the basic pathophysiology of Alzheimer’s disease
  • Evaluate and select amongst the appropriate screening tool(s) to be used in clinical practice to help diagnose Alzheimer’s disease
  • Utilize both psychosocial/nonpharmacological treatments and pharmacological options in the treatment of Alzheimer’s disease
  • Discuss the ongoing and potentially upcoming research into the pathophysiology and treatments for Alzheimer’s disease.


Alzheimer’s Disease: The Basics

According to the World Health Organization (WHO), the world currently contains around 50 million people with dementia, and this number is expected to triple to 152 million by 2050. They define dementia as a disease affecting memory, other cognitive abilities and behavior that interferes with daily functioning and activities of daily living (ADLs).  It is the 7th leading cause of mortality, and cost roughly $818 billion in 2015 worldwide. They estimate that Alzheimer’s Disease (AD) accounts for roughly 60-70% of all dementia cases. Risk factors include age over 65 (although as many as 9% of patients are under 65), physical inactivity, obesity, unhealthy diet, tobacco use, alcohol abuse, diabetes, midlife hypertension, depression, low educational attainment, social isolation, and cognitive inactivity (WHO, 2018). Additional risk factors for cognitive impairment include hypercholesterolemia, head trauma, learning disabilities (such as Down Syndrome), physical frailty, and having never been married (Moyer, 2014). According to the Alzheimer’s Association, deaths from AD has increased 123% since 2000, and now 1 in 3 seniors die with AD or another dementia (Alzheimer’s Association, n.d.). The number of patients with AD in the US is currently estimated at 5.6 million and expected to grow to 13.8 million by 2050. The total healthcare cost in the US in 2017 was estimated at $259 billion (Pandya, 2018).

The National Institutes of Health (NIH), and specifically the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), define AD as an “age-related, irreversible brain disorder” that starts with memory loss and eventually leads to behavioral and personality changes and cognitive decline. This process occurs gradually over years. It is currently the 6th leading cause of death in the US. The three pathophysiological findings in AD include amyloid plaques, neurofibrillary tangles, and a loss of connections between neurons involved in memory/learning (NINDS, 2018). Amyloid plaques are collections of bits of the amyloid precursor protein (APP) that break down into beta-amyloid and collect between neurons, the most toxic of which appears to be beta-amyloid 42. These plaques clump together and disrupt normal neuron function. Neurofibrillary tangles (NFTs) are found inside neurons in patients with AD. Small structures inside normal neurons called microtubules provide internal support and help guide nutrients and other molecules from the cell body out to the axon/dendrites. A protein, Tau, normally binds and helps to stabilize these microtubules. In neurons affected by AD, Tau molecules detach from microtubules and stick to each other, creating threads and eventually tangles that disrupt the neuron’s normal transport system and the synaptic communication between neurons. Abnormal Tau is believed to accumulate in the regions of the brain responsible for memory, and as the amount of beta-amyloid increases, there is a rapid spread of Tau throughout the brain. When neurons lose their connections to other neurons, they die, leading to severe tissue atrophy in the late stages of AD. Another pathophysiological finding common in patients with AD is chronic inflammation. This is believed to be caused by a build-up of glial cells, and microglia and astrocytes in particular. These cells are normally responsible for engulfing and destroying waste/toxins in a healthy brain, but do not function properly in destroying beta-amyloid plaques in AD. In addition to failing to clear the plaques and other cellular debris, they collect around neurons and emit pro-inflammatory biochemicals. There is also research that suggests the blood brain barrier in patients with AD contributes by preventing sufficient glucose delivery to neurons as well as waste removal. Vascular issues such as atherosclerosis, transient ischemic attacks (TIAs) and strokes are also common in patients with AD, further compounding the existing pathology (NIA, 2017).

Early-onset familial AD (EOAD or FAD) develops in the 30s-50s, and accounts for less than 10% of all AD. Most EOAD is believed to be caused by an autosomal mutation in one of three separate genes on chromosomes 1, 14, or 21. Each of these mutations affects the breakdown of APP (part of the process that leads to amyloid plaque formation) by altering the formation of presenilin 1 (chromosome 14), presenilin 2 (chromosome 1) or APP (chromosome 21). In late-onset AD (the most common form, developing in the mid to late 60’s), researchers have found a genetic risk factor via the apolipoprotein E (APOE) gene on chromosome 19. Of the three known alleles of APOE, one is thought to be protective against AD (APOE Ɛ2), one neutral (APOE Ɛ3) and one increases risk of AD as well as being associated with an earlier age of onset (APOE Ɛ4). Each individual has two copies of the APOE gene, and thus has a combination of zero, one, or two of each of the above alleles as a possibility. Currently, APOE allele testing is available and being used in research studies to study disease risk in large groups of people but is not yet used or helpful in determining an individual’s risk. Via the genome-wide association study (GWAS), by 2015 researchers had identified 33 regions of interest in the AD genome that may increase an individual’s risk of late-onset AD (NIA, 2017).

Prevention

            The treatment of AD at the current stage is sub-optimal, serving only to slow down progression of the disease in the best of scenarios. For that reason, much emphasis has been placed on determining if AD can in fact be prevented instead of waiting for treatment options to improve. Prevention of AD has been studied, and thus far managing cardiovascular risk and interventions for stroke prevention appear to be the most effective.  This includes mitigating any modifiable risk factors, such as smoking cessation efforts and weight loss programs to manage obesity, as well as aggressive management of diabetes, hypertension, and hypercholesterolemia. Diabetes has been estimated to increase an individual’s risk of AD by 50-100% and vascular dementia by 100-150%. The mechanism behind this likely involves both micro- and macrovascular disease, direct damage to central nervous system secondary to hyperglycemia, and increased inflammation secondary to insulin resistance. Conversely, weight loss, physical activity, and a diet lower in saturated fats have been shown to be protective against AD (Pandya, 2018). In a systematic review of 33 epidemiologic studies regarding modifiable risk factors and dementia, broad consensus emerged on the protective role of leisure activities, but conflicting results were found between dementia and smoking (as a risk factor) and mild alcohol consumption, dietary antioxidants, Mediterranean diet, and living with others (as protective factors) (DiMarco, et al., 2014)


Diagnosis

Despite some recent advances in neuroimaging and the detection of some biomarkers (such as beta-amyloid and tau), the diagnosis of AD is still fundamentally clinical (Moore, et al., 2014). Last revised in 2011 by a joint workgroup from the NIA and the Alzheimer’s Association, the diagnostic criteria for AD describes three stages of the disease. In the preclinical stage, there are no evident symptoms, but only underlying brain changes not yet detectable. This stage is an experimental concept only at this time, with the hope that imaging and biomarker studies will continue to progress and eventually lead to a profile that will identify individuals most likely to develop symptoms of AD. The second stage is marked by mild cognitive impairment (MCI) which includes symptoms of memory loss or thinking problems that are greater than expected given the individual’s age and education level, but not yet interfering with their ability to function independently. It requires concern about a change in cognition compared to previous and impairment of one or more cognitive functions, but preserved ability to function independently in daily life and the absence of dementia.  Finally, the third stage is Alzheimer’s dementia. This stage is characterized by memory loss, word-finding difficulty, and/or visuospatial problems that are significant enough to impair the person’s ability to function independently. Not all people with MCI progress to Alzheimer’s dementia. Dementia due to AD must involve a minimum of two of the following domains: ability to acquire/retain new information, reasoning/judgement/handling of complex tasks, visuospatial abilities, language functions, or changes in personality/behavior. They also define the terms possible AD (when the criteria for AD are met, but the disease follows an atypical course or there is evidence of a mixed presentation) and probable AD (when all of the diagnostic criteria for AD are met, with gradual onset over months/years). They define proven AD as occurring only after a positive autopsy (NIA, n.d.).

The National Association of Managed Care Physicians (NAMCP) published a list of differential diagnoses that PCPs should consider when confronted with a patient with cognitive impairment. These should be ruled out prior to a diagnosis of AD being administered. They include:

  • Medication-related cognitive changes
  • Depression
  • Delirium related to infection, etc.
  • Thyroid dysfunction
  • B12 deficiency
  • Vascular dementia/Stroke
  • Parkinson’s Disease
  • Lewy body dementia
  • Frontotemporal dementia
  • Normal pressure hydrocephalus (NPH)
  • Substance or alcohol abuse
  • Wernicke-Korsakoff’s syndrome (thiamine deficiency typically r/t alcoholism)
  • Creutzfeldt-Jakob’s disease (CJD)
  • Tumor
  • Syphilis or HIV-related dementia
  • Sleep deprivation

These diagnoses can often be ruled out with a complete history and physical exam (to include neurological exam). This would help identify delirium (onset over days/weeks, not months/years) and any medication that might be contributing to the cognitive decline. Standard laboratory tests recommended by the NAMCP and the Alzheimer’s Association should include thyroid stimulating hormone (TSH), complete blood count (CBC), vitamin B12 and folate levels, complete metabolic panel, and tests for HIV and/or syphilis. Imaging studies may be helpful in patients with younger age, history of head trauma, or focal symptoms (Pandya, 2018 and Cordell, et al., 2013).

In 2013, the Alzheimer’s Association published recommendations for primary care providers (PCPs) to better detect cognitive decline as a regular component of the Medicare annual wellness visit (AWV), one of the new benefits included in the 2010 Affordable Care Act (ACA). The AWV includes detection of any cognitive impairment as one of its seven components, but the Centers for Medicare and Medicaid Services (CMS) elected not to make a specific recommendation regarding how this should be done. The Alzheimer’s Association recommends reviewing the patient’s health risk assessment (HRA), asking the patient and any family/friends present about cognitive decline concerns, and observing the patient during the visit. Potential options for questions to include in the HRA that have been tested through the Behavioral Risk Factor Surveillance System include:

  1. During the past 12 months, have you experienced confusion or memory loss that is happening more often or getting worse?
  2. During the past 7 days, did you need help to perform everyday activities such as eating, getting dressed, grooming, bathing, walking, or using the toilet?
  3. During the past 7 days, did you need help to take care of things such as laundry, housekeeping, banking, shopping, using the telephone, food preparation, transportation, or taking your medications?

These questions will help identify any deficits in ADLs or instrumental ADLs (IADLs) such as cooking, shopping, etc. If any concerns exist based on this information, screening with a brief structured patient-completed assessment such as the General Practitioner Assessment of Cognition (GPCOG), the Memory Impairment Screen (MIS), the Mini-Cog, or the Mini-Mental State Exam (MMSE) is recommended. Positives features of all these exams included brevity (less than five minutes to administer), validated in a primary care setting, easily administered by a non-physician, good to excellent psychometric properties, and relatively free from educational, language, or cultural bias. A limitation cited for the GPCOG is the indeterminate range in the middle if being used without informant score, and if the informant score is being used alone there is a low specificity. GPCOG has been shown to have a low educational bias but there is not sufficient data regarding any potential language or cultural bias. The MIS is a verbal-only test that requires no writing/drawing and does not test executive function or visuospatial skills. Limitations of the Mini-Cog include variability in failure rates based on the use of different word lists, and the use of some study results based on longer tests with the Mini-Cog elements reviewed independently. An important downside of the MMSE is an associated copyright fee from the authors, while the other three options are currently free of charge. It also has been shown to have some education, age, language, and cultural bias as well as a ceiling effect in which highly educated individuals may pass despite significant impairment. Despite all of this, it is the most widely studied and therefore verified of the options available. If screening with informant input, the Alzheimer’s Association suggests using the GPCOG (patient and informant information can be combined for improved sensitivity and specificity), AD8, or the short Informant Questionnaire on Cognitive Decline in the Elderly (Short IQCODE). Of note, the Alzheimer’s Association algorithm also suggests screening any patient who does not have an informant present with a structured tool. If the brief assessment triggers concerns based on the score (GPCOG < 5 or 5-8 with informant score ≤ 3, MIS ≤ 4, Mini-Cog ≤ 3, AD8 ≥ 2, or Short IQCODE ≥ 3.38) then referral for full assessment should be made, or full assessment conducted (may be done same day with correct billing codes if informant present) (Cordell, et al., 2013). These tests can also be used to monitor disease progression. For example, in the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) it was recommended that a 3-point decline in a patient’s MMSE score within a 6-month time frame carries a poor prognosis and should therefore prompt their providers to explore comorbid conditions and review pharmacological management (Moore, et al., 2014). In 2014, the US Preventive Services Task Force (USPSTF) concluded that the current evidence was insufficient to assess the risks/benefits of formal universal screening of all adults over age 65 (I statement) (Moyer, 2014).

            Also in 2014, Barnes, et al. developed and published a dementia screening indicator for PCPs. This was based on the collective data of four large cohort studies (the Cardiovascular Health Study, the Framingham Heart Study, the Health and Retirement Study, and the Sacramento Area Latino Study on Aging). It includes a point system and is designed to help a PCP decide quickly if a patient is appropriate for formal screening with an assessment tool such as the GPCOG, Mini-Cog or MIS. First and foremost, if the patient or family expresses cognitive concerns, it recommends formal screening. Over age 80, it also recommends formal screening. However, if there are no explicit cognitive concerns, and the patient is age 65-79, the points are assigned based on:

  • Age (+1 point per year over 65)
  • Years of education (+9 points if less than 12 years of education)
  • BMI (+8 points if BMI < 18.5kg/m2)
  • History of type 2 diabetes (+3 points if history of DMII)
  • Stroke (+6 points if history of stroke)
  • Assistance required to manage medications/finances (+10 points if yes)
  • Depression (+6 points if yes, based on current use of antidepressant medication, or reports that “everything was/is an effort” ≥ 3 days per week over the past week)

If total score is ≥22, it recommends formal screening using a validated screening tool (Barnes, et al., 2014).


In 2015, the Gerontological Society of America (GSA) published their own recommendations for cognitive impairment detection, intentionally omitting the words mild and screening. Their intention was to incorporate this into the Medicare AWV. Their final recommendation was in the form of a four-step flowsheet:

  1. Kickstart the cognition conversation
  2. Assess if symptomatic
  3. Evaluate with full diagnostic workup if cognitive impairment detected.
  4. Refer to community resources and clinical trials, depending on the diagnosis.

Their recommendations were that PCPs routinely ask patients about any cognitive changes, and formally screen/assess any patients who express concern, whose family/friends express concern, or who exhibit signs/symptoms of cognitive impairment during the visit. If the screen is positive, the patient should be fully evaluated or referred to an outside provider for evaluation (GSA, 2015).

            In 2014 the CCCDTD4 published their findings regarding diagnostic criteria and treatment essentials for PCPs. They endorsed all the diagnostic criteria and definitions put forth by the joint efforts of the NIA and Alzheimer’s Association in 2011, although they rejected the use of “preclinical AD” as premature. They recommended against the use of biomarker testing in clinical practice at this time and cautioned against interpreting such test results if they are presented from another provider. They cautioned against neuroimaging all patients presenting with cognitive impairment but did recommend computed tomography (CT scan) or magnetic resonance imaging (MRI) for patients if the unexpected presence of cerebrovascular disease would change treatment. They explicitly recommend against routine use of positron emission tomography (PET) metabolic amyloid imaging, functional MRIs, and/or magnetic resonance spectroscopy except in research settings where appropriate (Moore, et al., 2014).


Treatment

            Realistic and achievable treatment goals for AD do not currently include curing the disease, but to slow deterioration, improve/preserve ADL and cognitive function, reduce caregiver burden, improve quality of life, create a safe environment, increase social engagement, enhance mood and behavior, and finally to manage any behavioral and psychological symptoms (BPSD) (Pandya, 2018). The decision of whether to treat a patient or refer is a complicated one for many PCPs. The CCCDTD4 recommends that PCPs refer dementia and AD patients to a specialist, such as a memory clinic with access to genetic testing and counseling, in certain circumstances. For example, in EOAD there are special circumstances that would warrant the resources of such a referral. Patients diagnosed with rapidly progressive dementia (RPD) which develops within 12 months after the first symptoms appear should also be referred to a practice with expertise in this subtype of patients once delirium has been adequately ruled out (Moore, et al., 2014).

Nonpharmacological treatments for AD and dementia include getting regular medical care as well as regular exercise, eating a healthy diet that is low in saturated fats and includes fruits, vegetables and whole grains, engaging in regular social activities/hobbies, and regular intellectual stimulation (NIA, 2016). A key in the effective management of AD is education regarding the diagnosis and prognosis with the patient and caregiver(s) (NIA, 2017). Other helpful items include resources for your patients regarding social support through local, regional, and national organizations such as the Alzheimer’s Association, Alzheimer’s Foundation of America and other local groups. Items that will help with daily functioning include calendars, to-do lists, technology/assistance for medication management (pill box, reminder, dispenser or organizer) and safety (emergency response system, door alarms, etc.). When appropriate, discuss and refer patients to open/enrolling clinical trials where available (NIA, 2016). Patients and their families should be encouraged to complete all necessary legal, financial, and long-term care planning, including a will, living will/advance directives, as well as a power of attorney, both healthcare and financial early in the disease process while reasoning and communication skills are still intact. Home safety and driver safety should be routine conversations that occur at each PCP visit with someone diagnosed with AD or other dementia to ensure safety measures are in place. Research and distribute local resources for driving evaluations, and if needed, a home safety evaluation may be paid for by the patient’s Medicare coverage through a local home health agency. Patients should be encouraged to stick to familiar places and try to establish a regular daily routine. When needed, refer to physical therapy for assistance ambulating safely to limit risk of falls and occupational therapy for assistance with independent living skills. For patients that are still working and having difficulty with job performance, suggest reducing hours or switching to a less demanding position and encourage your patient to consult their employer’s human resources department regarding employee assistance programs, family leave, and disability benefits (NIA, 2017).

Pharmacological treatments currently include five FDA-approved medications. Three of these are cholinesterase inhibitors (ChEIs) that function by reversibly binding to and thus inactivating acetylcholinesterase. This includes donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon). Donepezil is approved for all stages of AD, is available in a tablet as well as an orally disintegrating tablet (ODT) and is dosed once daily. Galantamine is available in both immediate release tablet (dosed twice daily, or BID) and extended release tablet (dosed daily) as well as a solution. Rivastigmine is available as a capsule that is dosed BID, or a transdermal patch (Pandya, 2018). Galantamine and rivastigmine are approved for mild to moderate AD. Common adverse effects of ChEIs include nausea, vomiting, poor appetite, and increased frequency of bowel movements (Alzheimer’s Association, n.d.). The fourth medication available, memantine (Namenda), functions as a N-methyl-D-aspartate (NMDA) receptor antagonist and regulates the activity of glutamate. This is believed to slow the influx of Ca+ into neurons and thus slow the process of nerve damage. It is available as an oral solution, a twice daily immediate release tablet or a once-daily extended release capsule. Common adverse effects include headache, constipation, confusion, and dizziness. There is also a combination product of memantine and donepezil called Namzaric which is dosed once daily. Both memantine and Namzaric are only approved for moderate to severe AD. All of these medications modestly improve cognitive function and may delay nursing home placement but should be stopped in the late stages of the disease (Alzheimer’s Association, n.d. and Pandya, 2018). The CCCDTD4 states that ChEIs have demonstrated efficacy for mild to severe AD and would therefore be an appropriate medication to trial in most patients with AD as well as patients with mixed pathology (i.e. those with a component of cerebrovascular disease). They concluded there is insufficient evidence for their use in strictly vascular dementia cases. They found any differences between the options of ChEIs are largely based on adverse effect profiles and pharmacokinetics, not efficacy. They list potential adverse effects of peripheral cholinergic stimulation related to ChEIs as:

  • Increased risk of GI bleeding (caution in patients with a history of ulcers or taking anti-inflammatory drugs)
  • Increased risk of bradycardia/heart block (in patients with or without cardiac impairment)
  • Exacerbation of asthma or other pulmonary disease
  • Cause urinary obstruction
  • Increased risk of seizures
  • Prolonged effects of succinylcholine, a muscle relaxant

They described the combination of memantine and a ChEI as “rational” and “apparently safe” but cautioned that the evidence to support this treatment plan is still preliminary and lacking. The Canadian group also agreed that medications could and should be stopped when desired by the patient or caregiver, when the patient is noncompliant, when the patient is experiencing intolerable side effects, when comorbidities make continued treatment too risky or futile, if ineffective (when the patient’s rate of decline is greater on the medication than prior to starting), or when the patient’s dementia progresses to a stage (Global Deterioration Scale 7) where there would be no meaningful benefit from continued treatment. ChEIs should be tapered and not stopped abruptly. They also recommend that if the medication was stopped due to perceived ineffectiveness, the patient should be monitored closely for 1-3 months after stopping for an observable decline and consider restarting medication in those cases (Moore, et al., 2014).

Behavioral and psychological symptoms of dementia (BPSD) affect up to 90% of patients with moderate to severe dementia. They include depression, hallucinations, agitation, aggression, wandering, and “sun-downing” (worsening cognition and behavioral symptoms later in the afternoon/evening). BPSD contribute to caregiver stress and burnout, and can lead to weight loss, falls, infection, incontinence, and institutionalization. Dementia patients with new-onset BPSD should undergo a medical evaluation to rule out pain, constipation, infection, vision/hearing loss, depression, sleep disorders, and/or adverse effects from medications. If a specific trigger in their environment (such as overstimulation, a medication, or a particular caregiver) can be identified, they should be removed if possible. Non-pharmacological treatments for BPSD include behavioral changes such as:

  • Establish and maintain consistent daily routine
  • Routine physical activity and optimized nutrition (but include comfort foods)
  • Incorporate enjoyable activities such as art/music, spirituality
  • Allow for regular reminiscing/story telling
  • Aromatherapy
  • Do not disagree/show respect when interacting
  • Maintain good eye contact but allow physical space when interacting
  • Avoid scolding or threatening but instead use a calm, slow voice when speaking
  • Validate and reassure

If these modifications do not alleviate the BPSD, then a medical professional should consider and evaluate the risks versus benefits of medications. There are currently no FDA-approved medications for the treatment of BPSD, but commonly used medications include antipsychotics, benzodiazepines, antidepressants, and anticonvulsants. For example, there has been shown to be benefit in the use of antipsychotics for aggression, but antipsychotics are also associated with significant adverse effects. Seventeen placebo-controlled trials of antipsychotics showed significant reduction in aggressive behavior at 12 weeks of use, but also showed a 1.6-1.7-fold increase in mortality, primarily due to infection and cardiovascular causes. This led to a black box warning from the FDA that all antipsychotics increase the risk of mortality in patients with behavioral disorders. They can also cause neuroleptic malignant syndrome, extrapyramidal symptoms, cerebral adverse events, increased risk of falls, sedation, QTc prolongation, metabolic syndrome/weight gain, and sudden death. Olanzapine can cause syncope (Pandya, 2018). Despite these risks, the CCCDTD4 listed risperidone, olanzapine, or aripiprazole as potential treatment considerations in AD patients with severe agitation/aggression and psychosis if there is risk of harm to self or others. For quetiapine, they found the evidence insufficient, and they specified that valproate should not be considered for this indication due to risk of toxicity, accelerated brain volume loss and greater cognitive impairment (Moore, et al., 2014). The 2015 Beers Criteria, published by the American Geriatric Society, submits strong evidence to avoid the use of antipsychotics in dementia patients with behavioral issues unless the patient is a threat to themselves or others and only after nonpharmacological treatments have been tried and failed due to the increased risk for stroke and mortality (Terrery and Nicoteri, 2016). Benzodiazepines carry their own significant list of risks, as they can cause depression, confusion, sedation, increased risk of falls/fractures, stroke/cerebral adverse events, sleep disturbance, and delirium (Pandya, 2018). The 2015 Beers Criteria stated there is strong evidence to avoid the use of benzodiazepines in the treatment of agitation secondary to this increased risk of falls (Terrery and Nicoteri, 2016). The CCCDTD4 stated that a trial of antidepressant medication could be considered in the case of a major depressive disorder, severe dysthymia, or severe emotional lability, but stated that there was insufficient evidence for the use of selective serotonin reuptake inhibitors or trazodone for the treatment of agitation in patients with AD (Moore, et al., 2014).

Staging of dementia can occur with multiple tools, but two that are commonly cited and utilized include the Functional Assessment Staging tool (FAST) and the Global Deterioration Scale (GDS). While the FAST looks at the patient’s functional abilities and ADLs, the GDS focuses more on cognition. Both can be helpful in monitoring patients progress through the disease, as well as a tool for decision making and educating patients and caregivers.

Functional Assessment Staging Tool (FAST)
Stage 1Has no objective or subjective difficulties
Stage 2Has subjective complaints of forgetting/awareness of some functional decline
Stage 3Has decreased job functioning that is evident to coworkers and difficulty traveling to new locations
Stage 4Has decreased ability to perform complex tasks (e.g., planning dinner for guests, handling finances, traveling)
Stage 5Requires assistance in choosing proper clothes for the day, season, or occasion
Stage 6ACannot dress without assistance, occasionally or frequently
Stage 6BCannot bathe without assistance, occasionally or frequently
Stage 6CCannot perform mechanics of toileting without assistance, occasionally or frequently
Stage 6DIs incontinent of urine, occasionally or frequently
Stage 6EIs incontinent of bowel, occasionally or frequently
Stage 7AHas speech limited to fewer than six intelligible words during an average day
Stage 7BHas speech limited to one intelligible word during an average day
Stage 7CIs unable to ambulate independently
Stage 7DCannot sit up independently
Stage 7ECannot smile
Stage 7FCannot hold up head independently



Global Deterioration Scale (GDS)
Stage 1No decline
Stage 2Very mild cognitive decline- the normal forgetfulness associated with aging
Stage 3Mild cognitive decline- increased forgetfulness, slight difficulty concentrating, decreased work performance, get lost more frequently, difficulty finding correct words
Stage 4Moderate cognitive decline- difficulty concentrating, decreased short term memory, difficulty managing finances, difficulty traveling alone to new places, trouble completing complex tasks efficiently or accurately, socialization becomes difficult
Stage 5Moderately severe cognitive decline- major memory deficiencies, requires some assistance choosing clothing, bathing, or preparing meals, unable to recall address/phone number or names of grandchildren
Stage 6Severe cognitive decline- requires extensive assistance to complete ADLs, forgetting names of close family members, little memory of recent events, difficulty counting backwards from 10, difficulty finishing tasks, incontinent of bladder and/or bowel, ability to speak declines, personality/emotional changes (BPSD)
Stage 7Very severe cognitive decline/late stage dementia- minimal speech/communication, require assistance for feeding/toileting, difficulty walking


Advanced AD or dementia can be especially challenging to manage. Referrals to care facilities are usually required when the burden of care extend beyond the capabilities of the family. Care decisions should be guided by carefully considered overall goal of care, whether that be a desire for all interventions that may prolong life, comfort care only, or something in between. This is best done by the patient though advance directives whenever possible, which relieves the pressure and stress off of the proxy decision maker. In the absence of an advance directive, the proxy will have to do their best to make substitute judgements or a decision based on the best interests of the patient. Common complications encountered in advanced dementia include eating problems and infections. Eating problems such as oral dysphagia, pharyngeal dysphagia, inability to feed oneself, or refusal to eat are the most common complications in advanced AD. As always, the patient should be evaluated and treated for any acute or reversible conditions (i.e. a tooth abscess). Conservative measures such as smaller meals, altered food textures, and high-calorie supplements may help with intake, but a review of the literature shows that of these options, only supplementation is supported by the research to promote weight gain, and none of the above interventions improved function or survival. More aggressive options include hand feeding and tube feeding. Hand feeding is time consuming and labor intensive but allows patients to enjoy tasting food and encourages social interaction with caregivers. A 2009 Cochrane review found insufficient evidence to support tube feeding in patients with advanced dementia, as it did not significantly improve survival, quality of life, nutrition, functional status, prevention of aspiration, or the prevention or healing of pressure ulcers. There are risks associated with tube feeding, such as insertion complications, tube blockages, tube dislodgments, and the use of restraints if patients attempt to remove or otherwise interfere with the tube itself. Infections are another extremely common complication in patients with advanced dementia, especially of the urinary tract and respiratory tract. In one study, between 52-66% of advanced dementia patients in a nursing home were prescribed antibiotics in the last 12 months. Inability to communicate the presence of any subjective symptoms such as dysuria or chest pain compounds the difficulty in diagnosing and treating infections in this group of patients.  As previously stated, clearly established goals of care will help guide treatment decisions in this instance as well. In the Study of Pathogen Resistance and Exposure to Antimicrobials in Dementia (SPREAD), 75% of suspected infections were treated with antimicrobials, but less than 50% of all treated infections (and less than 20% of all urinary tract infections, or UTIs) met appropriate criteria for initiation of antimicrobials. Urinalysis and urine cultures are frequently positive in patients with advanced dementia, and asymptomatic bacteriuria should not be treated. For this reason, a negative test can help rule out an infection, but a positive test does not necessitate treatment. For example, in a patient with no indwelling catheter, the minimal criteria for initiating antibiotics for a suspected UTI is acute dysuria if patient is verbal. If the patient is nonverbal, the requirements include an elevated temperature over 100℉ (or >2℉ above baseline) and at least one of the following: frequency (new or worse), urgency, costovertebral tenderness, hematuria, suprapubic pain, or mental status change.  In a patient with a catheter, the minimal criteria would simply be a fever over 100℉ or >2℉ above baseline, rigors, or a mental status change. In a suspected lower respiratory infection, the minimal criteria are a temperature over 102℉ in combination with an elevated respiratory rate above 25bpm or a new productive cough, or if the temperature is less than 102℉, they must also have a new productive cough as well as one of the following: pulse above 100 bpm, respiratory rate above 25 bpm, rigors, or a change in mental status. If antimicrobials are determined to be the best course of action, the least invasive route of administration should be used, and hospitalization should be avoided if possible (Mitchell, 2015).

Regarding end of life care, referrals to palliative and/or hospice care should be made when deemed appropriate in patients with advanced AD. A major limitation for enrollment in hospice care is the requirement of having a life expectancy of less than 6 months. Currently, the requirements for Medicare coverage of hospice for advanced dementia is a rating of 7c or below on the FAST scale with all the features of stages 6a-7c (see above for details of the FAST scale stages 6a-7c). The patient must have also had a medical complication in the previous year such as aspiration pneumonia, pyelonephritis or other upper urinary tract infection, septicemia, multiple pressure ulcers (stage 3-4), recurrent fevers after treatment with antibiotics, or eating problems (defined as food/fluid intake that is insufficient to sustain life or in tube-fed patients a weight loss of > 10% during the previous 6 months or serum albumin < 2.5g/dL). Observational studies of advanced dementia patients enrolled in hospice care have shown less hospitalizations, higher frequency of treatment for pain and dyspnea, and families that have greater satisfaction with patient care. If referral to a palliative care or hospice care specialist is available, these options should be offered and discussed with the patient’s health care proxy (Mitchell, 2015).


Research

            Given the pathophysiological findings of the plaques and tangles seen in AD, researchers are attempting to develop a noninvasive method for identifying the disease earlier. The most active area of research currently is that of molecular imaging of beta-amyloid deposits. Using one of four currently approved compounds, molecular imaging of beta-amyloid may help monitor disease progression or treatment effectiveness. It is indicated for select patients with persistent or progressive unexplained MCI, possible AD, and those patients with early onset dementia (before age 65). It is not indicated to determine dementia severity, to diagnose AD in patients with only a positive family history or presence of APOE mutation (APOE Ɛ4), for patients meeting the core diagnostic criteria for probable AD of average age (over 65), for patients with a cognitive complaint that is unconfirmed on clinical examination, or in lieu of genotyping for suspected autosomal mutation carriers. PET scanning with fluorodeoxyglucose (FDG-PET) is being developed and improved to potentially identify areas of decreased glucose intake in certain brain regions that may identify abnormal or pathological activity, but so far patterns of reduced activity have not been shown to provide diagnostic information in any one given individual patient. Cerebrospinal fluid (CSF) testing for biomarkers may eventually be used to complement the diagnosis of AD, but at this time is primarily being used in research trials. Biomarker ratios have a higher accuracy than single biomarkers, and are most useful in discriminating AD samples from normal controls, but there is significant measurement variability. Changes in 42-residue isoform of beta amyloid (Ab42), Tau, and phosphorylated Tau (pTau) may allow diagnosis of AD in its prodromal stage, with pTau being significantly more accurate than Ab42 or Tau in discriminating AD from non-AD dementia. If all three levels are normal, AD can be ruled out confidently. The Alzheimer’s Association is funding a quality control program for these biomarkers.

In addition to diagnostics, trials are ongoing regarding new and emerging treatments. Pioglitazone (Actos) is a thiazolidinedione that increases insulin sensitivity and is being studied in 3,500 asymptomatic people with known genetic mutations for AD to reduce insulin resistance. Crenezumab is an antibody against beta-amyloid that is currently being tested in patients with positive genetic mutations by the Alzheimer’s Prevention Initiative’s (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial. A monoclonal antibody that targets beta-amyloid called solanezumab is being tested in asymptomatic patients with high levels of amyloid on PET scans in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4). (Pandya, 2018). Solanezumab is also being tested in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) in combination with another drug, gantenerumab, in patients with mutations on chromosomes 1, 14, or 21. There are two currently ongoing Phase 3 trials for aducanumab, a recombinant monoclonal antibody that targets aggregated forms of beta-amyloid. Those trials are scheduled to be completed in late 2019 and 2020. The two enzymes, beta-secretase and gamma-secretase, that are responsible for clipping pieces of amyloid precursor protein (APP) to form beta-amyloid are current subjects of research for potential drug treatments of the future. In fact, researchers are investigating potential ways to interfere with the process at almost every point in the amyloid processing pathway. JNJ-54861911 works by inhibiting the activity of beta-secretase and is in Phase 3 trials scheduled to end in 2024 to determine if it slows cognitive decline in healthy people with elevated levels of beta-amyloid in the brain. The Generation Study, under the umbrella of the API, is testing the effects of two investigational drugs. They are attempting to determine if an active immunotherapy called CAD106 and a beta-secretase inhibitor CNP520 can prevent/delay the onset of AD symptoms in healthy older adults with two copies of the high-risk APOE allele Ɛ4. Tau protein, the chief component of tangles, is being targeted as a treatment option as well. AADvac1 is a vaccine in Phase 2 clinical trials expected to wrap up in 2019 to stimulate the immune system to attack the abnormal form of tau protein seen in Alzheimer’s disease. The inflammation seen in the brains of patients with AD is being studied as well. Sargramostim is a drug already approved for use in leukemia patients that functions by stimulating the bone marrow to elicit an immune response that may protect neurons from toxic proteins. The Phase 2 study for sargramostim is scheduled to complete in late 2018. Pimavanserin is an inverse agonist for the 5-HT2A receptors in the brain, having the opposite effect of serotonin, and potentially decreasing communication between neurons and reducing the symptoms of dementia-related psychosis. Current study is expected to be completed in September of 2020. The Alzheimer’s Association has a service to match patients with over 250 existing available clinical trials called TrialMatch (Alzheimer’s Association, n.d.). In 2017, the WHO launched a global action plan to help improve the lives of people with dementia worldwide, reduce caregiver burden, and decrease the impact of dementia on communities and countries. It aims to accomplish this by increasing prioritization and awareness of dementia, reducing the risk of dementia, improving diagnosis/treatment/care of dementia patients, supporting dementia caregivers, strengthening information systems for dementia, as well as research and innovation. Then in December of 2017, the WHO Global Dementia Observatory was launched to help collect and organize worldwide data to help researchers across the globe share information and function as a team to work towards a potential solution to AD (WHO, 2018).


Resources

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