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  • Review Article
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The clinical importance of suspected non-Alzheimer disease pathophysiology

Nature Reviews Neurology (2024)Cite this article

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Abstract

The development of biomarkers for Alzheimer disease (AD) has led to the origin of suspected non-AD pathophysiology (SNAP) — a heterogeneous biomarker-based concept that describes individuals with normal amyloid and abnormal tau and/or neurodegeneration biomarker status. In this Review, we describe the origins of the SNAP construct, along with its prevalence, diagnostic and prognostic implications, and underlying neuropathology. As we discuss, SNAP can be operationalized using different biomarker modalities, which could affect prevalence estimates and reported characteristics of SNAP in ways that are not yet fully understood. Moreover, the underlying aetiologies that lead to a SNAP biomarker profile, and whether SNAP is the same in people with and without cognitive impairment, remains unclear. Improved insight into the clinical characteristics and pathophysiology of SNAP is of major importance for research and clinical practice, as well as for trial design to optimize care and treatment of individuals with SNAP.

Key points

  • Suspected non-Alzheimer disease (AD) pathophysiology (SNAP) is a heterogeneous biomarker-based concept describing individuals with a normal amyloid biomarker and abnormal tau and/or neurodegeneration biomarkers.

  • SNAP is common in people with normal cognition (NC) or mild cognitive impairment (MCI) and is associated with a reduced frequency of the apolipoprotein E ε4 allele (a key genetic risk factor for AD) compared with individuals with abnormal amyloid biomarkers.

  • Evidence shows that NC-SNAP is associated with a low risk of cognitive decline over 7 years, whereas MCI-SNAP is associated with an increased risk of developing clinical AD dementia.

  • Cerebrospinal fluid (CSF) proteomics studies suggest a disturbance in amyloid metabolism and involvement of the blood–CSF barrier in people with MCI-SNAP.

  • Neuropathological studies indicate that SNAP can represent early AD pathology, presumed AD-spectrum pathologies such as primary age-related tauopathy or non-AD pathologies that occur with increased frequency in AD, such as limbic-predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathological change, argyrophilic grain disease or Lewy body disease.

  • More sensitive biomarkers of amyloid pathology and novel biomarkers for non-AD pathologies are needed to identify the underlying cause of SNAP in vivo and provide appropriate treatments.

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Fig. 1: Age-related prevalence of SNAP neuropathological correlates.
Fig. 2: SNAP neuropathological correlates.

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Acknowledgements

The authors thank P. Scheltens for the conception of this manuscript.

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Authors and Affiliations

  1. Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

    Stephanie J. B. Vos, Aurore Delvenne & Pieter Jelle Visser

  2. Department of Radiology, Mayo Clinic and Foundation, Rochester, MN, USA

    Clifford R. Jack Jr

  3. Laboratory for Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute, KU Leuven, Leuven, Belgium

    Dietmar R. Thal

  4. Department of Pathology, University Hospital Leuven, Leuven, Belgium

    Dietmar R. Thal

  5. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

    Pieter Jelle Visser

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Contributions

S.J.B.V. and A.D. researched data for the article. S.J.B.V., A.D. and P.J.V. contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Stephanie J. B. Vos.

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Competing interests

S.J.B.V. has received funding from ZonMW (SNAP VIMP grant no. 7330505021), Stichting Adriana van Rinsum-Ponssen and the EPND project, which received funding from the European Commision, IMI 2 Joint Undertaking (JU) under grant agreement no. 101034344. The IMI JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. D.R.T. has received speakers’ honoraria from Biogen and travel reimbursement from UCB and has collaborated with Novartis Pharma AG, Probiodrug, GE-Healthcare and Janssen Pharmaceutical Companies. He receives funding from Stichting Alzheimer Onderzoek (SAO/FRA 2020/017), Fonds Wetenschappelijk Onderzoek (Vlaanderen) (G0F8516N, G065721N), Alzheimer Association (22-AAIIA-963171) and KU-Leuven Internal Funding (C14/22/132; C3/20/057). P.J.V. has received funding from the European Commission, IMI 2 JU, AMYPAD grant no. 115952; European Commission, IMI 2 JU, RADAR-AD grant no. 806999; and European Commission, IMI 2 JU, EPND grant no. 101034344. He has also received funding from Zon-MW, Redefining Alzheimer’s disease, grant no. 733050824736; and Biogen (Amyloid Biomarker Study Group). Grants were paid to the university. A.D. and C.R.J. declare no competing interests.

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Glossary

AD polygenic risk score

A score that represents an individual’s predicted genetic susceptibility to AD. The score aggregates the genetic effects of single nucleotide variants identified in genome-wide association studies in AD.

Centiloid value

A unit that allows amyloid PET signals obtained with different radiotracers to be combined. Centiloid values can range from 0 (amyloid-β-negative brain) to 100 (typical Alzheimer disease (AD)).

Standardized uptake value ratio

The mean activity concentration in predefined anatomically relevant cortical regions of interest compared with that in a reference region.

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Vos, S.J.B., Delvenne, A., Jack, C.R. et al. The clinical importance of suspected non-Alzheimer disease pathophysiology. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00962-y

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