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Editorial
December 2016

Clinical Impact of Amyloid Positron Emission Tomography—Is It Worth the Cost?

Author Affiliations
  • 1Department of Neurology, Mayo Clinic Arizona, Scottsdale
JAMA Neurol. 2016;73(12):1396-1398. doi:10.1001/jamaneurol.2016.3792

For the past 25 years, the amyloid hypothesis has been the paradigm for Alzheimer disease (AD) pathogenesis and has guided the development of disease-modifying treatments. Evidence supporting the amyloid hypothesis is strong. Amyloid accumulation begins early in the disease process, and early-onset familial forms of AD can be caused by highly pathogenic variants in any of 3 genes, all of which affect cerebral amyloid production or aggregation, including the amyloid precursor protein gene (APP; OMIM 104300), presenilin 1, and presenilin 2.1 Furthermore, although most APP variants are pathogenic, one has been described2 that actually protects against AD by reducing β secretase cleavage and β-amyloid (Aβ) production. Therefore, the 2014 reports of amyloid-targeted immunotherapeutic failures disappointed a field that anticipated nothing less than a potential cure for AD based on a wealth of evidence that immunotherapy against Aβ should halt disease progression.3,4 Bapineuzumab3 and solanezumab4 are monoclonal antibodies directed against epitopes of Aβ. Passive immunization strategies with these agents were shown to safely engage their molecular targets with improvement in surrogate biomarkers and so seemed to be the perfect therapies aimed at the perfect target working exactly as planned. Yet neither drug reduced the rate of decline of either cognition or function. A subsequent secondary analysis5 has helped to maintain interest in this approach (and several agents are currently still in trials) because patients in the solanezumab trial with only mild stage AD appeared to show a 34% reduction in the rate of progression over 18 months. Although many have attributed the relative failure of immunotherapies as being “too little too late” in the disease course, another contributory factor has almost certainly been that up to one-third of apolipoprotein E ε4 noncarriers lack significant amounts of cerebral amyloid, implying that they lack the target for the immunotherapeutic agent.6 Since then, biomarker evidence of cerebral amyloidosis, and particularly amyloid positron emission tomography (PET), has become a frequent requirement of AD research trial design.

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