medRxiv : the preprint server for health sciences · 2025
Association between epigenetic aging acceleration and amyloid biomarkers in bipolar disorder.
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Fries Gabriel R, Garza Steven De La, Zhao Ning O, Bass Andres W, Lima Camila N C, Kobori Nobuhide, Barichello Tatiana, Turecki Gustavo, Schulz Paul E, Diniz Breno S, Soares Jair C
Аннотация
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.
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.