Objectives Bipolar disorder (BD) has been associated with an elevated risk of Alzheimer’s Disease (AD). We assessed AD biomarkers in BD and tested whether epigenetic aging (EA) acceleration is a potential mechanism driving variability in these markers.

Design, Setting, Participants Cross-sectional study of n=59 living individuals with BD and n=20 age- and sex-equated control participants, as well as analyses of postmortem brain samples (Brodmann area 9/46) from n=46 individuals with BD.

Measurements Amyloid beta (Aβ)40, Aβ42, and total Tau levels were measured in plasma from individuals with BD and controls, and Aβ42 levels were measured in brains. EA and its acceleration (blood: GrimAge and DunedinPACE; brains: DNAmClockCortical) were estimated for all samples. Individuals with BD were split into quartiles with accelerated or slower EA if they were in the first or fourth quartiles for GrimAge acceleration (AgeAccelGrim), DunedinPACE, or DNAmClockCortical acceleration (DNAmClockCorticalAccel).

Results Individuals with BD showed an increase in Aβ40 (p=.049) and a decrease in the Aβ42/40 ratio (p=.035) compared to controls. A decrease in the Aβ42/40 ratio was also found in individuals with BD with high versus low AgeAccelGrim (p=.028). Brain Aβ42 levels significantly correlated with DNAmClockCorticalAccel (r2=.270, p=.007), with those with high EA acceleration showing higher brain Aβ42 after controlling for confounders (p=.008).

Conclusions Our results provide preliminary evidence that EA may explain the variability in AD risk in individuals with BD and could act as a target for preventing dementia and AD in BD.

JCS serves on the Advisory Board of Alkermes, serves as a consultant for Johnson & Johnson and Sunovian, and has received research grants from Compass Pathways, Mind Med, and Relmada. For the remaining authors, no conflicts of interest were declared.

This study was partly funded by the National Institute of Mental Health (NIMH, MH121580 to GRF) and the Baszucki Brain Research Fund/Milken Institute (GRF). TB is funded by the Texas Alzheimer's Research and Care Consortium (TARCC 2022-26) and an NIH/NIA grant R01 AG072491. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Texas Alzheimer's Research and Care Consortium, or the Baszucki Research Foundation.

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Ethics committee/IRB of The University of Texas Health Science Center at Houston gave ethical approval for this work.

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