Alzheimer Disease

Author: Joseph S. Kass, MD, JD, FAAN

Definition

Dementia is a syndrome characterized by progressive loss of previously acquired cognitive skills, including memory, language, insight, and judgment. Alzheimer disease (AD) is thought to account for the majority of all cases of dementia.

ICD-10CM CODES
G30.0		Alzheimer disease with early onset
G30.1		Alzheimer disease with late onset
G30.8		Other Alzheimer disease
G30.9		Alzheimer disease, unspecified

Epidemiology & Demographics

Incidence:

Risk doubles every 5 yr after the age of 65. The Chicago Health and Aging Population study found that the average annual incidence in people ages 65 and above was 2.3%, with Blacks having a significantly increased risk compared to Whites.¹

Prevalence:

Approximately 1 in 9 people (10.7%) ages ≥65 has Alzheimer dementia. Currently an estimated 6.5 million Americans have AD; 5% of the population between the ages of 65 and 74, 13.1% between 75 and 84, and 33.2% at ≥85 yr. Between 12% and 18% of Americans over age 60 are thought to have mild cognitive impairment (MCI).²

Predominant Sex:

Females greater than males. In the U.S. 4 million women vs. 2.5 million men are affected (12% of women, 9% of men ≥65).²

Physical Findings & Clinical Presentation

•Spouse or other family member, usually not the patient, notes insidious memory impairment.
•Patients have difficulties learning and retaining new information and handling complex tasks (e.g., balancing the checkbook) and have impairments in reasoning, judgment, spatial ability, and orientation (e.g., difficulty driving, getting lost away from home).
•Behavioral changes, such as mood changes and apathy, may accompany memory impairment. In later stages, patients may develop agitation and psychosis.
•Rare variants: Three rare variants are described and are discussed later:
1. 1.Posterior cortical atrophy
2. 2.Dysexecutive variant
3. 3.Logopenic progressive aphasia

Diagnosis of AD has evolved with the development of biomarkers that indicate AD pathology in vivo such as brain amyloidosis and pathologic tau accumulation. The National Institute on Aging (NIA) and the Alzheimer Association (AA) recommended new diagnostic criteria and guidelines for AD in 2011, and these criteria were further revised in 2018 (Table 1). The NIA-AA criteria differed from prior DSM or NINDCS-ADRDA criteria in the following ways: (1) They recommend AD be considered a disease well before the onset of symptoms by incorporating biomarkers in diagnosis, and (2) they define three distinct stages of AD: (1) Preclinical AD, in which there is measurable biologic evidence of AD pathology but no symptoms; (2) MCI due to AD, in which the patient experiences mild memory loss but experiences no functional impairment at home or work but demonstrates biomarker evidence of AD; and (3) dementia due to AD, in which the patient experiences cognitive decline causing functional impairment and demonstrates biomarker evidence of AD. The 2018 NIA-AA criteria define AD not as three clinical syndromes but as a biologic process defined by biomarkers indicating the presence of beta amyloid (A+), pathologic tau (T+), and neurodegeneration or neuronal injury (N+). Using the ATN system and clinical status together allows an entire study population to be characterized (Fig. 1).

TABLE 1 New Diagnostic Criteria

RESEARCH CRITERIA
Criteria for Probable Alzheimer Disease	DSM-5 2013	NINCDS-ADRDA 2007	NIA-AA 2018
Insidious onset	X	X	X
Onset over months to years		X	X
Progressive decline	X	X	X
Deficits are not explained by delirium or other medical or psychiatric conditions	X	X	X
Social/occupational impairment	X		X
Presence of episodic memory deficit	X	X
Cognitive deficits in at least two domains	X		X
Neuropsychologic testing required for diagnosis?	Preferably	X	Only if routine history and mental status testing are inconclusive
Abnormal PET or MRI scan		Supportive feature *	Required if needed to show biomarker evidence of amyloidosis, tauopathy, neurodegeneration as part of the biomarker-based AT(N) diagnostic schema
Genetic markers?	X	Supportive feature *	For research purposes
Genetic markers?	Required only if there is evidence of multiple causes and no clear evidence of progression and decline in memory and another cognitive domain	Supportive feature *	For research purposes
Abnormal cerebrospinal fluid marker required?		Supportive feature *	Required if needed to show biomarker evidence of amyloidosis, tauopathy, neurodegeneration as part of the biomarker-based AT(N) diagnostic schema

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, fifth edition; MRI, magnetic resonance imaging; NIA-AA, National Institute on Aging-Alzheimer’s Association; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association; PET, positron emission tomography.

^*At least one supportive feature is required for diagnosis of probable Alzheimer disease.

Modified from Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

Figure 1 Descriptive nomenclature: Syndromal cognitive staging combined with biomarkers.

AD, Alzheimer disease; MCI, mild cognitive impairment. NOTE: Formatting denotes three general biomarker "categories" based on biomarker profiles: Those with normal AD biomarkers (no color), those with non-AD pathologic change (dark gray), and those who are in the Alzheimer continuum (light gray).

(From Clifford RJ Jr et al: NIA-AA research framework: toward a biological definition of Alzheimer’s disease, Alzheimer Dement 14:535-562, 2018.)

Biomarkers have not been commonly used in the clinic but have invariably been used in AD clinical trials. However, with the advent of monoclonal antibodies targeting beta amyloid, biomarker-based diagnosis-especially in patients with early-stage disease who may be eligible for new, disease modifying treatment-is becoming an important part of the diagnostic process. Biomarkers transform the diagnosis of AD into one that can be established definitively while the patient is still alive. In clinical practice, the diagnosis has been commonly made based on clinical history, a thorough physical and neurologic examination, and use of reliable and valid diagnostic criteria (i.e., DSM or NINDCS-ADRDA) such as the following:

•Loss of memory and one or more additional cognitive abilities (aphasia, apraxia, agnosia, or other disturbance in executive functioning)
•Impairment in social or occupational functioning that represents a decline from a previous level of functioning and results in significant disability
•Deficits that do not occur exclusively during the course of delirium
•Insidious onset and gradual progression of symptoms
•Cognitive loss documented by neuropsychologic tests
•No physical signs, neuroimaging, or laboratory evidence of other diseases that can cause dementia (i.e., metabolic abnormalities, medication or toxin effects, infection, stroke, Parkinson disease, subdural hematoma, or tumors)

Red flags for an AD diagnosis are summarized in Box 1.

BOX 1 Red Flags for an Alzheimer Disease Diagnosis

•Age <65yr
•Fluctuating level of consciousness (consider toxic-metabolic encephalopathy, dementia with Lewy bodies)
•Behavioral, emotional, or personality disturbances overshadowing cognitive impairment (consider frontotemporal dementia, HIV dementia)
•Rapidly (6-12 mo) progressive development (consider Creutzfeldt-Jakob disease, paraneoplastic limbic encephalitis, autoimmune encephalitis, HIV dementia, frontotemporal dementia)
•Presence of physical abnormalities:
1. 1.Gait impairment (consider vascular dementia, HIV dementia, NPH, chronic subdural hematomas, Parkinson disease and atypical Parkinsonian disorders)
2. 2.Lateralized signs, e.g., hemiparesis, spasticity, other corticospinal tract signs (consider vascular dementia)
3. 3.Movement disorders
4. 4.Myoclonus (consider Creutzfeldt-Jakob disease, paraneoplastic encephalitis)
5. 5.Rigidity, bradykinesia (parkinsonism) (consider dementia with Lewy bodies and Parkinson disease)

Modified from Kaufman DM et al: Kaufman’s clinical neurology for psychiatrists, ed 9, Philadelphia, 2023, Elsevier.

Differential Diagnosis (Table 2

•Other neurodegenerative dementia (Table 3):
1. 1.Primary age-related tauopathy
2. 2.Limbic predominant age-related TDP-43 encephalopathy (LATE)
3. 3.Argyrophilic grain disease
4. 4.Frontotemporal lobar degeneration
5. 5.Dementia with Lewy bodies
6. 6.Parkinson disease dementia
7. 7.Corticobasal syndrome
8. 8.Progressive supranuclear palsy
•Vascular cognitive impairment disorder (vascular dementia due to multiple strokes, severe small vessel changes, chronic vasculitis, or chronic subdural hematoma)
•Subjective memory loss
•Depression (pseudodementia) (Table 4)
•Neoplasm (benign or malignant brain tumor, leptomeningeal disease)
•Infection (HIV-associated dementia, neurosyphilis, progressive multifocal leukoencephalopathy [PML])
•Toxic/metabolic (EtOH, myxedema coma, subacute combined degeneration, pellagra, mercury exposure, drug effects)
•Organ failure (hepatic encephalopathy)

TABLE 2 Cognitive Disorders in Older Adults

Diagnosis (% of Dementias Attributable)	History	Physical Examination Findings	Imaging Findings	Comment
Normal aging changes (n/a)	Delayed retrieval (forgetting names, dates), slower processing (takes longer to learn new things). No functional limitations	None	Mild generalized cortical atrophy, mild ventricular enlargement. No focal findings	Patients may have white matter disease and/or prior lacunar infarcts related to HTN, DM, and cardiovascular disease, etc., but unrelated to memory complaints
Mild cognitive impairment (n/a)	Cognitive deficits beyond what is expected for age across one or more domains	None	Variable depending on etiology. Atrophy of medial temporal lobe and/or hippocampus (pre-Alzheimer disease)	Clinical course highly dependent on etiology. Amnestic MCI most likely to progress to dementia (50%) Neuropsychologic testing may help to clarify diagnosis
Alzheimer disease (67%)	Progressive memory loss and other cognitive deficits	Essentially normal in early stages Moderate: Patients may develop apraxia, aphasia	Medial temporal, parietal lobe, and/or hippocampal atrophy on MRI. Positivity on amyloid PET scan	Patients will occasionally present with unusual variants based on atypical neuroanatomic pathology; for example, fixed delusions or behavioral manifestations (dysexecutive variant) or prominent visual symptoms (posterior cortical atrophy)
Vascular dementia (20%, includes mixed dementia)	Prominent vascular risk factors, possible history of stroke/TIA, possible stepwise disease progression. Executive dysfunction may be prominent early symptom	Variable depending on distribution of disease	Cortical and subcortical infarcts and white matter disease	Commonly present in conjunction with Alzheimer disease-known as mixed dementia
Lewy body dementia and Parkinson dementia (15%)	Fluctuating cognition, well-formed visual hallucinations, REM sleep disorder, falls, sensitivity to neuroleptics	Orthostatic hypotension, postural instability, hyposmia, bradykinesia, resting tremor, rigidity	No specific findings on MRI. Positivity on dopamine transporter PET scan	Parkinson dementia occurs in patients with preexisting Parkinson disease of at least 1-yr duration, followed by onset of cognitive deficits
Frontotemporal dementia (<5%)	Two variants: Behavioral variant (50%) presents with progressive personality and behavioral changes Primary progressive aphasia presents with progressive language impairment	Frontal release signs	Frontal and temporal lobe atrophy	Executive function and episodic memory generally preserved in early stages of disease
Chronic traumatic encephalopathy (CTE, unknown)	History of multiple concussions and/or traumatic brain injury, most commonly in former athletes or military personnel. Concurrent behavioral changes and psychiatric disease common	None	Nonspecific white matter changes	Tauopathy in cortical and perivascular regions of the brain. CTE can only definitely be diagnosed by autopsy; there is currently no definitive clinical criteria for diagnosis
Rapidly progressive dementia (<1%)	Memory symptoms progressive over weeks to months	Variable depending on etiology Myoclonus/startle reflex suggestive of prion disease	Variable depending on etiology	Rapidly progressive dementias are rare and merit urgent referral to a neurologist Specialized testing should be based on patient-specific risk factors
Delirium (n/a)	Identifiable toxic, metabolic, or infectious etiology and/or precipitants (e.g., acute hospital admission). Rapid onset	Inattention, disorganized thinking, and/or altered level of consciousness. Fluctuating course	No specific findings	EEG will demonstrate acute slowing Generally reversible with correction of precipitant(s)

DM, Diabetes mellitus; EEG, electroencephalogram; HTN, hypertension; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; PET, positron emission tomography; REM, rapid eye movement; TIA, transient ischemic attack.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

TABLE 3 Features Distinguishing Alzheimer Disease and Frontotemporal Dementia

Feature	Alzheimer Disease	Frontotemporal Dementia
Age at onset (yr)	>65	53 (mean)
Memory impairments	Early, pronounced	Subtle, at least initially, with preserved visuospatial ability
Behavior abnormalities	None until middle or late stage	Early and prominent perseverative and compulsive behavior; hyperorality; impaired executive ability
Language impairment	Except for anomia, none until late stage	Paraphasias, anomia, decreased fluency
CT/MRI appearance	General atrophy, but especially parietal and temporal lobes	Frontal and temporal lobe atrophy
Histologic marker	Aβ accumulation	Tau accumulation

CT, Computed tomography; MRI, magnetic resonance imaging.

From Kaufman DM et al: Kaufman’s clinical neurology for psychiatrists, ed 9, Philadelphia, 2023, Elsevier.

TABLE 4 Clinical Features of Delirium, Depression, and Alzheimer Disease

	Delirium	Depression	Alzheimer’s Disease
Onset of initial symptoms	Abrupt	Relatively discrete	Insidious
Onset of initial symptoms	Difficulty with attention and disturbed consciousness	Dysphoric mood or lack of pleasure	Memory deficits-verbal and/or spatial
Course	Fluctuating-over days to weeks	Persistent-usually lasting months if untreated	Gradually progressive, over years
Family history	Not contributory	May be positive for depression	May be positive for AD
Memory	Poor registration	Patchy/inconsistent	Recent > remote
Memory complaints	Absent	Present	Variable-usually absent
Language deficits	Dysgraphia	Increased speech latency	Confrontation naming difficulties
Affect	Labile	Depressed/irritable	Variable-may be neutral

From Stern TA: Massachusetts General Hospital handbook of general hospital psychiatry, ed 8, Philadelphia, 2025, Elsevier.

Workup

History & General Physical Examination:

•Medication lists should always be reviewed for drugs or home remedies that may cause mental status changes, especially anticholinergic medications, benzodiazepines, opiates, barbiturates, and neuroleptics.
•Patients should be screened for depression, because it can sometimes mimic dementia but often occurs as a coexisting condition and should be treated.
•On examination, look for signs of metabolic disturbance, presence of psychiatric features, or focal neurologic deficits.
•Symptoms and preserved abilities of Alzheimer dementia by disease stage are summarized in Table 5.

TABLE 5 Symptoms and Preserved Abilities by Cognitive Domain Across Various Stages of Alzheimer Dementia

	Mild	Moderate	Severe
Memory
Symptoms	•Loss of short-term memory; may recall some aspects of important events •May lose enjoyment in reading because of difficulty following a story line	•Forgets entire events have occurred, some long-term memories remain •Repetitive questioning may become troublesome for caregivers	•Complete loss of short-term memory •May not recognize familiar individuals •Long-term memories fade
Preserved abilities	•May benefit from simple reminders, routines, and habits •May still derive enjoyment from reminiscing	•May still enjoy reminiscing with the assistance of visual or verbal stimulation	•Implicit memory may still be preserved •Familiar environments and persons may be comforting
Executive Function
Symptoms	•Difficulty acting on desired goals, resulting in irritation •Judgment may be poor •Social graces may suffer •May demonstrate anhedonia or apathy	•Problem-solving ability very limited •Angry outbursts •Impulsive •Difficulty in new situations •Requires reminders or physical support to complete ADLs	•Requires assistance with all ADLs •Cannot independently set goals or act upon them •Gradual loss of motor abilities, including dysphagia
Preserved abilities	•Decision-making capacity is likely to be intact •Comprehension may increase if information presentation is adapted	•Capacity for simple, every-day decision making may be preserved, even if capacity for complex decision making is lost
Language and Communication
Symptoms	•Some word-finding difficulties	•More pronounced difficulty understanding written or spoken language •Difficulty making needs known	•Gradual loss of speech
Preserved abilities	•Can engage in conversations, but may require environmental supports, such as those recommended by speech and language pathologists		•Ability to communicate needs nonverbally through emotional expression or other cues (e.g., grimacing to indicate pain)
Sensory/Perceptual
Symptoms	•Difficulty with interpreting complex visual figures or displays	•May develop hallucinations or delusions	•May react poorly to noxious stimulation from the environment
Preserved abilities	•Ability to follow and enjoy simplified visual displays		•May enjoy individually enhanced sensory environments •Tactile stimulation may be preferable to auditory or visual
	•May respond positively to interventions, such as personalized music

ADLs, Activities of daily living.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

Mental Status Testing:

Brief mental status testing can be done easily and quickly in the office. Formal neuropsychologic testing offers more nuanced data about a patient’s current cognitive and emotional function but is not required for straightforward cases. Formal neuropsychologic testing is indicated when patients present with atypical symptoms, have significant psychiatric comorbidities, and when patients’ or families’ report of cognitive dysfunction differs from findings on a bedside cognitive assessment. Also, neuropsychologic testing may be beneficial if there are concerns that in the future, the patient’s testamentary capacity will be challenged.

Commonly used cognitive tests to detect dementia include the Folstein Mini-Mental State Examination (MMSE), the Mini-Cog test, and the Montreal Cognitive Assessment. A newer self-administered gerocognitive examination (SAGE) that patients complete by themselves, usually in 15 minutes, is now available and consists of a validated 11-item instrument that compares favorably with MMSE and has the advantage of self-administration at home.³ A meta-analysis examining the performance of commonly used screening tests for dementia identified 11 commonly used tests, with the MMSE having the most data. The combined sensitivity and specificity for detecting dementia were 0.81 and 0.89, respectively, for the MMSE and 0.91 and 0.86, respectively, for the Mini-Cog. Subgroup analysis revealed that only the Montreal Cognitive Assessment had comparable performance to the MMSE for detecting MCI with 0.89 sensitivity and 0.75 specificity.

The Mini-Cog (https://mini-cog.com/) is a 3-min instrument consisting of a 3-item recall test for memory and a simply scored clock drawing test. The Montreal Cognitive Assessment (MoCA, www.mocatest.org/) is a 30-point test that takes approximately 10 min to administer and includes tests of visuospatial function, attention, verbal recall, language, abstraction, and orientation. A score of 25 points or less (26 points if the patient has <12 yr of education) indicates cognitive impairment. The test is available in >35 languages, and multiple forms in English allow for repeated assessments over time. A summary of commonly used tests may be found in Table E6.

TABLE E6 Commonly Used Neuropsychologic Tests

Domains to Be Assessed		Tests Used With Age-Corrected and/or Education Norms for Adults Older Than 65 Yr
Premorbid ability		•North American Reading Test (NART) •Vocabulary (WAIS-IV)
Verbal memory		•Rey Auditory Verbal Learning Test (RAVLT) •California Verbal Learning Test (CVLT) •Logical Memory Test (from WMS-IV) •CERAD Word List Test
Visual memory		•Visual Reproduction (from WMS-IV) •Rey Complex Figure Drawing Test (RCFT)
Simple attention		•Digit Span (from WAIS-IV) •Trail-Making Part A
Language		•Animal Naming Test (ANT) •Controlled Oral Word Association Test (COWAT) •Boston Naming Test (BNT)
Executive function		•Trail-Making Part B •Wisconsin Card Sort Test (WCST) •Stroop •Similarities (from WAIS-IV)
Visuospatial		•Coding (from WAIS-IV) •Rey Complex Figure Test (RCFT) •Clock Drawing Test
Motor		•Grooved Pegboard Test •Finger Tapping Test
Mood		•Geriatric Depression Scale (GDS) •Hamilton Depression Rating Scale (HDRS) •Beck Anxiety Inventory (BAI)

WAIS-IV, Wechsler Adult Intelligence Scale, fourth edition; WMS-IV, Wechsler Memory Scale, fourth edition.

From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

Mental status testing should include tests that assess the following cognitive functions:

•Orientation: Ask the patient to give the day, date, month, year, and place and to name the current president.
•Attention: Ask the patient to recite the months of the year forward and in reverse.
•Verbal recall: Ask the patient to remember three items; test for recall after a 1- and 5-min delay.
•Language: Ask the patient to write and then read a sentence; have the patient name both common and less common objects.
•Visuospatial: Ask the patient to draw a clock and to set the hands of the clock at 11:10.

Patients with AD typically have trouble with verbal recall in addition to experiencing visuospatial or language deficits. Attention is usually preserved until the later stages of AD, so consider alternative diagnoses in patients who perform poorly on tests of attention early in their disease. A summary of the pattern of cognitive deficits associated with different dementias and depression may be found in Table 7.

TABLE 7 Patterns of Cognitive Impairment by Domain and Dementia

Episodic Memory	Attention	Language	Executive	Visuospatial	Behavioral Symptoms
Alzheimer disease	(I)	Simple (P) Divided (I)	Phonemic (P) Semantic (I) Naming (I)	(I)	Simple (P) Complex (I)	Early apathy, late psychotic symptoms
Mild cognitive impairment-amnestic	Immediate and Delayed recall (I) Recognition (I)	Simple (P) Divided (P)	(P)	(P)	(P)	(P)
Vascular dementia	Immediate and Delayed recall (V) Recognition (P)	Simple (P) Divided (I)	(I)	(I)	(P)	Depression
Behavioral variant FTLD	(V)	Simple (P) Divided (I)	(I)	(I)	(P)	Disinhibition, apathy, hyperorality, inappropriate social interaction
Semantic variant PPA	(P)	(P)	(I) Comprehension (I) Fluency	(P)	(P)(I) Visual agnosia	(P)
Nonfluent variant PPA	(P)	(P)	(I) Fluency (P) Comprehension, (I) Expressive speech	(P)	(P)	(P)
Parkinson disease dementia	(V) Immediate and Delayed recall (P) Recognition	(I)	(P)	(I)	(I)	Depression, possible hallucinations, psychomotor slowing
Dementia with Lewy bodies	(V) Immediate and Delayed recall (P) Recognition	(V)	(V)	(I)	(I)	Hallucinations, delusions
Depression	(V) Immediate and Delayed recall (P) Recognition	(V)	(V) Fluency (P) Naming	I/V	(P)	Psychomotor slowing, apathy

FTLD, Frontotemporal lobar degeneration; I, impaired; P, preserved; PPA, primary progressive aphasia; V, variable.

From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

In addition to the common amnestic presentation, AD rarely presents as one of three rare nonamnestic syndromes that affect memory later in the course of the disease. These three rare presentations should also raise suspicion of another dementia type. A primary language variant presents as either logopenic expressive aphasia or progressive nonfluent aphasia and may be either a form of AD or of frontotemporal lobar degeneration. A primary visuospatial variant called posterior cortical atrophy presents with disturbances in complex visual processing and may be a form of either AD or dementia with Lewy bodies. An executive/behavioral variant presents with impaired executive function and/or behavior derangement and may represent either a frontal variant of AD or behavioral variant frontotemporal dementia.

Laboratory Tests (Table 8

•CBC
•Serum electrolytes
•Glucose
•Blood urea nitrogen/creatinine
•Liver and thyroid function tests
•Serum vitamin B₁₂
•Syphilis serology (rapid plasma reagin [RPR]), if supported by clinical history
•HIV screening as appropriate
•Lumbar puncture if history or signs of cancer, infectious process, or unusual clinical presentation (e.g., rapid progression of symptoms)
•Electroencephalogram (EEG) if there is history of seizures, episodic confusion, rapid clinical decline, or suspicion of Creutzfeldt-Jakob disease
•Cerebrospinal fluid (CSF) analysis can also be used to determine the presence of Alzheimer disease pathology in the brain by measuring CSF total tau (t-tau) (a general marker of neurodegeneration), phosphorylated tau (p-tau), and β-amyloid 42 levels. In Alzheimer disease, CSF t-tau and p-tau levels are elevated but β-amyloid is reduced.
•Serum biomarkers of Alzheimer disease such as p-tau181 and p-tau217 may become readily available in the coming years as biomarker evidence of Alzheimer disease without the need for CSF analysis or PET scans.
•The Centers for Medicare & Medicaid Services (CMS) pays for brain fluorodeoxyglucose (FDG)-PET to distinguish Alzheimer disease and frontotemporal dementia.
•Brain biopsy is usually reserved for diagnoses such as cerebral vasculitis. Generally performed postmortem. Neuropathologic lesions of AD are known as neurofibrillary tangles (NFTs) and neuritic plaques (NPs) (Fig. E2).

TABLE 8 Laboratory Evaluation of Patients With Dementia

Type of Study		Examples
Basic studies, excluding reversible with specific indication from history for causes of dementia or examination		•Complete blood count (CBC) •Chemistry or metabolic panel (SM-17) •Thyroid function tests (thyroid-stimulating hormone [TSH]) •Vitamin B₁₂, folate levels •Computed tomography (CT) or magnetic resonance imaging (MRI) •HIV testing •Sedimentation rate •Hemoglobin A1C (HbA1C) •Urinalysis •Chest x-ray •Urine or plasma for drugs or heavy metals
Adjuvant Studies to Aid Diagnosis
Other tests as indicated by history or physical or neurologic examination		•Single-photon emission computed tomography (SPECT) •Positron emission tomography (PET) •Lumbar puncture with cerebrospinal fluid for β-amyloid

From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

Figure E2 Plaques and tangles in Alzheimer disease.

Asterisks indicate neurofibrillary tangles. NP, Neuritic plaque.

(From Stern TA et al: Massachusetts General Hospital comprehensive clinical psychiatry, ed 3, Philadelphia, 2025, Elsevier.)

Imaging Studies

•MRI (Fig. E3) to rule out hydrocephalus, cerebrovascular disease, and mass lesions, including subdural hematoma and to look for typical patterns of neurodegeneration (i.e., regional brain atrophy) such as hippocampal atrophy. CT can be used if MRI is contraindicated.
•Amyloid PET: The FDA has approved several agents for beta-amyloid PET imaging, including florbetapir, flutemetamol, and florbetaben. As with these other imaging agents, a positive amyloid scan does not establish a diagnosis of AD or any other cognitive disorder, but a negative scan indicating sparse to no amyloid plaques is inconsistent with a neuropathologic diagnosis of AD. A positive amyloid scan indicates the presence of moderate to frequent amyloid neuritic plaques; neuropathologic examination has shown this amount of amyloid plaque is present in AD patients but may also be present in individuals with other types of neurologic conditions as well as in cognitively normal older adults. CMS now pays for amyloid PET testing since the presence of brain amyloidosis is a prerequisite for anti-amyloid monoclonal antibody treatment for Alzheimer disease.
•Tau PET: The FDA has approved one agent for tau imaging: Flortaucipir. Flortaucipir is used to estimate the density and distribution of aggregated tau neurofibrillary tangles in adult patients with cognitive impairment under evaluation for AD. It is not indicated for use in patients undergoing evaluation for chronic traumatic encephalopathy, which is also a tauopathy.

Figure E3 Longitudinal Coronal T1 Magnetic Resonance Imaging in a Patient that Progressed from Normal Cognition to Amnestic Mild Cognitive Impairment (Amci) to Dementia Due to Alzheimer Disease (AD)

Note Progressive Hippocampal and Cortical Atrophy. Top Image: Normal Cognition Age 75. Bottom Left Image: Amci Age 81. Bottom Right Image: Dementia Due to AD Age 86.

(From Jankovic J et al: Bradley and Daroff’s neurology in clinical practice, ed 8, Philadelphia, 2022, Elsevier.)

Nonpharmacologic Therapy

•Patient safety, including risks associated with impaired driving, wandering behavior, leaving stoves unattended, and accidents, must be addressed with the patient and family early and appropriate measures implemented.
•Wandering, hoarding, or hiding objects, repetitive questioning, withdrawal, and social inappropriateness often respond to behavioral therapies.
•Cognitive stimulation programs are beneficial for maintenance of cognitive function and improved self-reported quality of life in patients with mild to moderate AD.
•Person-centered care approach applied to care of people living with dementia is summarized in Table 9.

TABLE 9 Person-Centered Care Approach Applied to Care of People Living With Dementia

Key Component	Early Stage	Middle Stage	Late Stage
Develop a personalized, goal-oriented care plan, based on a thorough medical, functional, and social assessment	•Conduct a functional assessment, including sensory status, language abilities •Establish stage-appropriate, personally meaningful goals
	•Encourage advance care planning, including naming a surrogate decision maker		•Engage with family members and surrogate decision makers to interpret patient’s nonverbal communication
	•Discuss advantages and disadvantages of pharmacotherapy to help with cognitive or behavioral symptoms and monitor regularly for side effects		•If on ChE-I, consider discontinuation
Periodically review the person’s goals and care plan to assess ongoing effectiveness and to address evolving goals	•Refer to community resources to promote the person’s ongoing connection with and engagement in personally meaningful activities •Assess and address caregiver stress
	•Consider referral to senior centers or adult day programs to promote social engagement •In-home care services may be helpful		•Personalized music programs may be helpful •Hospice consultation may be indicated
Engage an interprofessional team that adapts its composition in response to the needs of the person living with dementia	•Care managers to refer to resources in community	•Care managers: Assist with symptom management, respite services	•Care managers: Assistance managing symptoms, referral for respite services
	•SLP referral to teach caregivers supported communication approaches	•SLP consultation for assistance with supported communication approaches and feeding techniques	•Palliative care or hospice consultation for symptom management and end-of-life care
	•PT/OT: In-home safety evaluation and customization of activities	•OT consultation to maximize functional independence	•OT sensory stimulation approaches to promote wellbeing
	•Pharmacy to assist with deprescribing and simplification of medication regimen •Specialty referrals (psychiatry, dementia care clinics) for management of BPSD
A specified team leader to facilitate information transfer, care coordination, and continuity	•Primary care provider or specialty-trained care manager, such as nurse specialist or social worker	•Primary care provider or specialty-trained care manager	•Primary care provider or hospice team

BPSD, Behavioral and psychologic symptoms of dementia; CHe-I, acetylcholinesterase inhibitors; OT, occupational therapy; PT, physical therapy; SLP, speech language pathology.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

Acute General Rx

None

Chronic Rx

•Symptomatic treatment of memory disturbance (Table 10):
1. 1.Cholinesterase inhibitors (ChEIs [Table 11]): Donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon)
  1. a.FDA approved for the treatment of mild to moderate AD with the exception of donepezil, which is approved for mild, moderate, and severe dementia. Common side effects include vivid dreams, bradycardia, and GI side effects (nausea, diarrhea, and anorexia). GI side effects may be bothersome enough to require either a slower escalation of dosage or switching to another agent. The rivastigmine patch has lower rates of GI side effects than the oral agents. Table 12 summarizes some instruments used to monitor clinical response of AD to pharmacologic therapy.
2. 2.NMDA receptor antagonist: Memantine (Namenda)
  1. a.FDA approved for the treatment of moderate to severe AD. Common side effects include constipation, dizziness, or headache. Memantine is contraindicated in patients with renal insufficiency or history of seizures.
3. 3.Anti-amyloid monoclonal antibodies:
  1. a.Lecanemab and donanemab are both anti-amyloid monoclonal antibody treatments approved by the FDA for the treatment of mild cognitive impairment and mild dementia due to Alzheimer disease. Lecanemab is a humanized IgG1 monoclonal antibody that binds to Aβ soluble protofibrils. Donanemab is a humanized IgG1 monoclonal antibody that binds to the N-terminal pyroglutamate Aβ epitope that exists only in established β-amyloid plaques.⁴ Both lecanemab and donanemab result in moderately less decline on measures of cognition and function compared with placebo.⁵^,⁶
  2. b.Anti-amyloid monoclonal antibodies can result in a potentially serious side effect called amyloid related imaging abnormalities (ARIA). ARIA can take two forms, ARIA-E (edema) and ARIA-H (hemosiderin deposition).
4. 4.ARIA-E is diagnosed when the MRI demonstrates focal cerebral vasogenic edema or sulcal effusions.
5. 5.ARIA-H is diagnosed with the development of microhemorrhage and/or superficial siderosis.
6. 6.ARIA may be mild, moderate, or severe. Even severe ARIA may be asymptomatic.
7. 7.Prescribing anti-amyloid monoclonal antibodies requires demonstrating the presence of amyloidosis using either CFS or amyloid PET. A baseline MRI is also required. ARIA usually occurs early in administration, and an MRI monitoring protocol must be used with this class of medication. Given the complexity of this medication and the restrictions surrounding Medicare reimbursement for these medications, patients should be referred to special centers with established protocols for the safe administration and monitoring of this medication.
•Symptomatic treatment of neuropsychiatric and behavioral disturbances (Table 13).
1. 1.Depression, agitation, delusions, or hallucinations may respond to medications. Brexpiprazole, a second generation antipsychotic drug, was recently FDA approved for once daily treatment of agitation associated with dementia due to AD. It provides modest improvements in agitation symptoms but can cause serious adverse effects. It has not been compared with older second generation antipsychotic drugs that are available generically and have been used off label for many years (Table 13). Nonpharmacologic treatments should always be tried first.
•A recent review and meta-analysis of cholinesterase inhibitors, memantine, and supplements determined that cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences vs. placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of behavioral and psychologic symptoms of dementia and on supplements for all outcomes.

TABLE 12 Instruments Used to Monitor Clinical Response of Alzheimer Disease (AD) to Pharmacologic Therapy

Mini-Mental State Examination
•Global measure of cognition widely used by physicians and third-party caregivers •Assesses orientation, registration, recall, language, and attention •Uses a 30-point scale •Requires ≈5-10 min to complete •Sensitivity, 80%-90%; specificity, 80% •Administered by psychometricians, nurses, and physicians •AD typically advances by 3 points/yr
Clock Drawing
•Global measure of cognition widely used by physicians •Multiple scoring systems with proven validity; sensitivity, 59%; specificity, 90% •Assesses multiple cognitive domains in a single test •1-2 min to complete •Minimal training to administer
Geriatric Depression Scale
•Evaluates depressive symptoms in patients •Requires 5 min to complete •Very useful in assessing depression in new patients and in follow-up •Minimal training to administer •Ease of administration has led to rapid spread in its use

From Fillit HM: Brocklehurst’s textbook of geriatric medicine and gerontology, ed 8, Philadelphia, 2017, Elsevier.

TABLE 11 Acetylcholinesterase Inhibitor Dosing

Drug	Initial Dose	Recommended Dose	Minimum Therapeutic Dose	Formulations
Donepezil	5 mg daily	10 mg daily	5 mg daily	5, 10, 23 mg
Galantamine IR	4 mg bid	12 mg bid	8 mg bid	4, 8, 12 mg
Galantamine ER	8 mg daily	24 mg daily	16 mg daily	8, 12, 24 mg
Rivastigmine	1.5 mg bid	6 mg bid	3 mg bid	1.5, 3, 4.5, 6 mg
Rivastigmine patch	4.6 mg daily	9.5 mg daily	9.5 mg daily	4.6, 9.5, 13.3 mg

bid, Twice daily.

Acetylcholinesterase inhibitor dosing and suggested titration intervals. From US Department of Veterans Affairs. Pharmacy Benefits Management Services. 2018 [cited October 15, 2019]. Available at: http://www.pbm.va.gov/. Note that medication doses can be increased every 4 wk as patient tolerates.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

TABLE 10 Symptomatic Treatment of Memory Disturbance

	Initial Dose	Target Dose
Donepezil	5 mg qd for 4-6 wk	10 mg qd
Rivastigmine	1.5 mg bid with food, increase by 1.5 mg bid weekly	3-6 mg bid
Galantamine	4 mg bid with food, increase by 4 mg bid every 4 wk	8-12 mg bid
Memantine	5 mg qd, increase by 5 mg weekly	10 mg bid

bid, Twice daily; qd, once daily.

TABLE 13 Treatment of Behavioral and Neuropsychiatric Symptoms

	Initial Dose	Maximum Dose
Atypical Antipsychotics
Olanzapine	2.5 mg qd to bid, may increase by 2.5 mg as needed	7.5 mg bid
Quetiapine	25 mg bid, may increase by 25 mg every 2 days	250 mg tid
Antidepressants
Sertraline	25-50 mg qd, may increase by 25 mg every wk	200 mg qd
Escitalopram	10 mg qd, may increase after 1 wk to 20 mg qd	10 mg qd

bid, Twice daily; qd, once a day.

Disposition & Referral

•Patients with complex or atypical presentations or challenging management issues should be referred to a neurologist, geriatric psychiatrist, or geriatrician with expertise in dementia.
•Patients early in the disease process who may be eligible for anti-amyloid monoclonal antibodies should be referred to a center with experience with these new drugs.
•Approximately one in eight hospitalized patients with AD who develop delirium will have at least one adverse outcome (e.g., institutionalization, cognitive decline, death) associated with delirium.
•Family education and support may help reduce need for skilled nursing facility and reduce caregiver stress, depression, and burnout.

The physician should make a thorough search for the treatable causes of dementia. Current American Academy of Neurology practice parameters recommend:

•Treat cognitive symptoms of AD with ChEIs.
•Treat depression.
•Treat agitation and psychosis using nonpharmacologic interventions first and use pharmacologic interventions at the lowest possible dose if other interventions have failed.
•Encourage caregivers to participate in educational programs and support groups.

In addition, refer patients with MCI or early AD to centers with experience with the new anti-amyloid monoclonal antibodies.

Comments

•Ginkgo biloba is marketed widely as effective in delaying cognitive impairment; however, trials have shown that it is not effective in reducing the incidence of Alzheimer dementia or dementia overall.
•Higher midlife fitness levels seem to be associated with lower hazards of developing all-cause dementia later in life independent of cerebrovascular disease. Exercise also may slow the rate of functional deterioration in mild AD.
•Even moderate adherence to the MIND (the Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, a hybrid of the Mediterranean and DASH diets specifically designed to optimize brain health, has been shown to reduce the incidence of AD.
•Strategies for prevention of dementia are summarized in Table 14.
•Antipsychotics should be used with extreme caution in treating dementia-related psychosis. All antipsychotics carry a warning from the FDA stating that the medication is not approved for dementia-related psychosis because elderly patients on either conventional or atypical antipsychotics experience an increased risk of death due to cardiovascular or infectious causes.
•Apolipoprotein E (APOE) is the main cholesterol-carrying molecule in the brain, and it exists in three allelic variants: E2, E3, and E4. The E3 allele is most common and has a neutral influence on developing AD, whereas the E2 allele, the rarest allele, may be protective against AD. The E4 allele increases the risk of developing AD and advances the age of first symptoms in those who experience the disease. However, neither E4 heterozygosity or homozygosity is required or sufficient to cause AD. Among Caucasians, E4 heterozygosity increases the risk of developing AD approximately threefold, whereas E4 homozygosity increases AD risk by approximately 15 times compared to the E3/E3 baseline. The APOE E4 allele is also associated with an earlier age of onset of AD. Because the benefits of genetic testing are often modest, and the tests themselves are often imprecise in identifying risk, the test is generally discouraged. Genes implicated in the development of AD are summarized in Table 15. Recent trials, however, reveal that the disclosure of APOE genotyping results to adult children of patients with AD did not result in significant short-term psychologic risks. Test-related distress was reduced among those who learned that they were APOE4 negative. Persons with high levels of emotional distress before undergoing genetic testing are more likely to have emotional difficulties after disclosure.

TABLE 14 Strategies for Prevention of Dementia

Recommendation		Quality of Evidence
Engage in physical activity		Moderate
In adults with mild cognitive impairment, engage in physical activity to slow cognitive decline		Low
Tobacco cessation		Low
Do not exceed maximum daily recommended amount of alcohol intake		Moderate ^a
Follow a healthy diet based on WHO recommendations ^b		Moderate ^c
Follow a Mediterranean diet		Moderate
Maintain a healthy weight		Low
Participate in cognitively stimulating activities or cognitive training		Low
Treatment of hypertension		High
Treatment of diabetes mellitus		Moderate
Treatment of dyslipidemia		Low

Strategies for Prevention of Dementia, as based on World Health Organization (WHO) 2019 Guidelines for Risk Reduction of Cognitive Impairment and Dementia.

^a4 units of alcohol per wk for men, 7 units of alcohol per wk for women.

^bComponents include 5 daily servings of nonstarchy vegetables, <10% dietary intake of free sugars, <30% dietary intake of fats (preferentially unsaturated fats), <5 g daily of salt.

^cStrength of evidence is variable based on individual dietary components.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

TABLE 15 Genes Implicated in the Development of Alzheimer Disease

Gene		Comment
APP		>30 known mutations associated with EOAD; located on chromosome 21; associated with elevated risk of AD in Down syndrome
PSEN1		>150 known mutations associated with EOAD
PSEN2		<20 known mutations associated with EOAD
APOE		Three known alleles: •Ε2 - protective of LOAD •Ε3 - Neutral risk of LOAD •Ε4 - Increased risk of LOAD

AD, Alzheimer disease; EOAD, early-onset Alzheimer disease; LOAD, late-onset Alzheimer disease.

From Warshaw G et al: Ham’s primary care geriatrics, ed 7, Philadelphia, 2022, Elsevier.

For additional information for patients, families, and clinicians, contact the following organizations:

•Alzheimer’s Association (http://www.alz.org/; 800-272-3900)
•Alzheimer’s Disease Education and Referral Center (https://www.nia.nih.gov/Alzheimers; 800-438-4380)

Available at Ebooks.health.elsevier.com.

Rajan KB : Prevalence and incidence of clinically diagnosed Alzheimer’s disease dementia from 1994 to 2012 in a population studyhttp://dx.doi.org/10.1016/j.jalz.2018.07.216Alzheimers Dement. 15(1):1-7, 2019.
Alzheimer’s Association: Alzheimer’s disease fact and figures, 2022. Available at https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf. Accessed Aug 20, 2022.
Scharre DW : Self-administered gerocognitive examination: longitudinal cohort testing for the early detection of dementia conversionAlzheimers Res Ther. 13(1):192, 2021.
Mintun MA : Donanemab in early Alzheimer’s diseaseN Engl J Med. 384(18):1691-1704, 2021.
van Dyck CH : Lecanemab in early Alzheimer’s diseaseN Engl J Med. 388(1):9-21, 2023.
Sims JR : Donanemab in early symptomatic Alzheimer’s disease: the TRAILBLAZER ALZ 2 randomized clinical trialJAMA. 330(6):512-527, 2023.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Reference(s) ⬆