Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions.
Joseph GiorgioCaroline JonsonYilin WangJennifer S YokoyamaJingshen WangWilliam J Jagustnull nullnull nullPublished in: Research square (2024)
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.
Keyphrases
- cerebrospinal fluid
- cognitive decline
- high fat diet
- high resolution
- bone marrow
- spinal cord injury
- inflammatory response
- healthcare
- gene expression
- adipose tissue
- oxidative stress
- functional connectivity
- acute myeloid leukemia
- spinal cord
- cell proliferation
- skeletal muscle
- mild cognitive impairment
- mass spectrometry
- chronic pain
- genome wide
- signaling pathway
- pain management
- combination therapy
- metabolic syndrome
- neuropathic pain