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Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease

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Abstract

In 2011, genome-wide association studies implicated a polymorphism near CD33 as a genetic risk factor for Alzheimer’s disease. This finding sparked interest in this member of the sialic acid-binding immunoglobulin-type lectin family which is linked to innate immunity. Subsequent studies found that CD33 is expressed in microglia in the brain and then investigated the molecular mechanism underlying the CD33 genetic association with Alzheimer’s disease. The allele that protects from Alzheimer’s disease acts predominately to increase a CD33 isoform lacking exon 2 at the expense of the prototypic, full-length CD33 that contains exon 2. Since this exon encodes the sialic acid ligand-binding domain, the finding that the loss of exon 2 was associated with decreased Alzheimer’s disease risk was interpreted as meaning that a decrease in functional CD33 and its associated immune suppression was protective from Alzheimer’s disease. However, this interpretation may need to be reconsidered given current findings that a genetic deletion which abrogates CD33 is not associated with Alzheimer’s disease risk. Therefore, integrating currently available findings leads us to propose a model wherein the CD33 isoform lacking the ligand-binding domain represents a gain of function variant that reduces Alzheimer’s disease risk.

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Fig. 1

These data (mean ± SD, n = 3) are derived from http://web.stanford.edu/group/barres_lab/brainseq2/brainseq2.html [77]. Other microglial RNAseq studies report similar SIGLEC expression profiles [78]

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Acknowledgements

This work was supported by the National Institute on Aging (RF1AG059717 and P30AG028383).

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Authors and Affiliations

  1. Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

    Steven Estus, Benjamin C. Shaw & Nicholas Devanney

  2. Department of Biostatistics and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

    Yuriko Katsumata & David W. Fardo

  3. Prides Crossing, MA, 01965, USA

    Eileen E. Press

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  1. Steven Estus
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Estus, S., Shaw, B.C., Devanney, N. et al. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol 138, 187–199 (2019). https://doi.org/10.1007/s00401-019-02000-4

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