Sex modulates the association between Alzheimer’s-related neuroinflammation and affective symptoms

Isabella Harb Bizzi1,2, Arthur Cassa Macedo2, Etienne Aumont2, Lydia Trudel2, Seyyed Ali Hosseini2, Marina Pereira Gonçalves2, Joseph Therriault2, Nesrine Rahmouni2, Tevy Chan2, Marcel Woo2, Gleb Bezgin2, Brandon Hall2, Delphine Lopez2, Aurélie Lebrun2, Juliana Godoy2, Kely Quispialaya Socualaya2, Jenna Stevenson2, Yansheng Zheng2, Gabriela Mantovani Baldasso2, Rodrigo Paes2, Cristiano Schaffer Aguzzoli3, Douglas T. Leffa4, Nicholas Ashton5, Thomas Karikari4, Henrik Zetterberg5, Kaj Blennow5, Tharick Pascoal4, Eduardo Zimmer6, Andrea Lessa Benedet5, Pedro Rosa-Neto2,7

Aim:

Investigate whether neuroinflammatory markers are associated with depressive and anxiety symptoms in a sex-dependent manner in the context of AD

Methods:

Participants: 50 cognitively unimpaired and 30 cognitively impaired individuals

Scanned with amyloid-β-PET ([¹⁸F]AZD4694) and  tau-PET ([¹⁸F]MK6240)

Plasma glial fibrillary acidic protein (GFAP), and CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) assessments

Depressive and anxiety symptoms evaluated using the Geriatric Depression Scale (GDS-30) and the Generalized Anxiety Disorder-7 (GAD-7)

Associations examined using multiple linear regression models

Results: 

Higher anxiety was positively associated with CSF sTREM2 in a sex-dependent manner, with a significant sTREM2 × male interaction.

There were significant three-way interactions between amyloid-β:

-GFAP and male sex for depressive symptoms

-sTREM2 and male sex for anxiety

No significant interactions were found in tau-based models.

In sex-stratified analyses, GFAP was negatively associated with depressive symptoms in women.

sTREM2 was positively associated with both depression and anxiety in men.

Conclusions: