Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions
Abstract The canonical Alzheimer’s Disease (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 multi-cohort study (ADNI, A4, H...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60370-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849238392440619008 |
|---|---|
| author | Joseph Giorgio Caroline Jonson Yilin Wang Jennifer S. Yokoyama Jingshen Wang William J. Jagust On behalf of the Alzheimer’s Disease Neuroimaging Initiative |
| author_facet | Joseph Giorgio Caroline Jonson Yilin Wang Jennifer S. Yokoyama Jingshen Wang William J. Jagust On behalf of the Alzheimer’s Disease Neuroimaging Initiative |
| author_sort | Joseph Giorgio |
| collection | DOAJ |
| description | Abstract The canonical Alzheimer’s Disease (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 multi-cohort study (ADNI, A4, HABS-HD) of 1354 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 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. |
| format | Article |
| id | doaj-art-9dea6ac1795840d4b81962d1e5f4a979 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9dea6ac1795840d4b81962d1e5f4a9792025-08-20T04:01:36ZengNature PortfolioNature Communications2041-17232025-07-0116111210.1038/s41467-025-60370-8Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regionsJoseph Giorgio0Caroline Jonson1Yilin Wang2Jennifer S. Yokoyama3Jingshen Wang4William J. Jagust5On behalf of the Alzheimer’s Disease Neuroimaging InitiativeDepartment of Neuroscience, University of California BerkeleyCenter for Alzheimer’s and Related Dementias, National Institutes of HealthDepartment of Statistics and Actuarial Science, The University of IowaMemory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San FranciscoDivision of Biostatistics, University of California BerkeleyDepartment of Neuroscience, University of California BerkeleyAbstract The canonical Alzheimer’s Disease (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 multi-cohort study (ADNI, A4, HABS-HD) of 1354 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 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.https://doi.org/10.1038/s41467-025-60370-8 |
| spellingShingle | Joseph Giorgio Caroline Jonson Yilin Wang Jennifer S. Yokoyama Jingshen Wang William J. Jagust On behalf of the Alzheimer’s Disease Neuroimaging Initiative Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions Nature Communications |
| title | Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions |
| title_full | Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions |
| title_fullStr | Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions |
| title_full_unstemmed | Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions |
| title_short | Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions |
| title_sort | variable and interactive effects of sex apoe ε4 and trem2 on the deposition of tau in entorhinal and neocortical regions |
| url | https://doi.org/10.1038/s41467-025-60370-8 |
| work_keys_str_mv | AT josephgiorgio variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions AT carolinejonson variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions AT yilinwang variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions AT jennifersyokoyama variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions AT jingshenwang variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions AT williamjjagust variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions AT onbehalfofthealzheimersdiseaseneuroimaginginitiative variableandinteractiveeffectsofsexapoee4andtrem2onthedepositionoftauinentorhinalandneocorticalregions |