Background
Alzheimer disease (AD) is the most common cause of dementia and is characterized by progressive decline in memory and other cognitive domains, including language, executive function, visuospatial abilities, and behavior. The disease exists on a continuum that ranges from preclinical AD and mild cognitive impairment (MCI) due to AD to overt dementia. [1, 2, 3]
AD is a major public health concern. In the United States, more than 7 million people are living with AD, and prevalence is projected to increase substantially with population aging. AD is among the leading causes of death in older adults and is associated with substantial caregiver burden, disability, institutionalization, and healthcare expenditures. [4]
Pathologically, AD is characterized by extracellular beta-amyloid deposition and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Biomarker-supported diagnosis using cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and emerging blood-based biomarkers is increasingly incorporated into clinical evaluation, particularly in patients with MCI or atypical presentations. [5]
Management includes both symptomatic therapies and disease-modifying therapies. Cholinesterase inhibitors and memantine may provide symptomatic benefit, while anti-amyloid monoclonal antibodies have emerged as treatment options for select patients with early symptomatic disease. [6]
Epidemiology
An estimated 7.4 million Americans aged ≥65 years are living with AD, and approximately 74% are aged ≥75 years. Approximately 1 in 9 adults aged ≥65 years (11%) has AD. Almost two-thirds of Americans with AD are women. Older Black Americans are approximately twice as likely to have AD or other dementias as older White Americans, while older Hispanic Americans are approximately 1.5 times as likely to be affected. Approximately 200,000 Americans aged <65 years are estimated to have younger-onset dementia. [4]
As the US population continues to age, the prevalence of AD is expected to increase substantially. By 2060, the number of Americans aged ≥65 years living with AD is projected to reach 13.8 million, barring the development of effective preventive or disease-modifying therapies. [4]
The prevalence of AD and other dementias increases substantially with age worldwide. AD is the leading cause of dementia globally and represents a growing public health challenge as populations continue to age.
Etiology
The etiology of AD is multifactorial and incompletely understood. Both genetic susceptibility and environmental or vascular risk factors contribute to disease development.
Increasing age is the strongest known risk factor for AD. Additional risk factors include family history, APOE ε4 genotype, hypertension, diabetes mellitus, obesity, dyslipidemia, smoking, physical inactivity, traumatic brain injury, Down syndrome, depression, hearing loss, vision loss, and social isolation. [7, 8]
Most cases of AD are sporadic and late onset. Rare familial early-onset forms are associated with autosomal-dominant mutations involving the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. [9]
Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist. Autosomal-dominant AD, which accounts for less than 5% of cases, is almost exclusively early-onset AD; cases occur in at least 3 individuals in 2 or more generations, with 2 of the individuals being first-degree relatives. [9]
Genetics
The APOE ε4 allele is the strongest known genetic risk factor for late-onset AD and is associated with increased risk and earlier disease onset. [10] However, APOE genotyping is not diagnostic, and many individuals with APOE ε4 never develop AD.
Rare early-onset familial forms of AD are linked to pathogenic variants in APP, PSEN1, and PSEN2, which alter amyloid processing and increase beta-amyloid accumulation. [9]
Growing evidence suggests that modification of vascular and lifestyle risk factors may help reduce dementia risk.
Pathophysiology
AD is characterized by progressive neurodegeneration associated with extracellular beta-amyloid deposition and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. [11]
Gross pathologic findings include diffuse cortical atrophy, particularly involving the temporal, frontal, and parietal lobes. Early pathologic involvement typically affects the hippocampus and medial temporal lobe, resulting in impairment of episodic memory. As the disease progresses, neuronal loss and cortical atrophy extend to additional brain regions involved in language, executive function, visuospatial processing, and behavior. [12]
Beta-amyloid is derived from abnormal cleavage of amyloid precursor protein (APP), resulting in aggregation of insoluble amyloid plaques. NFTs disrupt neuronal microtubule stability and intracellular transport, contributing to neuronal dysfunction and cell death. The burden of tau pathology correlates more closely with cognitive decline and disease severity than amyloid plaque burden.
Amyloid and tau pathology form the basis for current AD biomarker testing, including amyloid positron emission tomography (PET), cerebrospinal fluid (CSF) biomarkers, and emerging blood-based biomarkers. [13]
Cholinergic neuronal loss, particularly involving projections from the basal forebrain, contributes to cognitive symptoms and provides the rationale for treatment with cholinesterase inhibitors. [11]
Additional mechanisms believed to contribute to disease progression include neuroinflammation, oxidative stress, vascular dysfunction, mitochondrial impairment, and impaired protein clearance pathways.
Prognosis
AD is a progressive neurodegenerative disorder associated with gradual decline in cognition, function, and independence. Disease progression varies considerably among individuals, but patients typically experience worsening memory impairment followed by progressive deficits in language, executive function, visuospatial abilities, and behavior. [14]
As the disease advances, patients increasingly require assistance with instrumental and basic activities of daily living. Neuropsychiatric symptoms such as depression, agitation, apathy, psychosis, sleep disturbance, and wandering are common and contribute substantially to caregiver burden and institutionalization. [15]
In advanced disease, patients may develop gait impairment, falls, dysphagia, incontinence, immobility, malnutrition, and recurrent infections. Aspiration pneumonia and other medical complications are common causes of death.
Median survival after diagnosis varies widely and is influenced by age at onset, comorbidities, functional status, and disease severity. Early-onset AD is often associated with more rapid progression. [15]
Early care planning, caregiver support, and attention to safety, nutrition, behavioral symptoms, and palliative goals of care are important components of long-term management.
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Healthy neurons. Image courtesy of NIH.
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Cortical atrophy with hydrocephalus ex vacuo is seen in Alzheimer disease.
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APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell. Image courtesy of NIH.
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Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments of protein, one of which is called beta-amyloid. Image courtesy of NIH.
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The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques. Image courtesy of NIH.
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Preclinical Alzheimer disease. Image courtesy of NIH.
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Preclinical Alzheimer disease. Image courtesy of NIH.
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Mild Alzheimer disease. The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Image courtesy of NIH.
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Mild-to-moderate Alzheimer disease. Image courtesy of NIH.
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Severe Alzheimer disease. In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Image courtesy of NIH.
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Severe Alzheimer disease. Image courtesy of NIH.
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FDG-PET demonstrating reduced temporoparietal metabolism in Alzheimer disease. Image courtesy of NIH.
