About this course:
This course reviews Alzheimer's disease, including relevant statistics, pathophysiology, screening, diagnostic criteria, and pharmacologic and non-pharmacologic treatment strategies.
Alzheimer's Disease for APRNs
This course reviews Alzheimer's disease, including relevant statistics, pathophysiology, screening, diagnostic criteria, and pharmacologic and non-pharmacologic treatment strategies.
Upon completion of this module, learners should be able to:
- cite the national and international statistics regarding Alzheimer's disease
- review the basic pathophysiology of Alzheimer's disease
- evaluate appropriate screening tool(s) to be used in clinical practice to diagnose Alzheimer's disease
- describe psychosocial/nonpharmacological 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
Dementia affects memory, cognitive abilities, and behavior, interfering with daily functioning and activities of daily living (ADLs). Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60% to 80% of all cases. AD is a neurodegenerative disorder characterized by an insidious onset and progressive cognitive and behavioral function impairment, including comprehension, language, memory, reasoning, attention, and judgment (Huang, 2023a; Kumar et al., 2022). According to the World Health Organization (WHO, 2023), approximately 55 million people have dementia worldwide, with 60% living in low- and middle-income countries. With 10 million new cases annually, dementia significantly impacts global healthcare. It was estimated that dementia accounted for $1.3 trillion globally and was the seventh leading cause of death. The global prevalence of AD is approximately 24 million and is expected to quadruple by 2050. The number of people with AD in the US is estimated at 6 million and is expected to grow to 14 million by 2060. It is currently the sixth leading cause of death in the US and the fifth among those aged 65 and older. The total healthcare cost of AD in the US was $345 billion in 2023 (Alzheimer's Association, 2023; CDC, 2020).
The risk of developing AD is best predicted by age, with the incidence doubling every 5 years after age 65. The percentage of people with AD is 3% between the ages of 65 and 74, increasing to 17% between 75 and 84 and 32% after age 85. AD is twice as common in women as men, partly due to the longer life expectancy. The risk of AD is also higher in Hispanic and African American individuals. Additional risk factors include physical inactivity, obesity, unhealthy diet, tobacco use, alcohol abuse, diabetes, midlife hypertension, depression, low educational attainment, social isolation, head trauma, physical frailty, dyslipidemia, older parental age, and cognitive inactivity. Approximately 5% to 15% of AD cases are familial, with 50% developing as presenile, early onset (i.e., before age 65). The relationship between low hormone levels and metal exposure has been hypothesized as a potential risk factor but has not been established. Factors including higher education, use of anti-inflammatory agents, use of estrogen by women, healthy diet, regular exercise, and leisure activities like reading or playing a musical instrument have been associated with decreased risk of AD (CDC, 2019; Huang, 2023a; Kumar et al., 2022; WHO, 2023).
The National Institutes of Health (NIH), and specifically the National Institute of Neurological Disorders and Stroke (NINDS, 2023) and the National Institute on Aging (NIA), define AD as an "age-related, non-reversible brain disorder" that starts with memory loss/confusion and eventually leads to behavioral and personality changes and cognitive decline. This process occurs gradually over time. Three pathophysiological findings are associated with AD, including amyloid plaques, neurofibrillary tangles, and a loss of connections between neurons involved in memory/learning (NINDS, 2023). 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. As the amount of beta-amyloid increases, there is a rapid spread of abnormal 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 (Huang, 2023a; Kumar et al., 2022; NINDS, 2023).
Another pathophysiological finding common in patients with AD is chronic inflammation. This is believed to be caused by a build-up of glial cells, particularly microglia and astrocytes. 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. Research suggests that a reduced permeability of the blood-brain barrier in patients with AD contributes to the development of the condition by preventing sufficient glucose delivery to neurons and impairing 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 (Huang, 2023a; Kumar et al., 2022; NIA, 2017).
Early-onset familial AD (EOAD or FAD) develops in the 30s to 50s, accounting for less than 10% of all AD. Some 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 (PSEN1; chromosome 14), presenilin 2 (PSEN2; chromosome 1), or APP (chromosome 21). In late-onset AD (the most common form, developing in the mid to late 60s), 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 the 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 used in research studies to evaluate disease risk in large groups of people but is not yet used or helpful in determining an individual's risk. Genetic tests are not routinely done in the clinical setting to diagnose or predict AD; however, in some cases, if an individual has symptoms at an early age with a strong family history, a neurologist may order a genetic test (i.e., APP, PSEN1, and PSEN2). With the availability of at-home genetic tests, some people may learn their APOE status using these kits. Research into a genetic link to AD has come a long way, with only 10 genes linked to AD 10 years ago; currently, scientists have identified 70 genetic regions associated with AD (NIA, 2023a).
More recent research has focused on the duration of the presymptomatic period associated with AD, specifically the period between the ons
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The treatment of AD is sub-optimal currently, serving only to slow down the progression of the disease in the best of scenarios. Therefore, much emphasis has been placed on preventing AD instead of waiting for treatment options to improve. Prevention of AD has been studied, and thus far, managing cardiovascular risk and stroke prevention appear to be the most effective. This management includes mitigating any modifiable risk factors as well as aggressive management of cardiovascular disease, diabetes, hypertension, stroke/ischemia, obesity, epilepsy, depression, and hypercholesterolemia. Diabetes has been estimated to increase an individual's risk of AD by 50% to 100% and vascular dementia by 100% to 150%. The mechanism behind this likely involves both micro- and macrovascular disease, direct damage to the central nervous system secondary to hyperglycemia, and increased inflammation secondary to insulin resistance (Alzheimer's Association, 2019; Edwards et al., 2019; Huang, 2023a).
Conversely, weight loss, physical activity, a diet lower in saturated fats (such as the Mediterranean diet), and a diet rich in omega-3 fatty acids have been shown to protect against AD. While a Mediterranean diet may be beneficial against cognitive impairment, studies have found no significant association between diet and risk for dementia. Sleep disturbances increase the risk of AD, as sleep helps clear the brain of waste products, including amyloid and Tau, and sleep disturbances are among the earliest symptoms seen in patients with AD. Research regarding the impact of smoking and nicotine on AD risk is still unclear. Cognitive decline in smokers is directly related to the number of packs per day and has a negative effect on cardiovascular disease, a known risk factor for AD. However, nicotine appears to reduce APP secretion and inhibit amyloid aggregation, and epidemiological studies indicate that smoking may not be associated with dementia. Heavy alcohol consumption (more than four drinks for men or three drinks for women daily) is associated with an increased risk of AD, especially when combined with smoking. However, mild to moderate alcohol intake, especially of red wine, may lower the risk or ameliorate progression. Social interaction with others and mental stimulation increases gamma oscillations in the brain and may prevent AD (Alzheimer's Association, 2019; Edwards et al., 2019; Huang, 2023a). Prospective studies dating back to 2003 indicate that regular physical, mental, or socially stimulating leisure activities reduces the risk of dementia in older adults, as well as the presence of a rich social network as evidenced by social connections or support (Marseglia et al., 2019).
Initial Screening, Diagnosis, and Staging
AD should be suspected in any older adult presenting with subtle and progressive memory decline and dysfunction in at least one other cognitive domain leading to impaired functioning. HCPs should conduct a detailed cognitive and neurological examination. In 2013, the Alzheimer's Association published recommendations for HCPs to better detect cognitive decline as a standard component of the Medicare annual wellness visit (AWV), an added benefit of the 2010 Affordable Care Act. The AWV includes the detection of any cognitive impairment as one of its seven components. However, the Centers for Medicare and Medicaid Services 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 (Cordell et al., 2013):
- During the past 12 months, have you experienced confusion or memory loss that is happening more often or getting worse?
- During the past seven days, did you need help to perform everyday activities such as eating, getting dressed, grooming, bathing, walking, or using the toilet?
- During the past seven 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 deficits in ADLs or instrumental ADLs (IADLs) such as cooking and shopping. 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, the Mini-Mental State Exam (MMSE), or the Montreal Cognitive Assessment (MoCA) is recommended. The MoCA is often the preferred assessment tool because it has better sensitivity for executive and language dysfunction than other tools, such as the MMSE. The typical cutoff for normal performance on the MoCA is 26, with scores of 25 and below considered abnormal. The MoCA is available online and in several languages. 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), Aging and Dementia (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 (Cordell et al., 2013; Wolk & Dickerson, 2021).
In 2014, Barnes and colleagues developed and published a dementia screening indicator for HCPs. This screening indicator 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 designed to help an HCP decide quickly if a patient is appropriate for formal screening with one of the assessment tools mentioned above. First and foremost, if the patient or family expresses cognitive concerns, formal screening is needed. Formal screening is also recommended for individuals over the age of 80 (Barnes et al., 2014). However, if there are no explicit cognitive concerns, and the patient is aged 65 to 79, the points are assigned based on the following:
- 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 positive history)
- stroke (+6 points if positive history)
- assistance required to manage medications/finances (+10 points if yes)
- depression (+6 points if yes, based on the current use of antidepressant medication, or reports that "everything was/is an effort" at least three days per week over the past week; Barnes et al., 2014)
If the total score is greater than or equal to 22, they recommend formal screening using a validated screening tool (Barnes et al., 2014).
In 2015, the Gerontological Society of America (GSA) published its recommendations for cognitive impairment detection, intentionally omitting the words mild and screening. They intended to incorporate this into the Medicare AWV. Their final recommendation was in the form of a four-step flowsheet (GSA, 2015):
- STEP 1: Kickstart the cognition conversation
- STEP 2: Assess if symptomatic
- STEP 3: Evaluate with a full diagnostic workup if cognitive impairment is detected.
- STEP 4: Refer to community resources and clinical trials, depending on the diagnosis.
The GSA recommends that HCPs routinely ask patients about any cognitive changes and formally screen/assess 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 HCP for evaluation (GSA, 2015).
Positives features of the MIS, Mini-Cog, MoCA, and MMSE include brevity (less than five minutes to administer), validation in a primary care setting, easy administration by a non-physician, good to excellent psychometric properties, and a relative lack of education, language, or cultural bias. The GPCOG has been shown to have a low educational bias, but there is not sufficient data regarding any potential language or cultural bias. A limitation cited for the GPCOG is the indeterminate range in the middle if it is used without an informant score and a low specificity if the informant score is being used alone. The MIS is a verbal-only test that requires no writing/drawing; it does not test executive function or visuospatial skills. Limitations of the Mini-Cog include variability in failure rates based on using different word lists and that some of the study results are 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; the other three options are currently free of charge. The MMSE 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 verified of the available options. 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, Short IQCODE ≥ 3.38, or MoCA ≤ 25), then referral for a full assessment should be made, or a full assessment conducted (may be done the same day with correct billing codes if an informant is present; Cordell et al., 2013). The full evaluation should also consist of an assessment of functional status. A caregiver or family member/spouse can provide structured, objective information using the Functional Activities Questionnaire or similar with a cutoff score of 6 points or greater; this results in 85% accuracy for differentiating MCI from dementia (Cordell et al., 2013; Wolk & Dickerson, 2021). A list of related dementias and defining characteristics can be found in Table 1 below to help the HCP differentiate AD from other similar forms of dementia.
Clinical Differentiation of Common Dementias
Mental State Examination
Episodic memory loss
Memory loss initially, followed by all cognitive domains
Normal in the early stage
Normal in the early stage
Atrophy in the entorhinal, cortex, and hippocampus
Sudden onset with steady deterioration, falls, apathy, and focal weakness
Executive and frontal function and generalized slowing, memory may be intact
Apathy, anxiety, and delusions.
Focal neurological deficits, weakness, and spasticity
White matter disease with cortical/subcortical infarctions
Lewy body dementia
Visual hallucinations, REM sleep disorder, delirium, and Parkinsonism
Drawing, frontal, and executive; memory intact
Delirium/ delusions, hallucinations, and depression
Larger hippocampus than AD with posterior parietal atrophy
Apathy, behavioral/ personality changes, compromised judgment, speech/ language difficulties
Effects frontal, executive, and language; memory and drawing spared
Apathy, hyperorality, and disinhibition
Vertical gaze palsy, axial rigidity, and dystonia may be normal if they overlap with progressive supranuclear palsy/ corticobasal degeneration
The posterior parietal is spared, but frontal or temporal atrophy expected
(Huang, 2023a; Panegyres et al., 2016)
The tests discussed above can also be used to monitor disease progression. For example, the CCCDTD4 suggests that a 3-point decline in a patient's MMSE score within 6 months carries a poor prognosis and should prompt the HCP 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 65 (Moyer, 2014).
Despite 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). A conclusive AD diagnosis occurs only after a positive autopsy (i.e., histological evaluation of brain tissue; McKhann et al., 2011; NIA, n.d.). 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, only underlying brain changes that are 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 baseline cognition and impairment of one or more cognitive functions but the preserved ability to function independently in daily life and the absence of dementia (McKhann et al., 2011; NIA, n.d.). Some define early dementia as more substantial interference in daily function secondary to poor performance in more than one cognitive domain (Panegyres et al., 2016).
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 at least two of the following domains: the ability to acquire/retain new information, reasoning/judgment/handling of complex tasks, visuospatial abilities, language functions, or changes in personality/behavior (McKhann et al., 2011; NIA, n.d., Wolk & Dickerson, 2021).
Behavioral and psychological symptoms (BPSD) affect up to 90% of patients with moderate to severe dementia. BPSD includes depression, hallucinations, agitation, aggression, wandering, and "sun-downing" (i.e., worsening cognition and behavioral symptoms later in the afternoon/evening). BPSD contributes to caregiver stress and burnout, leading to weight loss, falls, infection, incontinence, and institutionalization. Patients with dementia with new-onset BPSD should undergo a medical evaluation to rule out pain, constipation, infection, vision/hearing loss, depression, sleep disorders, and adverse medication effects. 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 (Huang, 2023b; Press, 2022).
The 2011 NIA/Alzheimer's Association guidelines 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; McKhann et al., 2011; NIA, n.d., Wolk & Dickerson, 2021). The criteria for probable AD include the presence of dementia and the following characteristics:
- a decline in baseline functioning
- not explained by delirium or a major psychiatric disorder
- interference with the ability to function at work or daily activities
- cognitive impairment established by history taking from the patient and knowledgeable informant and objective mental status examination or neuropsychologic testing
- cognitive impairment, including a minimum of two of the following
- impaired reasoning or poor judgment
- impaired visuospatial abilities
- changes in personality, behavior, or comportment
- impaired ability to acquire and remember new information
- impaired language functions
- other core clinical criteria:
- insidious onset
- progressive worsening
- initial and most prominent cognitive deficits are one of the following:
- amnestic presentation (i.e., impairment in learning and recall of new information)
- non-amnestic presentation (i.e., language [word-finding deficits], visuospatial, or dysexecutive [impairment in reasoning or judgment])
- no evidence of substantial concomitant cerebrovascular disease, Lewy body dementia, frontotemporal dementia, active neurologic or non-neurologic disease, or medication use that could impact cognition (McKhann et al., 2011; NIA, n.d., Wolk & Dickerson, 2021)
The criteria for possible AD include the following:
- atypical presentation: core criteria for probable AD are met in terms of the nature of the cognitive effects; however, there is a rapid onset of impairment or insufficient historical data to support a progressive decline
- etiologically mixed presentation: core criteria for probable AD are met; however, there is evidence of concurrent cerebrovascular disease, features of Lewy bodies but not the diagnosis, or another neurologic or medical comorbidity or medication that could significantly impact cognition (McKhann et al., 2011; NIA, n.d., Wolk & Dickerson, 2021)
The Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) recognizes that memory might not be the first cognitive domain to be impaired in dementia, introducing the concept of major neurocognitive disorder. Less severe cognitive impairment may be diagnosed as a mild neurocognitive disorder; this closely resembles MCI but with less impairment in daily functioning (American Psychiatric Association, 2022).
There are various differential diagnoses that healthcare providers (HCPs) should consider and rule out when confronted with a patient with MCI before diagnosing AD. They include:
- medication-related cognitive changes
- depression: consider the Geriatric Depression Scale with a cutoff score of 6
- delirium related to infection or other causes
- thyroid dysfunction
- B12 deficiency: look for peripheral neuropathy symptoms
- vascular dementia/stroke: look for gait disturbance, sensory changes, weakness
- Parkinson's disease: look for speech impediment/gait disturbance
- Lewy body dementia: look for hallucinations
- frontotemporal dementia: look for gait disturbance, personality changes
- normal pressure hydrocephalus (NPH): look for gait disturbance
- substance or alcohol use disorder
- Wernicke-Korsakoff's syndrome (thiamine deficiency typically related to alcoholism)
- Creutzfeldt-Jakob’s disease (CJD)
- tumor: morning headaches or lateralizing signs on cranial nerve exam
- syphilis or HIV-related dementia
- sleep deprivation: look for a history of sleep apnea or restless leg syndrome (Kumar et al., 2022; Panegyres et al., 2016)
These diagnoses can often be ruled out with a complete history and physical exam, which should include a thorough neurological exam. Clinical criteria are 85% accurate in establishing a diagnosis of AD by eliminating other potential causes of cognitive impairment. This evaluation will help identify delirium (onset over days/weeks, not months/years) and any medication that could be contributing to the cognitive decline. Medications at increased risk for causing cognitive impairment include opioids, anticholinergics, tricyclic antidepressants, benzodiazepines and other hypnotics, muscle relaxants, antihistamines, and antiepileptics. Serum levels of potentially toxic medications such as digoxin (Lanoxin) and antiepileptics should be checked if appropriate. Routine laboratory testing cannot confirm an AD diagnosis but can exclude some contributing secondary causes. Standard laboratory tests recommended by the Alzheimer's Association include thyroid-stimulating hormone (TSH), complete blood count (CBC), vitamin B12 and folate levels, complete metabolic panel, fasting glucose, and tests for HIV and/or syphilis. Imaging studies may be helpful in younger patients or those with a history of head trauma or focal symptoms to rule out stroke, tumor, hematoma, or hydrocephalus (Cordell et al., 2013; Huang, 2023a; Jack et al., 2011; Panegyres et al., 2016).
In 2014, the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) published its findings regarding the diagnostic criteria and treatment essentials for HCPs. They endorsed all the diagnostic criteria and definitions put forth by the joint efforts of the NIA and Alzheimer's Association in 2011. The CCDTD4 recommended against obtaining biomarker testing in clinical practice and cautioned against interpreting such test results if presented by another provider. They cautioned against neuroimaging all patients presenting with cognitive impairment. However, they did recommend computed tomography (CT) scan or MRI for patients if the unexpected presence of cerebrovascular disease would change the treatment plan. The CCCDTD4 explicitly recommends 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).
The staging of dementia can be done with multiple tools, but three that are commonly cited and utilized include the functional assessment staging tool (FAST, see Table 2 below), the global deterioration scale (GDS, see Table 3 below), and the clinical dementia rating scale (CDR). While the FAST evaluates the patient's functional abilities and ADLs, the GDS focuses more on cognition. Both can monitor a patient's progress through the disease and assist in making decisions and educating patients and caregivers (Dementia Care Central, 2023; Petersen, 2020).
Functional Assessment Staging Tool (FAST)
Level of functional decline
Expected duration of stage
Normal older adult
Personal awareness of some functional decline
Noticeable deficits in demanding situations
7 year average
Requires assistance in complicated tasks (i.e., traveling, finances)
2 year average
Requires assistance in choosing proper clothing
1.5 year average
Moderately severe AD
Requires assistance with dressing, toileting, and bathing and experiences urinary and fecal incontinence
3.5- to 9.5-month average
Speech ability declines to approximately six intelligible words; progressive loss of ability to walk, sit up, smile, or hold head up
1- to 1.5-year average
(Dementia Care Central, 2023; Petersen, 2020)
Global Deterioration Scale (GDS)
Signs and symptoms
Expected duration of stage
1 (no cognitive decline; no Dementia)
2 (very mild cognitive decline; no Dementia)
3 (mild cognitive decline; No Dementia)
2- to 7-year average
4 (moderate cognitive decline; early-stage Dementia)
2 year average
5 (moderately-severe cognitive decline; mid-stage Dementia)
1.5 year average
6 (severe cognitive decline; mid-stage Dementia)
2.5 year average
7 (very severe cognitive decline; late-stage Dementia)
1.5- to 2.5-year average
(Dementia Care Central, 2023; Petersen, 2020)
The CDR tests memory and performs better when assessing for amnestic MCI highlighted by memory loss. It is also less effective at detecting very mild dementia. The CDR scale starts at 0, which represents normal cognitive function. A CDR of 0.5 indicates a suspicion of early dementia lasting 3 to 7 years. This is characterized by doubtful or mild impairment of independent function and mild, consistent forgetfulness. A CDR of -1 indicates mild dementia, with moderate memory loss and difficulty with problem-solving. They have difficulty with complex hobbies and daily activities and cannot function independently in community affairs. CDR of -2 indicates moderate dementia, characterized by profound memory loss, disorientation to time/place, poor judgment, and little to no independence at home. A score of -3 is severe dementia with incontinence, no orientation, judgment, or problem-solving skills, and requiring help with ADLs/personal care (Dementia Care Central, 2023; Panegyres et al., 2016; Petersen, 2020).
Advanced AD or dementia can be especially challenging to manage. Referrals to care facilities are usually required when the burden of care extends beyond the family's capabilities. Care decisions should be guided by carefully considered overall care goals, such as a desire for all interventions that may prolong life, comfort care only, or something in the middle. This is best done directly by the patient through advance directives whenever possible, relieving the pressure and stress of the proxy decision-maker. Without an advance directive, the proxy must do their best to make decisions based on the patient's best interest (Mitchell, 2015).
Realistic and achievable treatment goals for AD do not currently include curing the disease, but slowing deterioration, improving/preserving independence with ADLs and cognitive function, reducing caregiver burden, improving quality of life, creating a safe environment, increasing social engagement, enhancing mood and behavior, and finally managing any BPSD (Huang, 2023a; Press & Buss, 2021). The decision of whether to treat a patient or refer them is a complicated one for many HCPs. The CCCDTD4 recommends that HCPs refer dementia and AD patients to a specialist in certain circumstances, such as a memory clinic with access to genetic testing and counseling. For example, the special circumstances of EOAD warrant the resources of such a referral. Patients diagnosed with rapidly progressive dementia (RPD), which develops within 12 months of the first symptoms, should also be referred to a clinic with expertise in this subtype once other causes for the symptoms have been adequately ruled out (Moore et al., 2014).
Nonpharmacological treatments for AD and dementia include getting regular medical care to manage comorbidities, regular exercise, and obtaining regular cognitive stimulation. Supplements such as vitamin C, D, E, ginkgo biloba, and omega-3 fatty acid supplements appear to have minimal impact on preventing cognitive decline. A key to the effective management of AD is educating the patient and caregiver(s) regarding the diagnosis and prognosis, encouraging connection with others living with dementia, and focusing on activities that bring purpose to life. Other helpful patient resources include local, regional, and national social support 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). When appropriate and available, patients should be referred to open/enrolling clinical trials (Alzheimer's Association, 2019; NIA, 2023b).
Patients and their families should be encouraged to complete all necessary legal, financial, and long-term care planning early in the disease process while reasoning and communication skills are still intact; this includes a will, living will/advance directives, as well as a power of attorney, both healthcare and financial. Home safety and driver safety should be routine conversations at each healthcare visit with someone diagnosed with AD or other dementia to ensure safety measures are in place. HCPs should 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 avoid unfamiliar places and establish a regular daily routine. When needed, patients should be referred to physical therapy for assistance ambulating safely to limit the risk of falls and occupational therapy for assistance with independent living skills. For patients still working and having difficulty with job performance, reduced hours, a less demanding position, and a consult with their employer's human resources department regarding employee assistance programs, family leave, and long-term disability benefits are recommended (NIA, 2020).
Pharmacological treatments currently include various US Food and Drug Administration (FDA)-approved medications. Patients with AD have reduced cerebral content of choline acetyltransferase, which causes a decrease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinesterase inhibitors (ChEIs) function by reversibly binding to and thus inactivating acetylcholinesterase. ChEIs commonly used with AD include donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon). Donepezil (Aricept) is approved for all stages of AD, available in a tablet and an orally disintegrating tablet (ODT), and dosed once daily. Donepezil (Aricept) is usually preferred due to the once-daily dosing. The recommended dose is 5 mg orally daily for 4 to 6 weeks, then increased to 10 mg daily. Donepezil (Aricept) 23 mg daily may be more effective for moderate to severe AD. Treatment should be continued if functional improvement is apparent after several months; otherwise, it should be stopped. Galantamine (Razadyne) is available in both an immediate-release tablet (dosed twice daily, or BID) and an extended-release tablet (dosed daily), as well as a liquid solution. It can be used in end-stage renal disease or severe liver dysfunction. Rivastigmine (Exelon) is a slow, reversible inhibitor that is available as a capsule (dosed BID) or a transdermal patch. Galantamine (Razadyne) and rivastigmine (Exelon) are approved for mild to moderate AD. Common adverse effects of ChEIs include nausea, vomiting, poor appetite, and increased frequency of bowel movements. Sleep disturbances are common with donepezil (Aricept). These medications are contradicted in patients with severe cardiac conduction abnormalities (Huang, 2023a; Kumar et al., 2022; Press & Buss, 2021).
Another medication available, memantine (Namenda), functions as an N-methyl-D-aspartate (NMDA) receptor antagonist that regulates glutamate activity. 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. The dose is 5 mg orally daily, increased by 5 mg weekly, to 10 mg twice daily over 4 weeks. The dose should be reduced for patients with renal impairment, or this medication should be avoided. Memantine (Namenda) can be used with a ChEI. Common adverse effects include headache, constipation, confusion, and dizziness. A combination capsule contains immediate and extended-release components of memantine and donepezil (Namzaric), which is dosed once daily. Memantine (either Namenda or Namzaric) is only approved for moderate to severe AD. These medications modestly improve cognitive function and may delay nursing home placement but should be stopped in the late stages of the disease (Huang, 2023a; Kumar et al., 2022; Press & Buss, 2021).
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 and patients with mixed pathology (i.e., those with a component of cerebrovascular disease). They concluded that there is insufficient evidence for their use in strictly vascular dementia cases. They found that any differences between the options of ChEIs are primarily based on adverse effect profiles and pharmacokinetics, not efficacy (Moore et al., 2014). They list potential adverse effects of peripheral cholinergic stimulation related to ChEIs as follows:
- 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 diseases
- urinary obstruction
- increased risk of seizures
- prolonged effects of succinylcholine, a muscle relaxant (Moore et al., 2014)
The CCCDTD4 described a combination treatment using memantine (Namenda) and one of the ChEIs as "rational" and "apparently safe." However, they 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 non-adherent, when the patient is experiencing intolerable side effects, when comorbidities make continued treatment too risky or futile, when it is ineffective (i.e., 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 (GDS 7) where there would be no meaningful benefit from continued treatment. ChEIs should be tapered and not stopped abruptly. They also recommend that if medication is stopped due to perceived ineffectiveness, the patient should be monitored closely for 1 to 3 months after stopping for a noticeable decline and consider restarting medication in those cases (Moore et al., 2014).
Based on positive clinical results, the FDA has approved aducanumab (Aduhelm) using an accelerated approval pathway. A reduction in beta-amyloid plaques was observed in one of the two pivotal phase III trials. Aducanumab (Aduhelm) is a human IgG1 anti-amyloid monoclonal antibody specific for beta-amyloid oligomers implicated in AD. Some experts consider aducanumab (Aduhelm) the first efficacious disease-modifying treatment for AD; however, given the accelerated approval by the FDA, aducanumab (Aduhelm) should be used cautiously because the evidence of disease-slowing progress has been inconsistent. Aducanumab (Aduhelm) is a monthly infusion approved for patients with mild AD who have evidence of amyloid plaques in the brain. Adverse effects of aducanumab (Aduhelm) include amyloid-related imaging abnormalities (ARIA; i.e., MRI signal changes of cerebral edema and/or microhemorrhage and superficial hemosiderosis). Approximately 0.9% of patients with ARIA had severe symptoms, including disorientation, ataxia, gait disturbance, headache, nausea, falls, and visual disturbance. Similarly, lecanemab (Leqembi) is an intravenous (IV) anti-amyloid antibody for patients with mild AD and confirmation of elevated beta-amyloid plaques in the brain. Other medications being studied include high-dose vitamin E (i.e., 1000 IU orally once or twice a day), selegiline (Eldepryl), nonsteroidal anti-inflammatory (NSAIDs), Ginkgo biloba extracts, and statins, but evidence for their effectiveness remains unclear (Huang, 2023a; Kumar et al., 2022; Press & Buss, 2021).
Behavioral and Psychological Symptoms of Dementia
- Since many patients with AD experience BPSD, HCPs should be aware of the nonpharmacological treatments for BPSD, including behavioral changes such as:
- establish and maintain a consistent daily routine
- encourage routine physical activity and optimize nutrition (but include comfort foods)
- incorporate enjoyable activities such as art, music, and spirituality
- allow for regular reminiscing and story-telling
- caregivers should not disagree or argue with the patient
- caregivers should show respect when interacting
- maintain good eye contact but allow physical space when interacting
- avoid scolding or threatening; instead, use a calm, slow voice when speaking
- validate and reassure (Huang, 2023b; Press, 2022)
If these modifications do not alleviate the BPSD, then HCPs should consider and evaluate the risks versus benefits of medications. Currently, there are no FDA-approved medications for BPSD, but commonly used medications include antipsychotics, benzodiazepines, antidepressants, and anticonvulsants. For example, there is evidence of benefit from the use of antipsychotics for symptoms of aggression, but are also significant adverse effects. Seventeen placebo-controlled trials of antipsychotics showed a significant reduction in aggressive behavior at 12 weeks of use but also showed a 1.6- to 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 mortality risk 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 (Zyprexa) can cause syncope. Despite these risks, the CCCDTD4 listed risperidone (Risperdal), olanzapine (Zyprexa), or aripiprazole (Abilify) as potential treatment considerations in patients with AD with severe agitation/aggression and psychosis if there is a risk of harm to self or others. They found the evidence insufficient to recommend or discourage the use of quetiapine (Seroquel). They specified that valproate (Depakene, Depacon) should not be considered for this indication due to the risk of toxicity, accelerated brain volume loss, and greater cognitive impairment. Suvorexant (Belsomra) is approved for the treatment of insomnia in patients with mild to moderate AD. It works by blocking the activity of orexin, a chemical messenger involved in the sleep-wake cycle. Side effects can include impaired coordination, worsening depression or suicidal ideation, sleep paralysis, and compromised respiratory function (Alzheimer's Association, n.d.-b; Huang, 2023b; Moore et al., 2014; Press, 2022).
The 2019 Beers Criteria, published by the American Geriatric Society, suggests avoiding antipsychotics in patients with dementia 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. Benzodiazepines carry significant risks, including depression, confusion, sedation, increased risk of falls/fractures, stroke/cerebral adverse events, sleep disturbance, and delirium. The 2019 Beers Criteria states that strong evidence exists to avoid using benzodiazepines in treating agitation in older adults secondary to the increased risk of falls. The CCCDTD4 states that insufficient evidence supports the use of selective serotonin reuptake inhibitors (SSRIs) or trazodone (Oleptro) for treating agitation in patients with AD. However, they point out that a trial of antidepressant medication could be considered for a major depressive disorder, severe dysthymia, or severe emotional lability (American Geriatrics Society Beers Criteria Update Expert Panel, 2019; Moore et al., 2014).
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. However, the literature demonstrates that of these options, only supplementation has been shown to promote weight gain, and none of the above interventions affected 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. Various research studies have found insufficient evidence to support tube feeding in patients with advanced dementia since 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 feedings, 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 (Mitchell, 2015, 2023).
Infections are another prevalent complication in patients with advanced dementia, especially of the urinary tract and respiratory tract. In one study, 52% to 66% of patients with advanced dementia in a nursing home were prescribed antibiotics in the last 12 months. The 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. However, less than 50% of all treated infections (and less than 20% of all UTIs) met the 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 (Mitchell, 2015, 2023).
For this reason, negative test results can help rule out an infection, but positive results do 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 in a verbal patient. If the patient is nonverbal, the requirements include an elevated temperature over 100°F (or greater than 2°F above baseline) and at least one of the following: frequency (new or worse), urgency, costovertebral tenderness, hematuria, suprapubic pain, or mental status changes. The minimal criteria for a patient with a catheter would be a fever over 100°F or greater than 2°F above baseline, rigors, or a mental status change. The minimal criteria for a suspected lower respiratory infection are a temperature over 102°F in combination with an elevated respiratory rate above 25 bpm or a new productive cough. In a patient with a temperature less than 102°F, there must be a new productive cough and one of the following: heart rate 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, 2023).
Regarding end-of-life care, palliative and/or hospice care referrals should be made when deemed appropriate in patients with advanced AD. A major limitation of enrollment in hospice care is that it requires a life expectancy of 6 months or less. Currently, in order to qualify for hospice care for AD, Medicare requires a rating of 7 on the FAST (see Table 2 above for details of the FAST scale stages). The patient must have also had a medical complication in the previous year, such as aspiration pneumonia, pyelonephritis or other upper UTI, 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, a weight loss of greater 10% during the previous 6 months or serum albumin less than 2.5g/dL). Observational studies of patients with advanced dementia enrolled in hospice care have shown fewer hospitalizations, higher frequency of treatment for pain and dyspnea, and families that are more satisfied with patient care. If referral to a palliative or hospice care specialist is available, these options should be offered and discussed with the patient's healthcare proxy (Mitchell, 2015, 2023).
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. Currently, the most active area of research is 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 who report cognitive changes that are unconfirmed on clinical examination, or in lieu of genotyping for suspected autosomal mutation carriers (Pandya, 2018).
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. However, so far, reduced activity patterns have not been shown to provide diagnostic information in any individual patient. Cerebrospinal fluid (CSF) testing for biomarkers may eventually be used to complement the clinical diagnosis of AD, but it is primarily being used in research trials. Biomarker ratios are more accurate than single biomarkers and are most useful in discriminating AD samples from normal controls, but there is significant measurement variability. Changes in the 42-residue isoform of beta-amyloid (Ab42), Tau, and phosphorylated Tau (pTau) may eventually allow the 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 funds a quality control program for these biomarkers (Pandya, 2018).
In addition to diagnostics, trials are ongoing regarding new and emerging treatments. Pioglitazone (Actos) is a thiazolidinedione that increases insulin sensitivity and is known to have anti-inflammatory and antioxidant effects on the brain. In a recent review of the literature, Alhowail and colleagues (2022) found conclusive evidence of the effect of pioglitazone (Actos) on improving cognitive impairment. Despite these findings, further research is needed to explore the effects of pioglitazone (Actos) on memory function for patients with AD. Pioglitazone (Actos) is also associated with cardiovascular risks, such as weight gain and edema, which can increase mortality (Alhowail et al., 2022). Crenezumab is an immune-based therapy that produces antibodies against beta-amyloid that was recently evaluated for safety and efficacy in adults with early AD. In two phase-3 randomized placebo-controlled trials, the researchers found that crenezumab was well tolerated but did not reduce clinical decline for participants with early AD (Ostrowitzki et al., 2022). 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). 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. These trials did not show effectiveness in slowing AD progression. Phase 3 programs evaluating gantenerumab are expected to finish at the end of 2022 and will add critical information to understanding the effectiveness of gantenerumab in treating early symptomatic and asymptomatic AD (Bateman, 2022).
The Alzheimer's Association is the largest nonprofit funder of Alzheimer's research and is committed to accelerating global efforts to eliminate AD. They currently invest over $320 million in more than 1,000 research projects across 54 countries and 6 continents. Research efforts focus on advancing the understanding of AD and dementia, identifying new treatment strategies, improving care and support for people with AD, and improving knowledge of brain health and disease prevention (Alzheimer's Association, n.d.-c). The Alzheimer's Association is currently funding the NEW IDEAS Study, which seeks to ensure that the results of AD and dementia research represent all racial and ethnic groups. In this study, 4,000 of the projected 7,000 participants will be Black or African American and Hispanic or Latino. The researchers will examine brain amyloid PET scans in diverse populations with mild dementia (Alzheimer's Association, n.d.-a). 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. In December 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, 2021).
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