APOE ϵ2 vs APOE ϵ4 dosage shows sex-specific links to hippocampus-default network subregion co-variation

Savignac, C.; Villeneuve, S.; Badhwar, A.; Saltoun, K.; Shafighi, K.; Zajner, C.; Sharma, V.; Taliun, S. A. G.; Farhan, S.; Poirier, J.; Bzdok, D.

doi:10.1101/2022.03.15.484482

bioRxiv · 10.1101/2022.03.15.484482

APOE ϵ2 vs APOE ϵ4 dosage shows sex-specific links to hippocampus-default network subregion co-variation

Savignac, C.·Villeneuve, S.·Badhwar, A.·Saltoun, K.·Shafighi, K.·Zajner, C.·Sharma, V.·Taliun, S. A. G.·Farhan, S.·Poirier, J.·Bzdok, D.

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Abstract

Alzheimers disease and related dementias (ADRD) are marked by intracellular tau aggregates in the medial-temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we sought to clarify ADRD-related co-dependencies between the MTLs most vulnerable structure, the hippocampus (HC), and the highly associative DN at a subregion resolution. We confronted the effects of APOE {varepsilon}2 and {varepsilon}4, rarely investigated together, with their impact on HC-DN co-variation regimes at the population level. In a two-pronged decomposition of structural brain scans from [~]40,000 UK Biobank participants, we located co-deviating structural patterns in HC and DN subregions as a function of ADRD family risk. Across the disclosed HC-DN signatures, recurrent deviations in the CA1, CA2/3, molecular layer, fornixs fimbria, and their cortical partners related to ADRD risk. Phenome-wide profiling of HC-DN co- variation expressions from these population signatures revealed male-specific associations with air-pollution, and female-specific associations with cardiovascular traits. We highlighted three main factors associated with brain-APOE associations across the different gene variants: happiness, and satisfaction with friendships, and with family. We further showed that APOE {varepsilon}2/2 interacts preferentially with HC-DN co-variation patterns in estimating social lifestyle in males and physical activity in females. Our findings reinvigorate the often-neglected interplay between APOE {varepsilon}2 dosage and sex, which we have linked to fine-grained structural divergences indicative of ADRD susceptibility.

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Savignac, C., Villeneuve, S., Badhwar, A., Saltoun, K., Shafighi, K., Zajner, C., Sharma, V., Taliun, S. A. G., Farhan, S., Poirier, J., Bzdok, D.. 2022-03-15. APOE ϵ2 vs APOE ϵ4 dosage shows sex-specific links to hippocampus-default network subregion co-variation. https://doi.org/10.1101/2022.03.15.484482

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