Alzheimer's Disease & Dementia

• Most older adults maintain cognitive function in later years, but dementia incidence increases with age.

• Alzheimer's disease (AD) affects 5% to 13% of those over 65 and 30% of those over 85 and is the most common cause of dementia.

• By 2050, an estimated 12.7 million older adults (65+) will have AD.

• AD stands as the fifth leading cause of death in the United States for individuals over 65.

• Dementia is a frequent cause of institutionalization, affecting up to 50% of nursing home residents, according to the CDC.

• Early detection of dementia is crucial for managing risk factors, treating symptoms, and providing support to patients and families.

• Dementia includes progressive cognitive decline and behavioral changes that impair daily living activities.

• The DSM-5 classifies dementia as Major Neurocognitive Disorder, further dividing it by etiologies like AD, frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, etc.

• AD accounts for up to 80% of dementia cases.

• Approximately half of individuals over 80 with AD pathology also have other conditions, like vascular disease or Lewy body disease.

Mild Cognitive Impairment (MCI)

• MCI is increasingly common with age and represents mild cognitive decline due to various underlying causes.

• In the DSM-5, MCI is similar to mild neurocognitive disorder.

• MCI can be a transitional phase to dementia when caused by a neurodegenerative disease.

• 20% to 40% of individuals with MCI progress to dementia at a rate of 10% to 15% per year.

• MCI is considered a risk factor for all dementia types.

• Diagnosing MCI requires evidence of a change in cognitive abilities, gathered through interviews with the patient and a collateral source.

• Neuropsychological examination assesses memory, language, attention, executive functions, and visuospatial abilities to identify objective cognitive impairment.

• A diagnosis of MCI requires impairment in one or more cognitive domains, but the ability to maintain functional independence is preserved.

• Mild problems in instrumental activities of daily living (managing finances or appointments) may occur.

• MCI is classified into four subtypes:

  • Amnestic MCI (aMCI) single domain
  • aMCI multiple domain
  • Nonamnestic MCI (naMCI) single domain
  • naMCI multiple domain.

• aMCI indicates memory impairment, while naMCI is used when memory is intact but other cognitive domains are impaired.

• Deficits may be restricted to one cognitive domain (MCI single domain) or involve multiple cognitive aspects (MCI multiple domains).

• The MCI classification system helps understand cognitive deficits and may suggest underlying pathology (e.g., amnestic subtype raising concern for AD).

• Neuropsychological assessment helps differentiate between MCI and dementia using age- and education-appropriate normative data.

• Dementia and MCI must be distinguished from age-related cognitive decline.

• Age-related cognitive decline involves mild decreases in acquiring and retrieving new information, processing speed, cognitive flexibility, attention, and working memory.

• Age-related cognitive decline does not lead to functional impairment.

• Early characterization of cognitive changes is important for early intervention and treatment to preserve functioning.

Pathophysiology and Clinical Presentation of Alzheimer's Disease

• Over 95% of Alzheimer's Disease (AD) cases are idiopathic and occur after age 65 ("late onset").

• In rare cases, AD presents before age 65 ("early onset"), occurring in about 5% of cases.

• Early-onset AD is usually idiopathic, but about 1% of total AD cases (11% of early-onset cases) are associated with a genetic mutation (amyloid precursor protein, presenilin 1, or presenilin 2).

• These genetic cases tend to have an earlier onset, around age 45.

• Apolipoprotein E4 (ApoE4), involved in cholesterol transport, increases the risk of late-onset AD.

• Approximately 25% of people carry one ApoE4 allele, increasing risk 4 times, and 2% to 3% carry two alleles, increasing risk 14 times, compared to the neutral ApoE3/3.

• In AD, cortical atrophy occurs due to extracellular β-amyloid plaques and intracellular tau protein tangles.

• Cortical atrophy initially occurs in the medial temporal lobe (impacting the hippocampus and causing early memory difficulties).

• Cortical atrophy progresses along a temporal–parietal–frontal trajectory.

• Biochemically, there is disruption to the cortical pathways involved in catecholaminergic, serotonergic, and cholinergic transmission.

• AD is commonly divided into three stages: early, middle, and late.

• The initial symptom is typically memory loss for recent events.

• Repetitiveness may be a primary reported concern.

• Other early-stage symptoms include difficulties with word-finding in conversation and planning and organizing activities.

• The middle stage, typically the longest, involves worsening memory, impairments in other cognitive areas (language, executive functioning, visuospatial abilities), withdrawal, mood changes, psychiatric symptoms (paranoia, hallucinations, delusional thinking), disorientation, sleep problems, and trouble dressing or controlling bladder/bowels.

• The final stage involves complete loss of independence, severe cognitive impairment, loss of awareness, motor and communication difficulties, and vulnerability to infections like pneumonia.

• The average disease duration from diagnosis to death is 9 years, but can range from 4 to 20 years.

• Staging helps patients and families plan care and treatment.

Characteristics of Each Stage of Alzheimer's Disease

• Early stage includes memory loss for recent events, word-finding problems, and difficulty planning/organizing.
• Middle stage includes worsening memory, disorientation to place and time, difficulties across other areas of cognition, withdrawal, mood changes, psychiatric symptoms, sleep problems, and trouble dressing or controlling bladder/bowels.
• Late stage includes complete loss of independence, severe cognitive impairment, loss of awareness of surroundings, motor/communication difficulties, and vulnerability to infections like pneumonia.

Vascular Mild Cognitive Impairment/Dementia

• Ischemic and/or hemorrhagic cerebrovascular disease (CVD) is another common cause of MCI and dementia, accounting for about 17% of dementia cases.
• CVD typically occurs with AD pathology in >75% of cases.
• Individuals with hypertension, diabetes, hyperlipidemia, or peripheral vascular occlusive disease are at particular risk for developing vascular cognitive decline.
• Vascular MCI/dementia should be related to a vascular event, and/or there should be enough evidence of CVD on imaging to explain the cognitive impairment.
• Cognitive symptoms typically include difficulties in attention, processing speed, and executive functioning, often described as forgetfulness, confusion, or decreased ability to perform cognitively taxing daily activities.

Dementia With Lewy Bodies (DLB)

• DLB and Parkinson disease dementia (PDD) have been proposed as a spectrum of Lewy body disease and are termed together as Lewy body dementia (LBD).
• LBD is the second leading cause of dementia.
• DLB typically includes fluctuating alertness, visual hallucinations, REM sleep behavioral disorder, and at least one feature of parkinsonism (bradykinesia, resting tremor, or rigidity).
• DLB is diagnosed when dementia occurs before or concurrently with parkinsonism.
• PDD is diagnosed when dementia occurs after well-established PD.
• Patients with DLB show an increased sensitivity to neuroleptics such as haloperidol and may experience neuroleptic malignant syndrome; therefore, neuroleptics should be avoided when treating hallucinations.
• Survival is estimated at approximately 7 years after dementia onset.

Other Dementias

• In addition to AD, DLB, and vascular dementia, there are many other neurodegenerative diseases (FTD, PPA, PCA) and other disease processes (HIV-associated neurocognitive disorder, normal-pressure hydrocephalus) that can present with cognitive symptoms and dementia.
• Concerning behavioral/personality changes prior to age 65 warrant evaluation for FTD or rare variants of AD.
• Early language challenges in older adults could indicate PPA.
• Visuospatial difficulties could indicate PCA or other dementias.

Clinical Assessment of Dementia

• Common presenting symptoms include memory loss, personality changes, language disturbances, and independence challenges.
• A concerned family member or friend typically initiates evaluation.
• It may take months to years for family members to seek medical attention.
• Individuals with dementia may not worry about their condition and often have reduced insight.
• Some individuals may be concerned about self-perceived decline in cognitive functioning in the absence of objective cognitive impairment on neuropsychological assessment.
• These individuals should be monitored, as self-reported cognitive decline increases the risk of MCI and dementia.
• Evaluation includes detailed interviews with the patient and family, a complete physical and neurologic examination, and neuropsychological evaluation.
• A neuropsychologist can inform of the most likely underlying etiology of impairment.
• A thorough medication review is important, including those with anticholinergic properties, as cumulative anticholinergic use is linked to an increased dementia risk.
• All over-the-counter products should be carefully reviewed and documented.
• The physical examination should focus on neurologic signs, blood pressure, and carotid bruits.
• It is important to assess and monitor for changes in cognition, mood, and behavior.
• Brief screening measures may be carried out in the primary care setting to estimate cognitive impairment, mood symptoms, and independence.
• The Katz Index of Independence in Activities of Daily Living can evaluate change in functional status, and the Get Up and Go test can assess change in mobility.
• Cognitive screens such as the Mini Mental State Examination (MMSE), Mini-Cog, Montreal Cognitive Assessment (MoCA), and Memory Impairment Screen (MIS) can provide useful information about cognitive weakness.
• The Geriatric Depression Scale (GDS) and Patient Health Questionnaire-9 (PHQ-9) have shown utility for brief assessment of depression.
• Cognitive screening tools are brief and low-cost, track yearly score change, and provide families with an objective description of disease progression.
• These instruments lack diagnostic precision and are prone to false-positive results.
• Accuracy may be improved by supplementing with informant/caregiver questionnaires or interviews.
• The clinician should determine which individuals would benefit from more extensive neuropsychological assessment, particularly when the cause of MCI/dementia is unclear and the patient is willing to participate in a comprehensive evaluation.

Diagnostics

• The clinician should determine if the patient has a reversible condition that may be contributing to cognitive decline.
• The most important tests include a CBC, TSH, vitamin B12 and folate levels, and a metabolic screen.
• Medications with measurable levels should be measured.
• Current research refines biomarkers for clinical dementia diagnosis.
• Amyloid/tau/fluorodeoxyglucose PET, SPECT, and CSF analysis are available at some memory clinics.
• A referral to a dementia specialty program or neurologist is often required for additional workup.
• A baseline brain imaging study is recommended to identify atrophy patterns, mass lesions, vascular lesions, or infections.
• A non–contrast-enhanced CT scan is generally adequate, but many providers prefer an MRI study for better image resolution.
• PET and SPECT may be useful in difficult-to-diagnose cases.
• Amyloid PET scans are helpful in informing an AD diagnosis, but insurance coverage is not guaranteed.

Initial Diagnostics for Dementia

Laboratory

• Complete blood count (CBC)/differential
• Metabolic screen (Chem 14)
• Thyroid-stimulating hormone (TSH)
• B12 and folate
• Serum drug levels (if indicated)

Imaging

• Computed tomography (CT) or magnetic resonance imaging (MRI)
• Positron emission tomography (PET) (if indicated)
• Single-photon emission computed tomography (SPECT) (if indicated)

Physician Consultation

• Physician consultation is indicated for patients with delirium or rare neurodegenerative diseases.

• Cognitive changes have innumerable causes that cannot always be easily determined.

• Considerations for differentials include delirium and pseudodementia.

• It is important to determine if cognitive status has been evolving over several years or months or appeared more recently and suddenly.

Differential Diagnosis of Dementia

• Wernicke-Korsakoff syndrome or other substance-induced dementia
• Medication, organic toxin, heavy metal intoxication
• Medical illness
  • Liver disease
  • Hypothyroidism
  • Chronic hypoglycemia
  • Adrenal insufficiency
  • Cushing disease
• Vitamin deficiency
  • Thiamine
  • Vitamin B12
  • Folic acid
• Neoplasm and paraneoplastic syndromes
• Trauma, subdural hematoma, hydrocephalus
• Infectious disease
  • HIV-associated neurocognitive disorder (HAND) and dementia (HAD)
  • Viral encephalopathy, herpes simplex virus (HSV) infection
  • Syphilis, Lyme disease, Borrelia infection
  • Toxoplasmosis, cryptococcosis, cytomegalovirus (CMV) infection
• Delirium
• Depression or other mood disorder
• Neurodegenerative diseases
  • Alzheimer disease
  • Posterior cortical atrophy
  • Vascular dementia
  • Frontotemporal dementia (FTD)
  • bvFTD
  • Primary progressive aphasias (PPAs):
    • Nonfluent/agrammatic variant (also called progressive nonfluent aphasia)
    • Semantic dementia (also called temporal variant FTD or semantic variant FTD)
    • Logopenic variant (also called logopenic PPA, logopenia PPA, phonologic variant PPA)
    • Mixed or anomic PPA
  • FTD with motor neuron disease
• Movement disorders
  • Dementia with Lewy bodies
  • Parkinson disease dementia
  • Progressive supranuclear palsy
  • Cortical basal syndrome
  • Multiple system atrophy
  • Huntington disease
  • Creutzfeldt-Jakob disease

Delirium

• Delirium should be considered as a differential when assessing an older adult for possible dementia.
• Delirium represents an acute change in mental status, which develops from a general medical condition, substance intoxication or withdrawal, medications, or multiple etiologies.
• In older adults, delirium is often the first and only indicator of underlying physical illness.
• It is characterized by a disturbance in attention, consciousness, and cognition.
• The hallmark of delirium is a clouding of consciousness, with an inability to focus, sustain, or shift attention, as well as a change in cognition, including impairment in short-term memory, disorientation, and perceptual disturbances.
• Increasing duration of delirium is associated with long-term cognitive impairment.
• Delirium is the leading complication of hospitalization in older adults.
• Delirium affects 60% to 80% of mechanically ventilated patients and 20% to 50% of nonmechanically ventilated patients in intensive care settings.
• Patients with an underlying dementia are at even greater risk of developing delirium in the setting of acute illness, which is known as delirium superimposed on dementia.
• Delirium may manifest with similar symptoms as dementia.
• Delirium is characterized by prominent deficits in attention and awareness of the environment, rapid symptom development, and symptom fluctuation in severity, unlike dementia
• Patients may have periods of lucidity interspersed with inattention, motor restlessness, speech that is difficult to follow, and perceptual disturbances.
• Memory, particularly for recent events, is often impaired.
• Disorientation to place and/or time is frequently present.
• Individuals may also exhibit affective signs of fear, anxiety, or anger.
• There is currently no support for the clinical use of any delirium biomarkers.
• Delirium shares overlapping features with other neurologic and neuropsychiatric conditions.
• Detection relies on data derived from interviews with the patient and a reliable informant, records on preadmission functional status, repeated clinical observation, and cognitive and motor evaluations.
• There is no consensus on how best to conduct a delirium assessment.
• Delirium instruments can be used to assess whether the individual is arousable, screen, diagnose, or rate the severity of delirium, assess specific symptoms, etiology, and characterize distress.
• Given fluctuations in delirium symptoms, a single assessment may be insufficient to detect delirium.
• Dementia screens can inform diagnosis by helping to differentiate signs of delirium from the cognitive impairment of dementia.
• Treatment for delirium is aimed at identification and treatment of the precipitating causes.
• Care is directed toward the management of symptoms.

Pseudodementia

• Pseudodementia is another differential diagnosis to consider.
• Depression can impact cognition, which is referred to as pseudodementia.
• Depression and dementia have overlapping symptoms, as both can manifest with cognitive impairment.
• Cognitive symptoms often persist as residual symptoms in patients for whom depression has remitted.
• Cognitive difficulties that coincide with the onset of a major depressive episode in the context of previously normal cognition may be more likely due to the depression.
• Depression increases risk for dementia in older adults.
• Careful follow up of older adults with depression is important, even after remission.

Interprofessional Collaborative Management

• Management of dementia depends on the stage of disease.
• The goal of management includes treatment of all correctable factors that may impair cognition.
• Activities that promote physical and mental health, cognitive and social engagement, exercise, healthy diet, and good quality sleep are to be encouraged.
• It is important to address safety concerns, including safety behind the wheel.
• Laws regarding mandatory reporting of unsafe drivers vary by state.
• A kitchen safety evaluation alerts caregivers to possible challenges with cooking.
• Other functional hazards in the home include management of medication and finances, potential fall risks, and the need for adaptive equipment.
• Consultation with an attorney is recommended to plan for future legal and health matters.
• Discussion of the patient's preference for resuscitation and use of medical devices should take place while the patient is still able to express their wishes.

Pharmacologic Management

• Three classes of drugs are approved by the FDA to treat the cognitive symptoms of AD: cholinesterase inhibitors, NMDA receptor antagonists, and aducanumab.

• Aducanumab (Aduhelm) is the first FDA-approved disease-modifying therapy for AD and is an intravenous infusion treatment that targets aggregated forms of amyloid β to reduce its buildup.

• The efficacy and clinical utility of Aduhelm remain controversial, and clinical trials are still enrolling participants for continued research.

• Cholinesterase inhibitors prevent the breakdown of acetylcholine and include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne).

• These drugs can be used for the treatment of mild dementia due to AD and beyond.

• Donepezil may also be useful in improving cognitive symptoms in LBD.

• Donepezil has mixed evidence for vascular dementia and is currently not labeled for use; however, it is prescribed given the high co-occurrence of vascular dementia and AD.

• The choice between these medications is based on cost, mode of delivery, and individual patient tolerance.

• Side effects may include nausea, bowel changes, and dizziness.

• Memantine (Namenda) is an NMDA receptor antagonist that regulates glutamate and can be used alone or in combination with a cholinesterase inhibitor for patients with moderate disease and beyond.

• Namzeric is a combined cholinesterase inhibitor and glutamate regulator.

• Although these medications do not alter the course of dementia, they have been shown to delay or slow worsening of symptoms and improve functional status.

• Patients with vascular dementia should continue with treatment and management of risk factors.

• Selective serotonin reuptake inhibitors (SSRIs) are commonly used for the treatment of mood symptoms like depression and anxiety.

• Sertraline and citalopram have been shown to improve neuropsychiatric symptoms such as agitation and are preferred to other SSRIs in this population because of their wide therapeutic range.

• Mirtazapine and trazodone can also be useful when sleep disturbance is present; moreover, mirtazapine increases appetite and is therefore recommended in patients suffering from concerning weight loss.

• The use of antidepressant medications for depression in patients with AD has not been proven to be highly successful.

• Depression in individuals with dementia can often be improved with nonpharmacologic approaches.

• Cognitive-behavioral therapy (CBT) aims to change negative thinking patterns and has shown utility for the treatment of MCI or mild dementia but may also be useful for patients with moderate dementia.

• Determining the etiology of the dementia is important because overall management may differ.

• Mood and behavioral symptoms are often a major reason for institutionalization.

• Identifying reversible causes of these symptoms is crucial.

• Thorough search for reversible causes is necessary before pharmacologic treatment options are considered.

• Family members and other caregivers should be educated about the management of difficult situations.

• Medications can be used for behavior management, but only when nonpharmacologic interventions have failed and there is a need to protect the patient, caregivers, or both.

• Primary care providers should avoid the use of antipsychotics unless patients are at risk of harm to themselves or others; in such cases, referral to psychiatry should be considered.

• Risks and benefits must be discussed with patients and caregivers before using any of these drugs, and they should be used for the shortest duration possible and at the lowest effective dose.

• Benzodiazepines and opioids are both associated with cognitive dysfunction, and long-term benzodiazepine (not opioid) use increases risk of dementia and should be avoided.

• Patients and their families often turn to their primary care provider for advice and counseling regarding the use of over-the-counter preparations such as herbal products, dietary supplements, or medical foods.

Indications for Referral or Hospitalization

• Many patients with dementia are frail older adults with multiple needs.
• Involvement of other disciplines is helpful for patients, families, and providers.
• Physical therapists can optimize function.
• Occupational therapists perform driving evaluations and functional assessments of the living environment.
• Speech therapists may be consulted for dysphagia assessments and can teach compensatory strategies to individuals with language impairment.
• Referrals to neurology and neuropsychology are helpful to differentiate unusual or unclear presentations of dementia.
• Patients with end-stage dementia are eligible for referral to hospice.

Complications

• Dementia has many complications that vary with the stages of illness.
• In the early stages, functional issues and safety risks can occur.
• Middle stage: falls, incontinence, and sleep disturbances.
• Late and final stages: contractures, pressure sores, urinary tract infections, and pneumonia.
• Deconditioning, nutritional deficits, and apraxia are also commonly seen.
• Weight loss becomes inevitable, and death is often the result of infectious complications.

Patient and Family Education and Health Promotion

• The focus of patient education is to maintain independence by emphasizing patients’ strengths, being mindful of safety hazards and normal activities.
• Feeling robbed of self-esteem is a major impediment to function.
• Education for families is essential.
• Behavioral guidance, books, social support, and recognition of the difficult caregiver role will benefit both the patient and caregiver.
• Families need guidance and suggestions regarding appropriate settings and activities for their loved ones.
• Enrollment in programs specifically for people with dementia often accelerates functional decline, which leads to requiring a higher level of care when moving out of the home
• In cases of AD, assisted living offers multiple levels of care and/or specialized memory units.
• Staff members should be specifically trained to handle behavioral problems using nonpharmacologic approaches.
• Families also need to be educated about delirium and possible behavioral changes that may represent underlying medical illness.
• Behavioral changes noticeable only to those who know the patient well may be the only sign of illness.
• Families need to be given resources and information about support groups, financial and legal matters, and how to tell family and friends about the diagnosis.
• Encouraging families to contact the local chapter of the Alzheimer’s Association is an important step.
• The Alzheimer’s Association maintains a 24-hour help line at 800-272-3900.
• Patients and families should be encouraged to explore participation in clinical trials.

This lesson explores Alzheimer's Disease (AD) prevalence, early detection of dementia, and diagnostic categories according to the DSM-5. It also covers the relationship between mild cognitive impairment (MCI) and dementia.