Introduction
Dementia is any disorder in which decline from a previous level of cognition causes interference in a person’s occupational, domestic, or social functioning. Generally, dementia should be considered to be an acquired syndrome, with multiple possible causes, rather than a specific disease. A syndrome is a pattern of symptoms and cognitive changes that are observed by others and/or experienced by the person, whereas the term “disease” refers to the pathophysiologic process and/or the neuropathology that underlies and gives rise to the syndrome. For example, a patient’s experience and a family member’s observation of a syndrome of slowly progressive decline in language over 2 years could be caused by various diseases, such as Alzheimer disease (AD), a slow-growing tumor in the brain’s language cortex, or a frontotemporal dementia (FTD). In this way, it is useful to think of experiencing “dementia” as similar to experiencing chronic chest pain, in that they are both symptoms or syndromes that can have one or more underlying causes. This distinction may be most important to providers when they start to evaluate presenting dementia symptoms, as it is a reminder to keep one’s differential diagnoses wide during the diagnostic process ( Fig. 15.1 ).
Globally, there were at least 35 million older adults living with dementia in 2010 and more than 57 million in 2019. This number will continue to increase, with some global estimates predicting a dementia prevalence of more than 150 million individuals by 2050. Advancing age, genetic profile, and systemic vascular disease are major risk factors for developing dementia.
A traditional way to conceptualize the diseases that underlie dementia is to consider two broad categories: diseases that are neurodegenerative (which were classically considered irreversible) and those that are nonneurodegenerative (which, classically, were considered at least potentially reversible). This dichotomy is a helpful heuristic but is limited by oversimplicity. For example, patients with dementia can have multiple, concurrent, underlying diseases that can be neurodegenerative (e.g., dementia with Lewy bodies) and nonneurodegenerative (e.g., cerebrovascular disease, obstructive sleep apnea) which cumulatively account for the impairment in cognition and daily functioning. There are also diseases that can impair cognition without leading to a significant decline in individuals’ daily functioning, either at diagnosis or subsequently. The terms “mild neurocognitive disorder” (from DSM-V) and “mild cognitive impairment” (MCI) are used variously to characterize these states.
Most dementia in older adults is caused by some degree of neurodegeneration. Some common degenerative diseases that cause dementia in older adults are AD, dementia with Lewy bodies, vascular dementia, frontotemporal lobar degeneration, and Parkinson’s disease dementia.
Common causes of nonneurodegenerative MCI and dementia that can occur across the lifespan include vitamin deficiencies (e.g., B12, thiamine), hypothyroidism, normal pressure hydrocephalus, chronic alcohol abuse, chemotherapy-related cognitive dysfunction, infections (e.g., human immunodeficiency virus), intracranial masses (e.g., subdural hematomas, brain tumors), traumatic brain injury, and psychiatric illness (profound depression/anxiety).
Most frequently, patients or families will report initial symptoms of a dementia syndrome in primary care or family practice settings before having the opportunity to obtain specialized care. At these first touchpoints in the healthcare system, symptoms are sometimes presented to providers but then not further evaluated or ultimately diagnosed; these situations represent a missed opportunity for early interventions that can begin to improve patients’ morbidity and other care outcomes. Estimates suggest that fewer than half of the expected patients with dementia are recognized in the primary care setting, and many who are identified do not receive diagnoses. The number of patients that are missed who have early changes of a dementia-causing disease rises substantially when you consider that these diseases may have years of a preclinical phase, during which some biological and pathophysiological changes occur in the brain that are not yet causing noticeable signs or symptoms.
Therefore it is important that primary care providers and other nonspecialists in cognitive disorders and dementia be familiar with the topics presented here. This is particularly true considering recent pharmacotherapeutic developments, particularly for cognitive impairment and dementia due to AD. Multiple steps within the healthcare system are often needed to determine the probable causes of dementia. Thus, if diagnoses of MCI or mild dementia are delayed well after symptom onset, patients may receive proper care only after they have progressed to moderate stages of impairment, when treatments and care interventions are significantly less optimal.
For example, newer therapeutics such as lecanemab, a promising agent that was approved in 2023 by the US Food and Drug Administration to treat early AD, are likely to be effective only in milder stages of the disease. Failure to identify and diagnose dementia-causing diseases, especially at stages later than MCI, also leads to risks poorer patient understanding of the scope and expectations of treatment and higher rates of nonadherence to the schedule of any prescribed medications. Therefore, it is critical to consider screening guidelines to recognize symptoms, identify patients who are at risk, and provide early interventions, which will increasingly require tests for the biomarkers of AD and hopefully other diseases. Of note, the use of these newer AD therapeutics, which for now will likely be prescribed by neurology or psychiatry specialists, carries some risks of brain bleeds and edema, identified as amyloid-related imaging abnormalities (ARIA). Although these side effects are rarely consequential, additional studies are ongoing to help further characterize both risks and benefits, enabling more informed, personalized treatment discussions between providers and patients.
Approach to Evaluate for Cognitive Impairment and Dementia
Screening Overview
There are currently no standardized guidelines on who needs to be screened for cognitive impairment and dementia. This contributes to the underdiagnosis and delayed diagnosis of dementia described previously. Notably, in the United States and around the world, delays in diagnosis are even more pronounced in certain subpopulations, with factors such as level of education, living alone, and being part of a minority racial or ethnic group likely playing a contributory role. Screening is also difficult because dementia has many different etiologies, so different risk factors that may prompt screening are more relevant for one or several causes of dementia but not all. Currently in clinical practice, screening for cognitive impairment and its sometimes associated psychiatric or motor symptoms often occurs later than is optimal and after the patient or family has raised subjective complaints and observations. Despite the current finding in the United States by the US Preventive Services Task Force that evidence is insufficient to assess the balance of benefits and harms of screening for cognitive impairment in all older adults, we advocate a shift to early identification of dementia risk factors and universal dementia screening in older adult populations.
Consideration of Dementia Risk Factors
While risk factors can be specific to the cause of the dementia, there are some risk factors to consider in primary care settings that are common to all diseases that cause dementia and can aid in decision-making about further evaluation. For simplicity, we will divide these risk factors into those that are nonmodifiable and modifiable and discuss accordingly.
Age is the most prominent nonmodifiable risk factor, as the incidence of dementia increases proportionally with age. For example, estimates from the past census in the United States suggest that among individuals with AD, the most common dementing illness, about 15% are between the ages of 65 and 74 years, almost 50% are between 75 and 85 years, and about 35% are 85 years or older. Differences in prevalence also occur along the lines of self-identified race and ethnicity. Many studies in the United States, for example, suggest that compared to their White counterparts, dementia prevalence is up to 1.5–2 times higher in Black and Hispanic individuals. This is supported by a summary of data reported annually by the Alzheimer’s Association. The Association identifies two other nonmodifiable risk factors for dementia: low socioeconomic status and being a nonlocal language speaker. A family history of neurodegenerative dementia, especially of first-degree relatives, is another nonmodifiable risk factor and an appropriate consideration for screening and early provision of risk reduction recommendations.
Familial patterns of dementia are common, especially with AD, Parkinson disease, and FTD. Notably, there are currently minimal dementia “risk genes” available for testing in clinical settings in most countries, and genetic testing is not recommended for screening either by primary or specialist providers for most patients. In future years, recommendations for genetic testing may change when there is concern for AD, because carrying the apolipoprotein E-4 allele (APOE-4) increases the risk of side effects with novel disease-modifying anti-amyloid antibody therapies, such as lecanemab. At the time of publication, however, there are no guidelines for referral for available genetic testing that consider the newly developed disease-modifying therapies for AD. In some selective families in which neurodegenerative disease has occurred in at least three individuals in two or more generations, with two of the individuals being first-degree relatives of the third generation (e.g., grandparent, parent, and child), it is reasonable to refer to a genetics program with counseling to consider testing.
Genetic testing results are increasingly available to individuals through direct-to-consumer testing; understandably, these have begun to affect care discussions in the clinic. Our experience is that test results showing a higher risk of AD, for example, motivates both patients and providers to develop treatment plans to increase patients’ personalized, evidence-based brain health behaviors, which can mitigate important aspects of genetic risk over time.
There are 12 prominent modifiable risk factors to consider. These include five cardiovascular and cardiometabolic risk factors (hypertension, diabetes, obesity, physical inactivity, and smoking), three mental health risk factors (history of traumatic brain injury, depression, and alcohol use disorder), three social factors (social isolation, high air pollution, and low education), and hearing and vision impairment. As patients age, if cardiometabolic risk factors are not well controlled, the risk of vascular cognitive impairment, AD, and other neurodegenerative diseases increases significantly. In a prospective population cohort study with almost 230,000 patients, it was found that patients with controlled cardiometabolic risk factors over 9 years were less likely to develop dementia of any cause compared to their peers. In the same vein, it is critical to correct hearing and vision impairment to the extent possible in older individuals, especially those who are at higher risk of developing dementia. Modifiable dementia risk factors are essential clinical targets for interventions that should be discussed early and actively with patients and families.
Whether primary care providers or specialists identify nonmodifiable risk factors such as genetics or modifiable factors such as a sedentary lifestyle in older adults, it is essential that all providers adopt a proactive, prevention-oriented approach to dementia screening and risk reduction.
Clinical Evaluation
Overview
The initial evaluation and diagnosis of possible cognitive impairment or dementia should include at least the following four elements: (1) a thorough clinical history, (2) a basic cognitive assessment and neurologic exam, (3) selective labs to screen for relevant metabolic/physiologic abnormalities (e.g., basic chemistries, thyroid panel, B12, Vitamin D), and (4) a structural brain scan, with MRI preferable to CT whenever possible. In certain patients, serologic studies such as antinuclear antibody, erythrocyte sedimentation rate, treponemal pallidum antibody or venereal disease research laboratory, HIV-ab, and heavy metal screen are warranted. Depending on the practice or workflow within different healthcare systems, these four elements may be carried out entirely within primary care or in collaboration between primary care and specialists when services are accessible.
Emphasis in the clinical interview should be placed on determining the pace of symptom onset (e.g., sudden/rapid or gradual) and symptom progression (e.g., decline over months or over years). For example, human prion diseases that cause dementia, such as Creutzfeldt-Jakob disease, typically have a rapid progression over weeks to months. Diseases such as AD and FTD, by contrast, usually progress gradually over years. In addition to asking about the nature of cognitive changes being experienced or observed (e.g., short-term memory changes, word-finding difficulty, calculating numbers), the clinical interview should include whether there have been changes in gait and balance, personality and emotional connection (e.g., changes in empathy, manners), autonomic symptoms (e.g., presyncope when standing, significant heart rate or blood pressure fluctuation), sleep behaviors (e.g., acting out dreams, vocalizations), visual or auditory misperceptions or hallucinations, and changes in smell and taste. See Table 15.1 for features of diseases that may involve dementia.
| AD | DLB | FTD | CJD | VCI | |
|---|---|---|---|---|---|
| Signs Affected | |||||
| Cognition | Always . Short-term memory usually first. Multiple cognitive domains often impacted. | Frequent . Most impact on visuospatial, attention. Memory deficits also seen in later stages. | Always . Language, speech, and executive function initially or as disease progresses. | Always . Rapid progression. | Always . Stepwise or slowly progressive decline. Attention, executive function. |
| Motor | Infrequent . Can be present in later stages. | Always . Present and early on. Tremors, masked facies, limb rigidity, shuffling gait. | Infrequent | Always . Myoclonus, extrapyramidal signs. | Frequent . Depends on area of damage to the brain. |
| Behavior and psychological | Sometimes . Delusions more common in later stages. | Frequent . Delusions in later stages. | Frequent . Loss of sympathy, empathy, and behavioral control. | Frequent . Mutism. | Frequent . Depends on area of damage to the brain. |
| Sleep | Sometimes . Can be present in later disease. | Frequent . Dream enactment and vocalizations. | Infrequent | Sometimes | Frequent . Depends on area of damage to the brain. |
Cognitive Screening and Assessment
The Mini-Cog and Mini Mental Status Exam (MMSE) are two cognitive screening tools that are frequently used to assess older individuals at routine visits or when there is suspicion that a patient may have a cognitive disorder. The Mini-Cog is a three-step test that takes about 3 minutes to administer. The MMSE takes about 5 minutes. Some studies have supported comparable or improved sensitivity and sensitivity of the Mini-Cog compared to the MMSE in identifying MCI in community-dwelling older individuals.
A detailed mental status exam should assess multiple domains of mental function, including basic attention, memory, visuospatial abilities, executive function, and sociobehavioral aptitude. Although the 30-point MMSE can be used purely to determine whether further evaluation is warranted, it also remains a practical and helpful tool to provide enough information to help gauge the overall severity of cognitive impairment. Importantly, the MMSE is probably less informative in some populations, such as high-functioning and highly educated elders and those with low formal education. Other tests, such as the Montreal Cognitive Assessment (MoCA), offer a broader assessment of cognitive domains than the MMSE, providing more details that can sometimes help with differential diagnosis of the dementia-causing disease. Some evidence points to the MoCA as also being more sensitive than the MMSE for the early detection of cognitive impairment caused by a neurodegenerative disease. Importantly, tests such as the MoCA and MMSE are helpful in contributing to a diagnosis of dementia but are not sufficient to diagnose or exclude a dementia syndrome; results must be considered along with the other elements of evaluation, including clinical history of cognitive or daily functioning changes and imaging. Further cognitive testing, including neuropsychological evaluation, may be helpful in cases in which screening tests or clinical impression are equivocal.
In the United States, some patients are screened for cognitive concerns during their Medicare Annual Wellness Visit (AWV), which is focused on preventive care in older adults. During an AWV, any cognitive screening tool can be used by the primary provider. Current guidelines suggest the use of either the Mini-Cog, the General Practitioner assessment of Cognition (GPCOG), or the Memory Impairment Screen (MIS). Our experience in the United States is that there is currently limited knowledge and practice experience with the MIS and GPCOG.
Considering that there is also currently limited evidence to recommend any type of cognitive screen during an AWV, we suggest different screening strategies for primary care providers depending on practice setting. If the provider is in a resource-rich practice setting with timely access to knowledgeable specialists who can continue with dementia evaluations and management, a Mini-Cog should be sufficient as a screen to determine the need for a repeat screen or referral to a specialist. Other commonly used screening tests that also capture the person’s status of daily functioning include the Eight-Item Informant Interview to Differentiate Aging and Dementia and the Blessed Dementia Rating Scale. Both are also brief scales that can be completed by family members and sometimes patients to help identity those who need more attention or evaluation. If the provider is in a more resource-limited practice setting, we recommend using the MoCA or MMSE to fulfill multiple functions, including as an initial screen, as an assessment to aid with diagnosis, as way to track disease progression over time, and potentially to gauge patient responses to care interventions. Providers should be mindful that the Mini-Cog may have a specificity of only approximately 73%; therefore, patients who screen negative on the Mini-Cog should continue to be evaluated at least on an annual basis.
Most aspects of evaluation that were mentioned here can be conducted both in person and through virtual visits. Some older adults seem to prefer virtual care; individuals who are frail and have multiple illnesses may find it difficult and perhaps traumatic to have to present for in-person care. Care partners and family members sometimes prefer virtual care, which we find is frequently the case for patients with moderate to severe dementia. Therefore developing the ability to gather as much clinical information in a virtual format will prove to be helpful, such as being able to perform a telephone- or video-based MoCA.
Neuroimaging
If a patient is screened positive from the Mini-Cog and has a clinical history of concern for, or observations of, cognitive changes over 6 months or more, the patient may benefit from neuroimaging. Having additional risk factors for dementia may also contribute to a decision about neuroimaging. Where possible, a brain MRI is preferable to a CT scan. Brain MRIs must be interpreted in the context of an abnormal cognitive screen and a history of cognitive changes or decline. That is, cognitively normal older adults without early dementia can also have brain lesions detected on MRI or volume loss (atrophy). It is common but not necessary for patients with early AD to have MRI patterns of generalized cortical atrophy (atrophy in most regions), with some predominance of atrophy in the medial temporal lobe, surrounding and including the hippocampi. There is not a consistent MRI finding to aid with diagnosis of Parkinson Disease dementia. For FTD, there is often prominent atrophy in the frontal and temporal regions on MRI, with dominance in the right hemisphere for behavioral variant of FTD (bvFTD) and the left hemisphere for the Primary Progressive Aphasia variant of FTD. MRIs with focal tissue loss in a region that reflects a prior stroke or that has significant white matter changes are common in vascular dementia.
It is clinically challenging to differentiate cognitive changes associated with normal, healthy aging from changes due to early neurodegenerative disease. The continuum from normal cognitive aging to dementia is detailed in Table 15.2 . Differentiating normal aging from subjective cognitive decline (SCD), MCI, and major neurocognitive disorder or dementia relies on both detailed history taking and performance on objective clinical tests such as a MoCA. It is important to understand that, according to the DSM5, MCI is synonymous with mild neurocognitive disorder , and major neurocognitive disorder is synonymous with dementia. Regarding cognition, understanding the basics of major cognitive domains, which include attention, executive function, social cognition, learning and memory, language, and visuospatial function, is also useful for both history taking and interpreting the results of cognitive testing. For example, if clinicians identify specific examples of changes in cognition in one or more of these domains or in daily functioning for a single patient, they can reason in a measured way about whether and how much that patient has declined.
| SCD | MCI | Major Neurocognitive Disorder (Dementia) | |
|---|---|---|---|
| Subjective Complaints | Present | Often present | Often Present |
| MoCA | Normal (above 26) | 18–26 | Frequently below 18 |
| Instrumental activities of daily living | Independent | Independent | Dependent |
| Activities of daily living | Independent | Independent | Dependent |
Understanding patients’ motor function, which can include balance, muscle tone, strength, and abnormal movements (e.g., tremor, twitching, and myoclonus), can augment one’s clinical reasoning when coupled with clinical history and the identification of a patient’s cognitive deficits.
Dementia Classification Continuum
The mildest form of cognitive concern is SCD. In this state, patients notice cognitive changes, but their objective cognitive scores, such as those on the MoCA, are within normal limits, and their functioning in daily activities remains entirely independent. When even subtle cognitive deficits are detected objectively on testing but the patient remains independent in all activities, the condition is labeled mild cognitive impairment. In MCI, a MoCA score is frequently between 18 and 26 out of 30. Once cognitive decline begins to affect activities of daily living (ADLs), whether instrumental ADLs (IADLs), such as managing finances or medications or preparing meals, or basic ADLs, such as using the bathroom, maintaining personal hygiene, or eating, the patient is considered to have a major neurocognitive disorder or dementia; MoCA scores typically are less than 18. Table 15.3 provides a summary of how to conceptualize these different clinical presentations and lists of activities that are included in IADLs and basic ADLs.
| IADL | ADL |
|---|---|
| Ability to use the phone | Bathing |
| Shopping | Showering |
| Food preparation | Dressing |
| Housekeeping | Walking |
| Laundry | Using the toilet |
| Independent transportation | Eating |
| Ability to take medications | Getting in and out of bed |
| Ability to handle finances | Getting in and out of chair |
Within the syndrome of dementia (major neurocognitive disorder), one helpful model for staging severity is the tripartite classification of mild, moderate, and severe. In this model, the staging is based on clinical information rather than any cognitive testing or laboratory or imaging markers. A patient with mild dementia typically has lost independence in one or more IADLs but is independent in basic ADLs. With moderate dementia, patients are dependent on others for all IADLs and dependent for some basic ADLs. With severe dementia, patients are fully dependent on others for ADLs.
While it is not possible to predict the timeline of any one patient’s progression through these stages, the model can be helpful for caregivers to understand more about what changes they may look out for. Since a majority of longitudinal care for dementia in the United States and globally is provided by primary providers and there are not enough subspecialty dementia experts (e.g., neurologists, geriatric psychiatrists, geriatricians) to provide initial or ongoing care, it is important for primary providers to be comfortable with the basics of classifying dementia severity and to be familiar with available and appropriate recommendations for the major stages. Of course, if specialists are available for either an initial consultation or longitudinal care, a referral to examine all evidence for the neurologic disorder and to help elucidate the cause, is sensible when these conditions of SCD, MCI, or dementia are identified.
Evaluation of Cognitive Complaints: Clinical Pearls
A noteworthy clinical pearl is that many older adults have impairment in some aspect of their motor function, hearing, or vision acuity. These can sometimes be mistaken as clear evidence of a cognitive or neurologic disorder, or they can be the dominant cause of a cognitive complaint or errors on testing. For example, older patients may have the ability to perform normally on cognitive testing and in everyday life but score below normal on the MMSE due to hearing impairment. These common changes with aging are especially confounding to providers who do not know the patient well. Of course, the physical limitations of visual or hearing deficits are themselves independent risk factors for the development of dementia and should be addressed. Generally, providers should be attuned to potentially false positive cognitive screens or misdiagnosis of a cognitive disorder in these circumstances. As was mentioned earlier, the MoCA does have versions that are validated for individuals with significant hearing or visual impairment, which can be utilized.
It is often difficult to decide whether to evaluate cognitive complaints in the older population beyond obtaining a clinical history and administering a brief cognitive screen. From the perspective of a primary provider for the initial presentation of cognitive concerns, if a patient or the patient’s care partner(s) endorse new psychiatric symptoms associated with the cognitive concerns, frequent unexplained falls, or drastic changes in weight, we do recommend further evaluation or referral to a specialist, as each has a strong correlation to many dementia-causing diseases.
Some common cognitive concerns include forgetting names, having trouble keeping track of daily events, taking longer than before to complete mentally complex tasks, experiencing word-finding difficulty, having trouble with mental calculations, and being unable to recall recent salient events. More concerning complaints include frequently getting lost or uncharacteristically misplacing household items, especially when attempts to organize have fallen short. Sometimes a false belief (i.e., a delusion), such as a belief that someone has entered the house and stolen an item that is now missing or a belief that a family member who has died is still alive, can be the initial presentation of early dementia, though it is more commonly seen in later stages. In contrast, apathy and disengagement are commonly seen in early mild dementia.
Wandering behaviors, which may manifest as regularly returning from a routine walk or drive later than usual, can lead to patients getting lost, and this should be considered an issue to be addressed urgently. Actions may include escalation of care to an inpatient hospital admission if there are clear, immediate safety concerns. Wandering and other unsafe behaviors are mostly observed in later stages of dementia but can sometimes occur in early stages. Psychiatric symptoms can range from development of depressive or anxious symptoms to becoming more irritable or even agitated.
Neurodegenerative Dementias
Alzheimer Disease
AD is the most common neurodegenerative cause of dementia in middle-aged and older individuals. Dementia due to AD has a global prevalence of 5%–6% of all individuals age 65 and above and up to 30% in those over age 85. About 5% of all Alzheimer dementia occurs before age 65, which is conventionally termed “early-onset.” The disease typically begins with slowly progressive memory decline, although behavioral, visuospatial, or language symptoms can dominate early in less common variants, which are most often observed in early-onset cases (under 65 years old). The mean survival after symptom onset in AD tends to be 10–12 years.
Current models of AD include a preclinical stage, in which the first changes of AD biology may occur up to 20 years or more before onset of symptoms. The pathophysiologic process is characterized by the gradual accumulation of beta-amyloid-rich neuritic plaques and a buildup of tau protein into so-called neurofibrillary tangles throughout the brain. Beta-amyloid protein is dominant in the hardened, neuritic plaques and also exists in toxic, soluble forms that are found in the brain. These two findings define AD pathologically (see Fig. 15.2 ). Notably, based on autopsy studies of AD patients, it is very common to find other pathologies cooccurring with AD, including cerebrovascular disease and Lewy body disease, even if patients do not exhibit symptoms that clearly reflect those brain changes.
Early on in symptoms, patients may have subtle, everyday forgetfulness or occasionally repeat stories; they can also exhibit irritability, apathy, or low mood. (See the later discussion about mild behavioral impairment.) Patients or family members often first notice cognitive symptoms before any decline in daily functioning, which defines a stage described as MCI. (See the earlier section on evaluation and diagnosis for discussion about the MCI/dementia continuum.) As the disease advances, brain MRI can show medial temporal lobe atrophy, involving the hippocampi, surrounding structures and diminished brain tissue in other regions (see Fig. 15.3 ). A fluorodeoxyglucose positron emission tomography (FDG-PET) scan classically shows bilateral temporoparietal hypometabolism, reflecting dysfunction of synapses and neural networks in these regions.
As disease-modifying medications to treat AD emerge in clinical care beginning in 2023, patients are increasingly being tested for biological markers (biomarkers) to identify the underlying amyloid and tau pathologies. This testing is currently carried out mostly by neurology or psychiatry specialists, but the practice may generalize to primary care settings over time. In the last decade, biomarkers have helped to catalyze a shift in the conception of AD from a clinical-pathologic condition, in which diagnoses are confirmed only after death, to a clinical-biological condition, in which diagnoses by biomarkers are confirmed during life. In the coming years, this shift toward a biologically centered understanding and treatment of AD will continue, with relevant impacts on patients, care partners, providers, insurance carriers, and healthcare systems alike.
Currently, Alzheimer biomarkers both help to confirm a diagnosis that is made clinically (i.e., one based on symptoms, cognitive testing, and sometimes MRI scans) and ensure that patients’ brains have the relevant targets for novel, disease-modifying medications. Cerebrospinal fluid tests are a commonly used Alzheimer biomarker and may be abnormal even early in the preclinical phase, when levels of the 42-residue long beta-amyloid protein (Aβ42) begin to decrease and levels of phosphorylated tau protein increase. PET scans that reveal amyloid plaque deposition (amyloid PET) and tau protein aggregates (tau PET) are biomarkers with emerging use in clinical care but have been limited by their financial cost. The earliest detection of AD may be by blood-based markers (BBMs) of tau and amyloid. At the time of publication, the evidence for clinical utility of BBMs to diagnose and track AD is still emerging and they are rarely used in clinical care. Expert opinion currently discourages the use of BBMs in a nonspecialist setting. Thus, apart from blood tests, AD is best detected by amyloid/tau PET, CSF-based biomarkers, or a combination of MRI and FDG-PET, both early on and through all stages of the disease (see Fig. 15.4 ).
Recent clinical and translational research has focused on early detection and therapeutic targeting of the underlying pathology. At the time of this chapter’s writing, two medications that remove amyloid protein from the brain and that seem to slow the rate of decline of cognition and daily functioning in patients with MCI and mild dementia due to AD show promise. To be specific, one (lecanemab) has received full FDA approval, and another (donanemab) is likely to be reviewed relatively soon. These and other medications will likely soon be prescribed by specialists in clinical AD care throughout the United States and globally. If patients are thought to have probable MCI or mild dementia due to AD by their clinical evaluation, that is sufficient reason to refer to a specialist so that they may be considered for these medications.
Older medications, including cholinesterase inhibitors (i.e., donepezil, rivastigmine, galantamine) and an NDMA-receptor antagonist (memantine), which have been used globally for over 20 years, are still prescribed for patients at all stages of AD. Although these medications do not alter patients’ inevitable decline in cognition or daily abilities, they may improve cognitive and behavioral symptoms for periods of 6 months to several years. There are also medications available for symptomatic treatment of depression, anxiety and other neuropsychiatric symptoms associated with AD, which are discussed later in the chapter. Substantial evidence suggests that regular aerobic exercise, adherence to a Mediterranean-style diet, and participation in socially and cognitively stimulating activities can decrease one’s risk of AD and affect the rate of progression along the disease continuum.
Frontotemporal Dementias
The frontotemporal dementias are a group of neurodegenerative diseases linked by the selective degeneration of the frontal and temporal lobes. FTDs are relentless, devastating diseases in which the dominant symptoms usually include changes in some or all of social behavior, speech, language, and motor function. Overall, FTDs are much rarer than AD. Although the age range for FTDs can be anywhere from the second to the tenth decades of life, it is a relatively common cause of early-onset dementia (symptoms prior to age 65). In fact, the FTDs are the second most common disease causing early-onset dementia after AD, accounting for close to 20% of all cases. In older age, FTDs are the third most common type of neurodegenerative disease, behind AD and dementia with Lewy bodies (an alpha-synculeinopathy).
The exact prevalence of FTDs is an ongoing subject of research but is likely between 1 and 17 patients per 100,000 overall, decreasing to 1–4 per 100,000 in patients over the age of 70. FTDs are most commonly diagnosed in middle age (age in the 50s), with ~13% of cases occurring before age 50.
The FTDs are dementia syndromes that most commonly arise from a group of underlying pathologies, unified by the term “frontotemporal lobar degeneration” (FTLD). FTLD includes at least three distinct pathologic subtypes: transactive responsive DNA-binding (TDP-43), tau protein, and fused-in-sarcoma. As discussed in this chapter’s introduction, different syndromes (or clusters of symptoms) can arise from the same underlying pathology or pathologic subtype. The symptoms and signs that patients demonstrate largely depend on which brain regions are most affected. Knowing the pathology subtype may be more relevant when we have reliable biological markers to identify FTD or treatments that modify FTLD pathology, which are active goals of research.
The most common FTD syndromes that arise from underlying FTLD include the behavioral variant of FTD; language variants, which include nonfluent agrammatic and semantic variant primary progressive aphasia; corticobasal syndrome; and progressive supranuclear palsy syndrome. Less commonly, patients show signs and symptoms of one of these syndromes and amyotrophic lateral sclerosis together, which constitutes an FTD/amyotrophic lateral sclerosis spectrum syndrome.
Behavioral variant FTD is characterized by early personality changes (i.e., decline in social comportment and empathy), disinhibited and/or compulsive behaviors, and executive dysfunction (i.e., mental inflexibility). Patients with primary progressive aphasia initially develop speech and language problems, which could be gross articulatory speech errors, impairments in syntax, the loss of word meaning, or word-finding difficulties or pauses in conversation. This can present with impairments in speech output and syntax (nonfluent, agrammatic variant) or in understanding the meaning of words (semantic variant). MRIs can show focal frontal or temporal lobe atrophy in these conditions (see Fig. 15.5 ). In corticobasal syndrome, which usually arises from either FTLD or AD, the initial symptoms frequently include asymmetric parkinsonism (e.g., limb rigidity, slowed movements); limb apraxia; executive dysfunction; behavioral changes; and, in subsequent years, aphasia, “alien limb” phenomenon, frequent falls, and impairments in gait. Progressive supranuclear palsy syndrome is usually characterized by axial rigidity, postural instability with early falls, and vertical gaze palsy, with subsequent progressive motor and cognitive decline. Some subtypes of progressive supranuclear palsy can also have prominent cerebellar ataxia and apraxia of speech. Importantly, while we name these syndromes based on symptoms to fit a classification scheme, it is common for patients to exhibit a mixture of symptoms seen across the different syndromes, especially as the FTD progresses. For example, patients who have the core symptoms of behavioral variant FTD sometimes have or develop a progressive language difficulty (aphasia) as well.
