AD‐causing variants that affect <i>PSEN1</i> transmembrane domains are associated with faster neurodegeneration and cognitive decline compared to those affecting cytoplasmic domains.

Schultz, Stephanie A.;Allegri, Ricardo Francisco;Schultz, Aaron P.;Goate, Alison;Chhatwal, Jasmeer P.;et.al.
(2022) Alzheimer’s Association International Conference (AAIC) - Alzheimer’s Imaging Consortium 2022 — Location: (United States) San Diego, CA (30.July.2022)

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Authors
  • Schultz, Stephanie A.
    Author
  • Allegri, Ricardo Francisco
    Author
  • Schultz, Aaron P.
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  • Goate, Alison
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  • Hanseeuw, Bernardorcid-logoUCLouvain
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  • Chhatwal, Jasmeer P.
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Abstract
BACKGROUND: Rates of cognitive and biomarker change in Autosomal Dominant Alzheimer disease (ADAD) vary substantially across individuals. Prior cross-sectional work suggests that the location of the pathogenic variant within PSEN1, specifically whether the underlying variant affects transmembrane (TM) or cytoplasmic (CY) domains in PSEN1, may be a key determinant in these differential rates of progression. Here we use longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN-Obs) to examine whether variants affecting TM versus CY domains in PSEN1 have differential rates of change in key cognitive and neurodegenerative markers, and whether these differences are relevant to ADAD clinical trials. [...]
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Schultz, S. A., Allegri, R. F., Schultz, A. P., Goate, A., Levey, A. I., Fagan, A. M., Hanseeuw, B., Koeppe, R. A., Gordon, B. A., Cruchaga, C., Karch, C. M., Chen, C. D., Xiong, C., Jack, C. R., Fitzpatrick, C. D., McDade, E., Chui, H. C., Mori, H., Lee, J.-H., et al. (2022). AD‐causing variants that affect <i>PSEN1</i> transmembrane domains are associated with faster neurodegeneration and cognitive decline compared to those affecting cytoplasmic domains. Alzheimer’s & Dementia, 18(Suppl 1), e068221 [1-3]. https://doi.org/10.1002/alz.068221 (Original work published 2022)