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Editorial |

Cognitive Decline in Preclinical Stage 2 Alzheimer Disease and Implications for Prevention Trials

Elizabeth C. Mormino, PhD1; Kathryn V. Papp, PhD2
[+] Author Affiliations
1Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
2Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Neurol. 2016;73(6):640-642. doi:10.1001/jamaneurol.2016.0281.
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In 2011, a National Institute on Aging−Alzheimer’s Association (NIA-AA) work group published criteria for classifying clinically normal older individuals into biomarker-defined stages of preclinical Alzheimer disease using measures of Aβ and neurodegeneration (ND).1 These staging criteria assume a trajectory that begins with aberrant Aβ accumulation, followed by tau-mediated ND and subsequent cognitive decline. Clinically normal individuals in stage 1 are Aβ+/ND−, stage 2 are Aβ+/ND+, and stage 3 are similarly Aβ+/ND+ but also show subtle cognitive impairment (Figure). These criteria have created a common rubric to advance the study of preclinical Alzheimer disease and to move the field toward early intervention, when disease-modifying therapies may be the most efficacious. Along these lines, secondary prevention trials are using biomarker data to recruit clinically normal older individuals in the preclinical stage of Alzheimer disease to test whether an anti-Aβ therapy may prevent or mitigate cognitive decline.2

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Figure.
Hypothetical Sequence of Events in Preclinical Alzheimer Disease and Corresponding National Institute on Aging−Alzheimer’s Association Preclinical Stages

Prevention strategies targeting different stages of preclinical Alzheimer disease may require different therapeutic targets and end points to assess drug efficacy. For instance, treatment strategies for stage 0 may involve an anti-Aβ therapy, with efficacy measured as the prevention of Aβ accumulation. Treatment strategies for stage 1 may involve anti-Aβ therapy, with efficacy measured as the prevention of neocortical tau accumulation. Last, treatment strategies for stage 2 and stage 3 may involve a combination of anti-Aβ and anti-tau therapies, with efficacy measured as the prevention of further tau accumulation, the slowing of cognitive decline, or both. MTL indicates medial temporal lobe; ND, neurodegeneration.

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