The mechanisms linking a history of major depressive disorder (MDD) to an increased risk of Alzheimer disease and related dementia (ADRD) are not fully understood. Using the UK Biobank available proteomic and genomic data, we evaluated the biological mechanisms linking both conditions. In participants with a history of MDD at baseline (n=3,615), we found that plasma levels of NfL, GFAP, PSG1 were associated with higher risk (HR=1.38; 1.37; 1.34, respectively; all adjusted p-values<0.05), while VGF, GET3, and HPGDS were associated with lower risk of incident ADRD (n=150) (HR=0.73; 0.71; 0.66, respectively; all adjusted p-values<0.05) during a mean follow-up of 13.7 years (SD=2.2). Two-sample Mendelian randomization analysis using cis-pQTLs genetic instruments revealed that a lower protein expression of apolipoprotein E and higher IL-10 receptor subunit B were causally linked to incident ADRD. Finally, we developed a Proteomic Risk Score (PrRSMDD-ADRD), which showed strong discriminative power (C-statistic = 0.84) to identify participants with MDD that developed ADRD upon follow-up. In addition to demonstrating an association between plasma proteins associated with inflammation and future ADRD risk in individuals with MDD, our findings include an element of causality using Mendelian Randomization (MR) and PrRSMDD-ADRD can be useful to identify individuals with the highest risk to develop ADRD in a highly vulnerable population.

Dr. Diniz serves as a consultant to Bough Bioscience Inc in an area unrelated to this work. The other authors report no conflict of interest.

This work was supported by NIH grant P30AG067988

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