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INTRODUCTION

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  • Alzheimer disease (AD), which accounts for about 60% of dementias, is a progressive and eventually fatal dementia of unknown cause characterized by loss of cognitive and physical functioning, commonly with behavior symptoms.

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PATHOPHYSIOLOGY

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  • Dominantly inherited forms of AD are fewer than 1% of cases. More than half of young-onset, dominantly inherited cases are attributed to alterations on chromosomes 1, 14, or 21. Genetic susceptibility to late-onset AD is primarily linked to the apolipoprotein E (APOE) genotype, but an interaction of multiple genes with the environment may be at play.

  • Risk factors associated with AD include age, decreased reserve capacity of the brain, head injury, Down syndrome, depression, mild cognitive impairment, and risk factors for vascular disease, including hypertension, elevated homocysteine, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, obesity, metabolic syndrome, and diabetes.

  • Signature findings include intracellular neurofibrillary tangles (NFTs), extracellular amyloid plaques in the cortex and medial temporal lobe, degeneration of neurons and synapses, and cortical atrophy. Density of NFTs correlates with severity of dementia.

  • Proposed mechanisms for these changes include: (1) β-amyloid protein aggregation, leading to formation of plaques; (2) hyperphosphorylation of tau protein, leading to NFTs; (3) synaptic failure and depletion of neurotrophin and neurotransmitters; (4) mitochondrial dysfunction; and (5) oxidative stress. The amyloid cascade hypothesis states that there is an imbalance between production and clearance of β-amyloid, with aggregation and accumulation of β-amyloid leading to AD. Whether this is the primary pathology in most forms of AD remains to be shown.

  • Of neurotransmitter deficits, loss of cholinergic activity is most prominent, and it correlates with AD severity. Cholinergic cell loss seems to be a consequence of AD pathology, not the cause of it.

  • Other neurotransmitter considerations include: (1) Serotonergic neurons of the raphe nuclei and noradrenergic cells of the locus ceruleus are lost; (2) monoamine oxidase type B activity is increased; (3) glutamate pathways of the cortex and limbic structures are abnormal; and (4) excitatory neurotransmitters, including glutamate, may be neurotoxic.

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CLINICAL PRESENTATION

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  • Cognitive decline is gradual and includes memory loss, aphasia, apraxia, agnosia, disorientation, and impaired executive function. Other symptoms include depression, psychotic symptoms, aggression, motor hyperactivity, uncooperativeness, wandering, and combativeness. Patients become increasingly unable to care for themselves. Table 52–1 shows the stages of AD.

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Table Graphic Jump Location
TABLE 52–1Stages of Alzheimer Disease

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