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Chapter 48. Neurobiology of Alzheimer's Disease

Albert A. Davis, B.S.; James J. Lah, M.D., Ph.D.; Allan I. Levey, M.D., Ph.D.
DOI: 10.1176/appi.books.9781585623860.415496

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Of the broad spectrum of brain diseases that can produce dementia, Alzheimer's disease (AD) is the most common. AD is a devastating disorder characterized by progressive loss of memory and intellectual abilities, affecting more than 40% of individuals older than 85 years of age. The remarkable increase in disease prevalence that has accompanied the growth of the oldest segment of the population has heightened public awareness and accelerated research efforts to understand the disease. AD has been recognized as a clinical and neuropathological entity for more than 100 years, but specific therapies were unavailable until the development of the first cholinesterase inhibitor, tacrine, about 20 years ago. Since that time, several new cholinesterase inhibitors have been approved for the treatment of AD patients, and novel therapies, such as the N-methyl-d-aspartate (NMDA) receptor antagonist memantine, have shown modest benefit in improving cognitive function in patients with AD. Common clinical practice has also embraced the use of high-dose vitamin E as an antioxidant that may provide some neuroprotective benefit. Research on AD funded by the government, private foundations, and the pharmaceutical industry commits billions of dollars annually for achieving better understanding of the disease and for developing more effective treatments. These efforts will inevitably lead to continued improvement in clinical practice in the coming years.

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FIGURE 48–1. Pathological hallmarks of Alzheimer's disease.(A) Low-magnification view of cerebral cortex showing multiple A-immunopositive plaques. (B) Higher magnification of a Bielschowsky silver stain showing argyrophilic amyloid plaques (arrow) and neurofibrillary tangles (arrowhead) in cerebral cortex. (C) High-magnification view of a single neuritic plaque. The central core of the plaque contains amyloid peptides that are surrounded by a clear halo and then swollen silver-positive dystrophic neurites. (D) High-magnification view of a neurofibrillary tangle.

FIGURE 48–2. Molecular basis of cholinergic neurotransmission.Acetylcholine (ACh) is synthesized in the nerve terminal cytoplasm and is incorporated into synaptic vesicles via the vesicular acetylcholine transporter (VAChT). Upon nerve impulse, cholinergic vesicles release ACh into the synaptic cleft, where the transmitter binds to pre- and postsynaptic muscarinic and nicotinic receptor subtypes. Transmission is terminated by the rapid hydrolysis of ACh by acetylcholinesterase (AChE). The degradation product choline is recycled into the terminal by the high-affinity choline transporter (CHT). This reuptake process is a key regulated and rate-limiting step in ACh synthesis. AcCoA = acetyl coenzyme A.

FIGURE 48–3. Proteolytic cleavage of amyloid precursor protein (APP) and amyloidogenesis.The APP molecule is metabolized via alternate pathways with distinct cleavages. A nonamyloidogenic pathway involves an -secretase cleavage (1) within the A peptide sequence (lightly shaded), shedding an N-terminal ectodomain. Degradation of the membrane-bound C-terminus does not produce A, because part of the peptide sequence has been cleaved. In contrast, A is produced via the amyloidogenic pathway involving sequential cleavages by -secretase (2) and -secretase (3). Presenilin is a necessary component for -secretase activity. The final -secretase cleavage releases A peptides of predominantly 40–42 amino acids. The longer 42-residue peptide is more toxic and hydrophobic, and it seeds aggregation into extracellular deposits of amyloid plaques. BACE = beta-site APP cleaving enzyme.
Table Reference Number
TABLE 48–1. Risk factors for developing Alzheimer's disease (AD)

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Sample questions:
1.
Alzheimer’s disease (AD) is characterized by pathological changes in the brain. Which of the following are intracellular accumulations of hyperphosphorylated tau?
2.
Abundant evidence suggests that the clinical syndrome of Alzheimer’s disease (AD) involves failed neurotransmission at synapses in the neocortex and hippocampus. What type of synapses are these?
3.
Currently, the standard treatment for the cognitive decline that occurs with Alzheimer’s disease (AD) has been the use of acetylcholinesterase inhibitors. However, the improvement produced by these medications has been modest. Current research has focused on the development of cholinergic agonists and, in particular, agents that bind on one of the subtypes of the muscarinic acetylcholine (mACh) receptor. Xanomeline is one of these new agents, and it binds at which of the mACh receptors?
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