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Suspected non-Alzheimer disease pathophysiology — concept and controversy

Abstract

Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. The term SNAP has been applied to clinically normal individuals (who do not meet criteria for either mild cognitive impairment or dementia) and to individuals with mild cognitive impairment, but is applicable to any amyloid-negative, neurodegeneration-positive individual regardless of clinical status, except when the pathology underlying neurodegeneration can be reliably inferred from the clinical presentation. SNAP is present in 23% of clinically normal individuals aged >65 years and in 25% of mildly cognitively impaired individuals. APOE*ε4 is underrepresented in individuals with SNAP compared with amyloid-positive individuals. Clinically normal and mildly impaired individuals with SNAP have worse clinical and/or cognitive outcomes than individuals with normal levels of neurodegeneration and amyloid-β biomarkers. In this Perspectives article, we describe the available data on SNAP and address topical controversies in the field.

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Figure 1: Signature patterns of AD.
Figure 2: Imaging differences between preclinical AD stage 1 and SNAP.
Figure 3: Comparisons of clinical outcomes of individuals with preclinical AD and SNAP across different cohorts.
Figure 4: Topographic atrophy patterns.

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David S. Knopman, Helene Amieva, … David T. Jones

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Acknowledgements

C.R.J.Jr receives research funding from the NIH and the Alexander Family Alzheimer disease Disease Research Professorship of the Mayo Foundation. D.D. receives research support from the NIH (P50-AG016574; P50-NS072187; P01-AG003949) and CurePSP: Foundation for PSP/CBD and Related Disorders. A.M.F. receives research funding from the the DIAN Pharma Consortium and the Alzheimer disease Association. R.A.S. received research support from the BrightFocus Foundation. W.M.v.d.F. receives research funding from the Netherlands Organization for Scientific Research (NWO), ZonMw, Cardiovasculair Onderzoek Nederland, and European Union (EU) 7th Framework Programme (FP7); all funds are paid to her institution. P.J.V. receives research funding from EU Joint Programme–Neurodegenerative Disease Research (JPND) and ZonMw, and from EU FP7 and Innovative Medicines Initiative joint resources, which are composed of financial contributions from EU FP7 (FP7/2007-2013) and in-kind contributions from the European Federation of Pharmaceutical Industries and Associations (EFPIA). S.J.B.V. receives research support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n°115372, resources that are composed of financial contributions from EU FP7 (FP7/2007-2013) and in-kind contributions from EFPIA.

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C.R.J.Jr researched data for the article and wrote the article. All authors provided substantial contribution to discussion of content and reviewing/editing of manuscript before submission.

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Correspondence to Clifford R. Jack Jr.

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C.R.J.Jr has provided consulting services for Eli Lilly. D.S.K. is on a data safety monitoring board for Lundbeck Pharmaceuticals and is participating in clinical trials sponsored by Lilly Pharmaceuticals and TauRx Pharmaceuticals. A.M.F. has provided consulting services for Eli Lilly, Roche, AbbVie, IBL International and Novartis. W.J. is a consultant to Synarc–Bioclinica and to Banner Alzheimer disease Institute–Genentech. R.C.P. is on a data monitoring committee for Pfizer and Janssen Alzheimer Immunotherapy; is a consultant for Merck, Roche, and Genentech; receives royalties from publishing Mild Cognitive Impairment (Oxford University Press, 2003). R.A.S. has been a consultant for Janssen Eisai, Lundbeck, Isis, Boehringer Ingelheim, Roche and Genentech; and receives research support from the Fidelity Biosciences, and Janssen. W.M.v.d.F. has provided consulting services for Boehringer Ingelheim and received research funding from Boehringer Ingelheim; all funds are paid to her institution. V.L.V. has provided consulting services for Bayer Healthcare and Novartis, and has received speaker's honouraria from AstraZeneca, GE Healthcare and Piramal Imaging. P.J.V. has provided consulting services for Bristol–Myers Squibb, Élan–Wyeth, Ipsen, and Roche Diagnostics. G.C. and G.B.F. declare no competing interests.

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Characteristics of individuals with SNAP in different study cohorts (DOCX 44 kb)

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Jack, C., Knopman, D., Chételat, G. et al. Suspected non-Alzheimer disease pathophysiology — concept and controversy. Nat Rev Neurol 12, 117–124 (2016). https://doi.org/10.1038/nrneurol.2015.251

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