Distinct Multimodal Imaging Correlates of Depression in Middle-Aged Adults With and Without a Family History of Alzheimer Disease

Duarte Abritta, B.; Abulafia, C.; Fiorentini, L.; Tafet, G.; Brusco, L. I.; Tsuchiyagaito, A.; Mathew, S. J.; Villarreal, M. F.; Guinjoan, S. M.

doi:10.64898/2026.04.13.717731

bioRxiv · 10.64898/2026.04.13.717731

Distinct Multimodal Imaging Correlates of Depression in Middle-Aged Adults With and Without a Family History of Alzheimer Disease

Duarte Abritta, B.·Abulafia, C.·Fiorentini, L.·Tafet, G.·Brusco, L. I.·Tsuchiyagaito, A.·Mathew, S. J.·Villarreal, M. F.·Guinjoan, S. M.

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Abstract

BackgroundDepression is associated with risk for late-onset Alzheimers disease (LOAD), but its underlying pathogenesis in at-risk individuals remains unclear. We examined multimodal imaging correlates of depressive symptoms in cognitively normal middle-aged offspring of patients with LOAD (O-LOAD) compared with control individuals without LOAD history up to a 4th degree of kinship (HC). MethodsParticipants (n=58; 52{+/-}3 years; 74% female) underwent assessment with the Beck Depression Inventory-II (BDI), structural MRI, resting-state fMRI, FDG-PET, and PiB-PET. Resting-state fMRI data were available for 28 O-LOAD and 24 HC; PET data for 24 O-LOAD and 22 HC. General linear models tested associations between imaging measures and BDI, including group interactions. ResultsIn O-LOAD, higher BDI scores were associated with reduced cortical thickness in the left postcentral gyrus. Resting-state fMRI revealed significant group-by-BDI interactions involving cingulate and orbitofrontal networks. In O-LOAD, greater depressive symptom severity was associated with reduced cingulate connectivity across distributed corticolimbic, prefrontal, insular, occipital, and cerebellar regions ({beta} range -0.10 to -0.18). In HC, depressive symptoms were associated with reduced right orbitofrontal and somatosensory-medial orbitofrontal connectivity ({beta}=-0.13), with divergent patterns of cingulate connectivity. FDG-PET showed no significant associations with depressive symptoms. PiB-PET demonstrated regionally specific associations between amyloid signal and BDI in HC, involving an inverse pattern in anterior and posterior insular cortices. ConclusionsDepressive symptoms in middle-aged individuals at familial risk for LOAD are associated with distinct structural and functional alterations, involving circuitry subserving salience and reward, and suggesting early network-level mechanisms linking affective symptoms with vulnerability to neurodegeneration.

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Duarte Abritta, B., Abulafia, C., Fiorentini, L., Tafet, G., Brusco, L. I., Tsuchiyagaito, A., Mathew, S. J., Villarreal, M. F., Guinjoan, S. M.. 2026-04-17. Distinct Multimodal Imaging Correlates of Depression in Middle-Aged Adults With and Without a Family History of Alzheimer Disease. https://doi.org/10.64898/2026.04.13.717731

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