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INTRODUCTION

  • Alzheimer disease (AD) affects ∼7.5 million Americans of all ages and is a progressive illness of unknown cause characterized by loss of cognitive and physical functioning, commonly with behavior symptoms.

PATHOPHYSIOLOGY

  • Dominantly inherited forms of AD are fewer than 1% of cases. More than half of young-onset, dominantly inherited cases are attributed to chromosomal alterations that affect processing of the amyloid precursor protein. 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.

  • AD risk factors 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. AD-affected individuals appear to have a higher burden of plaques and NFTs in their younger years compared to age-matched controls.

  • 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.

CLINICAL PRESENTATION

  • Cognitive decline is gradual and includes memory loss, aphasia, apraxia, agnosia, disorientation, and impaired executive function. Other non-cognitive symptoms include depression, psychotic symptoms, aggression, motor hyperactivity, uncooperativeness, wandering, and combativeness. Patients become increasingly unable to care for themselves. Table 53-1 shows the stages of AD.

TABLE 53-1Stages of Alzheimer Disease

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