Variable and interactive effects of Sex, APOE [Formula: see text] and TREM2 on the deposition of tau in entorhinal and neocortical regions

Joseph Giorgio; Caroline Jonson; Yilin Wang; Jennifer S Yokoyama; Jingshen Wang; William Jagust; Alzheimer’s Disease Neuroimaging Initiative; Health and Aging Brain Study (HABS-HD) Study Team

doi:10.21203/rs.3.rs-4804430/v1

Variable and interactive effects of Sex, APOE $ε4$ and TREM2 on the deposition of tau in entorhinal and neocortical regions

Res Sq [Preprint]. 2024 Aug 9:rs.3.rs-4804430. doi: 10.21203/rs.3.rs-4804430/v1.

Authors

Joseph Giorgio^{1

2}, Caroline Jonson^{3

4

5

6}, Yilin Wang⁷, Jennifer S Yokoyama^{6

8}, Jingshen Wang⁹, William Jagust¹; Alzheimer’s Disease Neuroimaging Initiative; Health and Aging Brain Study (HABS-HD) Study Team

Affiliations

¹ Department of Neuroscience, University of California Berkeley, Berkeley, California, USA, 94720.
² School of Psychological Sciences, College of Engineering, Science and the Environment, University of Newcastle, Newcastle, New South Wales, Australia, 2308.
³ Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD USA 20892.
⁴ DataTecnica LLC, Washington, DC, USA, 20037.
⁵ Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA, 94158.
⁶ Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA, 94158.
⁷ Department of Statistics and Actuarial Science, The University of Iowa, Iowa City, IA, USA.
⁸ Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
⁹ Division of Biostatistics, University of California Berkeley, Berkeley, California, USA, 94720.

Abstract

The canonical AD pathological cascade posits that the accumulation of amyloid beta ( $Aβ$ ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and $APOE- ε4$ homozygotes are more susceptible to the effects of $Aβ$ on the primary accumulation of tau, with greater EC tau for a given level of $Aβ$ . Furthermore, we observed for individuals who have rare risk variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and/or $APOE- ε4$ homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression, and have implications for determining personalised treatment with drugs targeting $Aβ$ and tau.

Publication types

Preprint

Abstract

Publication types

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