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Commentary in Neurology |

Amyloid-Dependent and Amyloid-Independent Stages of Alzheimer Disease

Bradley T. Hyman, MD, PhD
Arch Neurol. 2011;68(8):1062-1064. doi:10.1001/archneurol.2011.70.
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Optimism about therapeutic interventions in Alzheimer disease is based largely on a growing confidence that we understand the underlying pathobiology of the illness. Breakthroughs in genetics led to the identification of 3 early-onset Alzheimer disease autosomal dominant genes, each of which affects the metabolism of the small β-amyloid (Aβ) peptide.1 This peptide is the core component of senile plaques, 1 of the 2 major histopathological hallmarks of the disease. Biochemical and molecular analyses ultimately led to the identification of the β- and γ-secretases, enzymes important in generating Aβ, and innovative approaches aimed at clearing Aβ, including immunotherapy, have emerged.2 Given this intensive investigation into the pathology of Aβ, and the emergence of pharmacological targets directly related to Aβ metabolism, hope was strong that effective ways of halting or reversing the disease were near at hand. However, a series of disappointing results from large clinical trials have ensued. Perhaps it would have been unrealistic to expect the first generation of pharmacologic agents to be blockbusters, but even modest signals of clinical efficacy have been elusive. The first active immunization program was halted because of meningeal encephalitis in a small percentage of the patients, but long follow-up of patients who were in the trial to autopsy showed no clear change in clinical course despite dramatic clearance of amyloid.35 In a more recent failure, the development of a γ-secretase inhibitor was halted because of systemic adverse effects, as well as because patients' cognition not only did not improve, but apparently got worse.6

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