Primary care is usually the front door to the healthcare system, and primary care providers (PCPs) are accountable for the integration, continuity, and coordination of services for the whole person.1 For this reason, PCPs play a critical role in the assessment, diagnosis, and management of complex diseases such as Alzheimer disease and related dementias (ADRD). Unfortunately, many cases of dementia go unrecognized and undiagnosed for years after symptom onset.2,3 By the time an individual is diagnosed, the dementia has often already progressed to a moderate or severe stage of disease.4 In addition, when dementia is diagnosed, the cause is often not assigned.5 Further, about 40% of people with a dementia diagnosis or their care partners are not aware of the diagnosis.6 Missed and delayed diagnoses using sensitivity analyses for providers' clinical diagnoses relative to standardized assessments range from 0.26 to 0.69, a large variation, according to a systematic review.7 Reasons for this reflect a wide range of gaps in the healthcare system including lack of knowledge about dementia, the mistaken belief that memory loss and cognitive symptoms are a part of normal aging, denial or lack of recognition of symptoms of dementia by patients and families, and the absence of available and simple biomarker tests.8 Dementia due to Alzheimer disease (AD), which typically includes the classic symptom of memory loss, was detected with greater sensitivity than other dementias in the systematic review.7 Other factors affecting the sensitivity of providers' diagnoses in primary care included the patient's degree of impairment or dependence on a care partner, the clinician's frequency of contact with the person living with dementia, and the presence of depression co-occurring with dementia symptoms.7 Missed and delayed dementia diagnoses contribute to lost opportunities for treatment and increase patient and care partner burden.
Dementia describes the broad clinical syndrome that represents a cluster of cognitive, behavioral, and functional symptoms that interfere with daily functioning. Dementia can be caused by various neurodegenerative diseases such as AD, Parkinson disease, dementia with Lewy bodies (DLB), and/or frontotemporal dementia (FTD). Cerebrovascular disease may cause symptoms of dementia independently, as in the case of vascular dementia, or concurrently with another neurodegenerative disease. Other conditions associated with increased likelihood of dementia include major depressive disorder, sleep disorders, substance use disorder, and polypharmacy.9
Pathology: Disease vs. dementia
Our understanding of the development and progression of AD has evolved. What was formerly understood to be a cluster of cognitive symptoms, primarily memory loss, that could only be confirmed as AD by autopsy is now an illness with both clinical and pathologic signs, which do not necessarily coexist. The concept of the evolution of disease pathology years before symptom expression was introduced by Jack et al. and forms the basis for the most recently approved treatments and emerging diagnostic tests.10 AD includes three core features: positive findings of amyloid-beta protein, phosphorylated tau protein (p-tau), and neurodegeneration, especially in the hippocampal region. These are known as the AT(N) criteria.11
Further complicating the clinical evaluation and diagnostic process, a patient may have biological evidence of a disease with no clinical symptoms, depending on the disease's stage.12 For example, a patient may have alpha-synuclein protein deposits in cerebral tissue, as is associated with DLB, but may or may not have symptoms of DLB. Likewise, a patient may have amyloid-beta and p-tau, which are associated with AD, but may or may not have symptoms of Alzheimer dementia. In each of these cases, the patient would have a diagnosis of Lewy body disease or AD but not DLB or Alzheimer dementia, respectively. Currently, there are only biomarker tests to confirm amyloid-beta and p-tau in cerebrospinal fluid (CSF) or blood. Specific positron emission tomography (PET) scans for amyloid-beta and p-tau deposits exist but are limited to research at this time. There are no equivalent biomarker tests for DLB or FTD.
Definitions
Mild cognitive impairment (MCI)
Mild cognitive impairment (MCI) is defined as impairment in one or more cognitive domains, often including memory, that does not interfere with activities of daily living (ADLs). Between 30% and 50% of patients with MCI will convert to Alzheimer dementia over a 5- to 10-year period.12 MCI can be categorized as amnestic (primarily affecting memory) or nonamnestic as well as single-domain (affecting only one cognitive domain) or multidomain. Patients with amnestic MCI are more likely to progress to Alzheimer dementia. Other factors that indicate a likely progression to dementia include accumulation of amyloid-beta and p-tau in the brain and atrophy of the hippocampal region of the brain.12
AD
The most common cause of dementia syndrome is AD. It is characterized by memory loss, especially an inability to retain newly learned information, due to degeneration in the hippocampus. Apathy and depression may also be early symptoms of this dementia type. As the disease progresses, judgment and abstraction are impaired such that disorientation results, leading to wandering while driving or walking. Behavioral or neuropsychiatric symptoms may appear in the moderate stage of the syndrome followed by difficulty swallowing, talking, and walking in the late stage.8 In the US, AD affects nearly 7 million people, most of whom are over the age of 75 years. Age is the primary risk factor, and two-thirds of people living with AD are women. Prevalence is higher among Black and Hispanic individuals than among White individuals; furthermore, diagnosis among Black and Hispanic individuals is delayed even when signs and symptoms are reported to healthcare providers.8,13
Diagnosing AD. The disease begins with accumulation of amyloid-beta in the brain, which is believed to trigger poor clearance of p-tau, with both amyloid-beta and p-tau becoming less soluble and denser, thereby causing the neurodegeneration seen on structural imaging such as MRI scans. Amyloid-beta can be measured early in the disease process with an FDA-approved serum test, such as PrecivityAD(R).14 CSF collected via a lumbar puncture or PET imaging with an amyloid-tracer (Amyvid(R) [florbetapir F 18]) can allow for more specific analysis of presence and density of amyloid-beta and/or p-tau. Significant challenges of diagnosing AD through blood tests, CSF analysis, or imaging alone are that the pathology of any given patient can vary and that practice guidelines reserve these tests for dementia specialty practices at this time. Patients may have amyloid-beta only, amyloid-beta and p-tau, p-tau only, or either of these proteins with no neurodegeneration. We now understand AD to be not just one disease but a group of disorders.11
Drug treatments for AD. Symptomatic treatments for AD include acetylcholinesterase inhibitors (ChEIs) (donepezil, rivastigmine, and galantamine) and an N-Methyl-D-Aspartate (NMDA)-receptor antagonist (memantine). ChEIs increase the available acetylcholine and work by optimizing the cholinergic pathway, which declines in AD. In meta-analyses, ChEIs demonstrate improvement in prolonging global cognition measures and functional (self-care) ability. Results are mixed for behavioral symptoms. Adverse reactions include bradyarrhythmias, vivid nightmares, and many gastrointestinal symptoms including nausea and diarrhea, which may impede appetite. Timing of the medication and gradual dose titration can typically mitigate these adverse reactions. The NMDA-receptor antagonist, memantine, blocks excess glutamate stimulation in the brain to prevent neuronal death due to hyperexcitability. In moderate to severe AD, studies show benefit in slowing cognitive and functional decline when used alone or in combination with ChEIs. Memantine is typically better tolerated than ChEIs are, with low (1%-10%) rates of dizziness, headache, constipation, and hypertension.15
There are a number of new drug therapies with a variety of targets in the pipeline for AD that are moving beyond symptom management toward disease modification.16 About 28% of phase 3 trials of disease-modifying therapies target amyloid-beta and/or p-tau. These drugs are being tested in people living with AD in its earliest stages of symptom expression-not in the moderate or late stage of the disease, when most patients are diagnosed. For appropriate patients to have access to treatment, they will require an accurate and timely diagnosis, which will likely begin in primary care.17 Given the large and growing population of people living with dementia due to AD, a timely diagnosis for patients in primary care represents a significant opportunity to improve access to novel therapies for appropriate patients, potentially preserving their independence and quality of life.
Most cognitive impairment symptoms brought to the attention of the PCP are attributed to AD and/or cerebrovascular disease. Thus, the majority of guidance contained herein focuses on dementia due to AD; interventions that improve the quality and quantity of cerebrovascular perfusion are a mainstay of treatment in addition to any pharmacologic therapy. (See Common causes of dementia for an overview of common causes of dementia, their associated pathology, and their typical initial symptoms.)
DLB
DLB is a disease associated with abnormal deposits of a protein called alpha-synuclein in the brain.18 These deposits, called Lewy bodies, affect chemicals in the brain which can lead to problems with thinking, movement, behavior, and mood. DLB is the second most common type of neurodegenerative dementia in people age 65 or older. DLB affects over 1 million people in the US and is more often diagnosed in people over the age of 50 and in men.19 Symptoms of DLB are many and varied and could include visual hallucinations; changes in alertness and attention; and parkinsonism features such as rigidity, bradykinesia, gait changes, falls, and tremors. Additional symptoms are often related to sleep disturbances such as having vivid dreams; acting out dreams; fighting, yelling, or screaming during sleep; falling out of bed; and injuring self or others while sleeping. These findings constitute a disorder known as rapid eye movement sleep behavior disorder (RBD). Cognitive symptoms may include memory loss, confusion, visuospatial abnormalities, and poor attention.19
Diagnosing DLB. The most recent revised guideline for diagnosis and management of DLB by the Dementia with Lewy Bodies Consortium identifies the following four core clinical features used to diagnose DLB (in addition to impairment in two or more cognitive domains): fluctuating cognition with pronounced variation in attention and alertness; recurrent visual hallucinations that are well formed and detailed; RBD; and one or more cardinal features of parkinsonism (bradykinesia, resting tremor, or rigidity).18 Although there are several indicative and supportive biomarkers that may assist in a probable or possible diagnosis of DLB, no currently available test is diagnostic of DLB on its own; this is an area of ongoing research efforts.18,20 Brain imaging such as MRI and PET scans may be helpful to assess for any focal or global changes. Management strategies include medications to help alleviate or reduce specific distressing symptoms.
FTD
FTD is an umbrella term for a group of brain disorders that cause atrophy in the frontal and temporal lobes of the brain. The degeneration of brain tissue in these areas leads to problematic changes in personality, behavior, and/or language. It is the second most common type of dementia in people younger than age 65. It is often confused with and misdiagnosed as a psychiatric disorder due to its striking behavioral changes. Signs and symptoms vary, depending on which part of the brain is affected. Some people with FTD have dramatic personality changes, becoming socially inappropriate, impulsive, or emotionally indifferent, whereas others lose the ability to find and use words appropriately, which can lead to severe aphasia over time.21
Diagnosing FTD. Clinical diagnosis is made by a detailed history and brain imaging to identify atrophy involving the frontal and/or temporal lobes of the brain. There is currently no biomarker testing available to aid in the diagnosis of FTD. The underlying pathology for most types of FTD includes a transactive response DNA-binding protein of 43 kDa, known as TDP-43. TDP-43 will likely be a target for biomarker testing in the future. Medication management is aimed at mitigating distressing, bothersome, or dangerous behaviors. For people with language variant FTD, speech therapy can sometimes be helpful early in the course of the disease.21,22
Vascular dementia
Vascular dementia causes about 15% of cases of dementia.23 There is a lack of clear consensus on what actually constitutes vascular dementia; thus, some clinicians prefer to use the term "vascular cognitive impairment" to describe this condition. Much of the literature points to cerebrovascular disease that leads to micro- and macrovascular changes and insults, such as strokes, as the cause of vascular dementia. Having a stroke places people at a high risk for developing symptoms of dementia. Risk factors for developing dementia after a stroke include increasing age, vascular risk factors (such as hypertension, diabetes, coronary artery disease, atrial fibrillation, and elevated total cholesterol levels), smoking, and lower physical activity.23 Many of these risk factors are also risk factors for AD. Not all people presenting with vascular dementia have a history of stroke.
Diagnosing vascular dementia. It is generally thought that there are two main syndromes of vascular dementia: poststroke dementia and vascular dementia without recent stroke. In general, patients with vascular dementia experience a stepwise cognitive decline. For patients who have not had a recent stroke, this stepwise progression suggests there could be unrecognized strokes. There are no treatments available at this time that are targeted exclusively to vascular dementia. Management of vascular risk factors and comorbidities is indicated. Additionally, while off-label for vascular dementia, ChEIs and memantine are often prescribed for this population, as many patients have concomitant AD.
Assessment is not screening
Evaluation for symptoms of dementia should be part of the PCP's regular practice. A timely diagnosis of any form of dementia at an early stage can allow for improved patient and family experience, preservation and optimization of brain function for a longer period, and the opportunity to avoid or mitigate crises; therefore, the PCP should maintain vigilance and active inquiry for emerging cognitive, behavioral, or functional symptoms or changes (see Benefits of early diagnosis of cognitive impairment).17 Additionally, as office visits are notoriously brief and often only allow for self-report of the patient's daily functional abilities, the clinician must maintain an open door to those surrounding the patient to allow them share their concerns and observations, as family/friend input can be extremely valuable in informing the symptom history. Special attention should be given to cognitive signs and symptoms among patients who have a family history of AD or dementia of unknown origin, who are at an advanced age, or who have experienced hypertension, obesity, or diabetes since midlife.24,25
It is also relevant to note that routine screening for cognitive impairment among older adults has a US Preventive Services Taskforce recommendation of "I," meaning that there is insufficient evidence for or against screening.26 However, evaluation of reported or observed symptoms is not equivalent to screening. In fact, further investigation of a patient- or family-reported symptom is the responsibility of the PCP.
The Centers for Medicare and Medicaid Services requires assessment for cognitive impairment as part of the Annual Wellness Visit (AWV). Additionally, if cognitive impairment is discovered during the AWV or any other routine visit, Medicare will cover a separate visit for more detailed assessment (Cognitive Assessment and Care Plan Services).
Clinical evaluation
A comprehensive assessment of cognitive impairment consists of a focused history of present illness and contributing factors, measures of cognition, observer-rated measures of function and neuropsychiatric symptoms, care partner assessment, structural brain imaging, physical exam, and serologic testing.17
History of present illness
Many, but not all, people experiencing cognitive impairment are unaware of their deficits, a condition called anosognosia. Thus, the assessment should include both self- and informant-reported symptom history. (See Symptom assessment tools for a list of tools to assess cognitive, behavioral, and functional symptoms.) Detection of cognitive impairment can be ascertained by asking specific questions about changes in memory, language, and the ability to complete ADLs. In addition to subjective complaints of cognitive symptoms, individuals may also report work-related difficulties; abandonment of hobbies or interests; trouble managing finances; difficulty remembering appointments, important dates, or to take prescribed medications; or difficulty with travel, such as using public transportation.
A comprehensive cognitive evaluation includes a structured and detailed history of functional ability and neuropsychiatric symptoms. Measures of functional ability and neuropsychiatric symptoms are valid when completed by an observer, defined as someone who spends time (ideally on a daily basis) with the patient. Instruments to capture the patient's ability to perform ADLs and instrumental ADLs may be completed in advance of or during a cognitive assessment visit, typically without the patient's input.27,28 The clinician may also gather the patient's own assessment of their ability to complete ADLs successfully for additional information. Likewise, measures of neuropsychiatric symptoms rely on an observer's input. These symptoms include those within the affective (anxiety, depression), motor (pacing, rummaging), verbal (repetitive questions, aggression), and psychosis-related (delusions, paranoia, hallucinations) domains, among others. Standardized tools such as the Neuropsychiatric Inventory or the Revised Memory and Behavior Problems Checklist are questionnaires that can be completed independently by the observer at or prior to the visit.29,30 Both capture the frequency of symptoms and distress caused by the symptoms.
Relevant medical and social history
It is important for providers to be aware of substance use or misuse, current or past, given its potential influence on cognition. It is also critical to identify history of any psychiatric disorders, such as depression, bipolar disorder, or attention-deficit/hyperactivity disorder, or history of inpatient psychiatric hospitalizations, as these disorders and incidents may increase risk of dementia.24 Likewise, it is critical to determine previous or current use of psychiatric medications, which also may increase risk.24 Because of their effect on patients' cognitive and functional status, diabetes, thyroid disease, cardiovascular disease, cerebrovascular disease, and other neurologic conditions should be assessed for by providers.25
Medication review of all prescribed and over-the-counter drugs and supplements is crucial. Clinicians should pay attention to those that may affect alertness (such as antiepileptic drugs, opiates, and sedatives) and those with anticholinergic properties (such as first-generation antihistamines, urinary and gastrointestinal antispasmodics, and tricyclic antidepressants).
Objective assessment
For objective cognitive assessment, structured tools are superior to unstructured approaches that rely on clinician intuition.31 Tools such as the Montreal Cognitive Assessment (MoCA), Memory Impairment Screen (MIS), Mini-Cog, Saint Louis University Mental Status (SLUMS) examination, or another validated instrument should be used.32-35 In a busy primary care practice, the choice of tool may depend on staff training, competence, and time required to complete as well as sensitivity and specificity.
The Mini-Cog requires 3 minutes of trained staff time and consists of short-term recall of three items and a simply scored clock-drawing test. This may be ideal as part of the workflow of a standard visit such as the AWV. The scoring is likewise simple to tally: 1 point for each word remembered and 2 points for a correctly drawn clock. The highest possible total is 5; it is unlikely the patient has a dementia syndrome if the score is 3 or greater.34
The MoCA test and SLUMS examination are more comprehensive screening tools. They require about 10 minutes each to complete by a trained staff member. Both are more sensitive at detecting MCI than older instruments, and the MoCA is validated across cultural groups and available in more than 60 languages.32
The syndrome of dementia is defined as impairment in two of the six cognitive domains: learning and memory, executive function, perceptual-motor function, language, complex attention, and social cognition.36 Although the aforementioned tools are helpful screening instruments, a comprehensive evaluation measures performance in each domain. Often a referral to a neuropsychologist is required to conduct in-depth testing of the domains. These tests along with the deficits identified can direct the provider to the correct diagnosis. Neuropsychological testing is most helpful early in symptom expression and may help to distinguish dementia from other psychiatric diagnoses such as depression. The PCP should be aware that detailed neuropsychological testing requires at least an hour, though typically several hours, of focused examination. Referrals may not be appropriate for patients who cannot tolerate or participate in detailed testing or for patients in whom the results would not alter the treatment plan.
Assessment of lab tests serves primarily to identify contributing factors that may worsen cognitive, functional, or psychiatric symptoms rather than to identify an alternative cause for the dementia symptoms. A comprehensive metabolic panel, thyroid function testing, vitamin B12 level, hemoglobin A1C, and lipid profile form the basic analysis. Any other tests would be based on the patient's current and past medical history. Elevated or low levels of vitamins, minerals, or hormones may require further workup or further medical management by either a PCP or a specialist.
Care partner assessment
Patients living with neurodegenerative diseases become increasingly dependent on others as their diseases progress. In the US, most people living with dementia are community-dwelling, and about 85% of their care is provided by unpaid care partners (usually family or friends).8 Care partners should be assessed for their comfort and ability to fulfill the role and their degree of distress or strain. The clinician should document the care partner's name and contact information, their relationship to the patient, their living situation (co-residing, local, or distance), and the specific support the care partner provides, which may include transportation, financial and legal proxy, direct care, medication assistance, and/or healthcare or other service navigation. Standardized assessment tools for care partner well-being should be incorporated into the visit flow. Some examples include the Modified Caregiver Strain Index, Pearlin Mastery scale, or Zarit Burden Interview (see Care partner assessment tools).37-39
Synthesis and interpretation
As described previously, pathologic amyloid-beta, p-tau, and neurodegeneration form the criteria for diagnosis of AD. In the absence of biomarker data, the clinician is left to consider the patterns of symptom manifestation, measures in each of the cognitive domains, and the informant-provided observations to arrive at a reasonably confident diagnosis.
Diagnosis of dementia should include four elements: whether the neurocognitive disorder is major (dementia) or mild (MCI), the probable underlying pathologic cause, the stage of impairment (in major neurocognitive disorder), and whether neuropsychiatric symptoms are present.36 Notably, both diagnosis and stage should be disclosed to the patient and/or their care partner.40
Disclosing the diagnosis
Disclosing the diagnosis is a process that begins at the point of deciding to pursue a clinical evaluation. Patient preferences for detailed, general, or no information about their diagnosis should be ascertained. In addition to the patient, an informant or care partner of their choice should be engaged in the conversation about diagnosis and stage of dementia. In these conversations, a framework such as Setting-Perception-Invitation-Knowledge-Empathy-Summary (SPIKES) can be applied.41 Within this framework, the clinician chooses a time and place for the conversation and offers to include a support person for the patient (Setting). Next, the clinician assesses the degree to which the patient and/or support person already know or suspect about the patient's cognitive symptoms (Perception). The clinician asks how much information the patient and/or support person want to know about the diagnosis (Invitation). The clinician shares the diagnosis in direct and simple terms (Knowledge). The clinician should be prepared for an emotional response and should respond empathetically (Empathy). Finally, it is often meaningful to offer next steps to the patient; the degree of specificity can be determined based on the patient's openness to discussing the treatment plan or can be scheduled as a next visit (Summary).
When to refer to specialists
For patients for whom the diagnostic evaluation described herein is inconclusive, referral to a cognitive neurology or dementia specialist is warranted. Unclear diagnoses may be due to unusual symptom presentation and timing, age younger than 65 years, or rapid disease progression (in weeks to months rather than over months to years).17 Specialists can pursue a more detailed and comprehensive query into both the subjective and objective assessments. Specialized testing- such as of blood or CSF biomarkers, detailed neuropsychological evaluation, or specialized imaging-is often available in a dementia specialty practice such as the Alzheimer's Disease Research Centers.
Conclusion
Early and accurate diagnosis offers the best opportunity for lifestyle modification, protection of well-being and assets, and access to disease-modifying therapies. The first approved disease-modifying treatments for AD have arrived on the market, albeit with limited availability. Other similar drug treatments will likely follow in the next few years. PCPs can play a major role in overcoming the challenge of late dementia diagnoses, as they are optimally positioned to detect the earliest signs and symptoms of cognitive, functional, and behavioral changes that may be due to ADRD.
REFERENCES