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  • Review Article
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The paradox of syndromic diversity in Alzheimer disease

Nature Reviews Neurology volume 8, pages 451–464 (2012)Cite this article

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Abstract

Variant syndromes of Alzheimer disease (AD), led by deficits that extend beyond memory dysfunction, are of considerable clinical and neurobiological importance. Such syndromes present major challenges for both diagnosis and monitoring of disease, and serve to illustrate the apparent paradox of a clinically diverse group of disorders underpinned by a common histopathological substrate. This Review focuses on the most common variant AD phenotypes: posterior cortical atrophy, logopenic variant primary progressive aphasia and frontal variant AD. The neuroanatomical, molecular and pathological correlates of these phenotypes are highlighted, and the heterogeneous clinical presentations of the syndromes are discussed in the context of the emerging network paradigm of neurodegenerative disease. We argue that these apparently diverse clinical phenotypes reflect the differential involvement of a common core temporoparietofrontal network that is vulnerable to AD. According to this interpretation, the network signatures corresponding to AD variant syndromes are produced by genetic and other modulating factors that have yet to be fully characterized. The clinical and neurobiological implications of this network paradigm in the quest for disease-modifying treatments are also explored.

Key Points

  • Alzheimer disease (AD) represents a phenotypically diverse group of syndromes underpinned by a common pathology

  • The most common variant AD syndromes are posterior cortical atrophy, logopenic variant primary progressive aphasia and frontal variant AD

  • Variant AD syndromes are associated with distinct but overlapping clinical, neuroanatomical, molecular and pathological profiles

  • Differential modulation of a core temporoparietofrontal network by genetic, environmental and physiological factors might underlie the phenotypic diversity of AD

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Figure 1: Representative brain MRI scans of patients with AD.
Figure 2: Core network paradigm of neurodegeneration in AD.

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Acknowledgements

The authors thank Dr C. Mahoney for technical assistance in preparation of brain images. J. D. Warren holds a Wellcome Trust Senior Clinical Fellowship (Grant No 091673/Z/10/Z). P. D. Fletcher holds a Medical Research Council Clinical Research Training Fellowship. H. Golden holds an Alzheimer Research UK Ph.D. Fellowship.

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  1. Dementia Research Centre, Institute of Neurology, University College London, 8–11 Queen Square, London, WC1N 3BG, UK

    Jason D. Warren, Phillip D. Fletcher & Hannah L. Golden

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  1. Jason D. Warren
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  2. Phillip D. Fletcher
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  3. Hannah L. Golden
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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Jason D. Warren.

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Warren, J., Fletcher, P. & Golden, H. The paradox of syndromic diversity in Alzheimer disease. Nat Rev Neurol 8, 451–464 (2012). https://doi.org/10.1038/nrneurol.2012.135

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