The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depression, gender and the apolipoprotein E (APOE) e4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of APOE’s specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer’s Research and Care Consortium (TARCC). APOE was associated only with C-Reactive Protein (CRP), Adiponectin (APN) and Amphiregulin (AREG), although the latter two’s associations did not survive Bonferroni correction for multiple comparisons. All three proteins were associated with δ and had weak potential mediation effects on APOE’s association with that construct. Our findings suggest that APOE’s association with cognitive performance is specific to δ and partially mediated by serum inflammatory proteins. The majority of APOE’s significant unadjusted effect on δ is unexplained. It may instead arise from direct central nervous system effects, possibly on native intelligence. If so, then APOE may exert a life-long influence over δ and therefore all-cause dementia risk.

The latent variable “δ” (for “dementia”) uniquely explains dementia severity. Depressive symptoms are independent predictors of δ. We explored 115 serum proteins as potential causal mediators of the effect of depressive symptoms on δ in a large, ethnically diverse, longitudinal cohort. All models were adjusted for age, apolipoprotein E, education, ethnicity, gender, hemoglobin A1c, and homocysteine, and replicated in randomly selected 50% subsets. Alpha1-antitrypsin (A1AT), FAS, Heparin-binding EGF-like Growth Factor (HB-EGF), Insulin-like Growth Factor-1 (IGF-1), Luteinizing Hormone (LH), Macrophage Inflammatory Protein type 1 alpha (MIP-1α), Resitin, S100b, Tissue Inhibitor of Metalloproteinase type 1 (TIMP-1), and Vascular Cell Adhesion Molecule type 1 (VCAM-1) each were partial mediators of depression’s association with δ. These proteins may offer targets for the treatment of depression’s specific effect on dementia severity and Alzheimer’s Disease (AD) conversion risk.

The latent variable “δ” (for “dementia”) appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depressive symptoms, gender and the apolipoprotein E (APOE) ε4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of age's specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). 22 serum proteins were recognized as partial mediators of age's association with δ. These include Insulin-like Growth Factor-Binding Protein 2 (IGF-BP2), which we had previously associated with age-specific cognitive change, and both Pancreatic Polypeptide (PP) and von Willebrand Factor (vWF), previously associated with δ. Nine other δ-related proteins were not confirmed by this ethnicity adjusted analysis. Our findings suggest that age's association with the disabling fraction of cognitive performance is partially mediated by serum proteins, somatomedins and hormones. Those proteins may offer targets for the specific treatment of age-related effects on dementia severity and conversion risk.

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