Alzheimer Disease

GENERAL PRINCIPLES

Alzheimer disease (AD) is the most common neurodegenerative disorder in older individuals (older than 60 years), typically characterized by memory problems and inability to independently perform activities of daily living.

Epidemiology

• Prevalence is lt;1% before age 65 years, 5%-10% at age 65 years, and approximately 45% by age 85 years. Approximately 5.7 million Americans have AD.

• Inherited forms of AD manifest typically before age 65 years and are associated with mutations in amyloid precursor protein (APP) gene on chromosome 21, presenilin-1 (PSENl) gene on chromosome 14, and presenilin-2 (PSEN2) gene on chromosome 1.

• The greatest risk factor for late-onset/sporadic AD is the presence of the apolipoprotein #949;4 variant.

• Lifetime risk doubles if a sibling or parent is diagnosed with AD.

• It is common for AD patients to present at late stages of the disease after an unrelated medical illness unmasks signs and symptoms of the disease that had previously gone unrecognized by the family.

• Pseudodementia (cognitive impairment related to comorbid depression) should be considered in the appropriate clinical context.

Pathophysiology

Pathologic diagnosis requires presence of both neurofibrillary tangles due to tau and neuritic plaques composed of amyloid.

DIAGNOSIS

Clinical Presentation

• For a diagnosis of AD, the patient must exhibit cognitive impairment that is a change from baseline.

• Episodic memory for newly acquired information is impaired, whereas memory for more remote events is not affected.

• Declarative memory for facts and events is affected, whereas procedural memory and motor learning are spared in earlier stages of the disease.

• With progression of disease, language, visuospatial skills, abstract reasoning, and executive function deteriorate. Some patients will also develop apraxia, alexia, and delusions.

Differential Diagnosis

See Table 27-3.

TABLE 27-3

DIFFERENTIAL DIAGNOSIS OF ALZHEIMER DEMENTIA

Frontotemporal dementia

Changes in personality, behavior, and executive functioning

Vascular dementia

Stepwise course due to repeated strokes or strokelike events

Dementia with Lewy bodies

Visual hallucinations, dream enactment behavior (i.e., REM behavior disorder), cognitive fluctuations, parkinsonism, sensitivity to neuroleptics

Normal pressure hydrocephalus

Triad of dementia, urinary incontinence, and gait instability (“wacky, wet, and wobbly”)

Vitamin B₁₂ deficiency

Neurosyphilis

Thyroid dysfunction

HIV

Creutzfeldt-Jakob disease

Autoimmune encephalopathies (including paraneoplastic syndromes)

REM, rapid eye movement.

Diagnostic Testing

Progression of disease can be assessed by the Mini-Mental State Examination, the Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating Scale.

LABORATORY STUDIES

• Definitive diagnosis of AD requires histopathologic confirmation (i.e., autopsy).

• Reversible causes of dementia such as B₁₂ deficiency, neurosyphilis, HIV, and thyroid abnormalities should be ruled out.

IMAGING

• Brain MRI can suggest potential alternative diagnoses.

• MRI may show diffuse atrophy with hippocampal atrophy that is seen with AD.

• [¹⁸F]Fluorodeoxyglucose positron emission tomography (PET) or perfusion single-photon emission computed tomography (SPECT) may demonstrate hypometabolism and hypoperfusion, respectively, within the parietotemporal cortex.

• Amyloid PET tracers (Aorbetapir) can measure amyloid deposition in the brain and are approved for clinical use but are quite expensive. New PET tracers for tau are being actively developed.

DIAGNOSTIC PROCEDURES

• Neuropsychological testing can establish a baseline cognitive status. This testing can sometimes differentiate dementia from depression (i.e., pseudodementia).

• Both structural MRI and PET imaging may assist in early diagnosis.

• CSF measures of reduced A#946;₄₂ and increased tau can be obtained and may assist in the diagnosis.

TREATMENT

• Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine can be considered for early AD.

• Memantine, a noncompetitive A-methyl-d-aspartate receptor antagonist, can be considered for moderate to severe dementia.

• A combination of the above medications is sometimes used in more advanced AD patients. Additional therapies (including antiamyloid agents) are being investigated.

• Aducanumab, an amyloid #946;-directed monoclonal antibody, was approved by the US Food and Drug Administration (FDA) in 2021 but its use remains controversial and will not be covered here.