Blood-based protein mediators of senility with replications across biofluids and cohorts

Abstract

Dementia severity can be quantitatively described by the latent dementia phenotype 'δ' and its various composite 'homologues'. We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium. However, it would be convenient to replicate them in the Alzheimer's Disease Neuroimaging Initiative. To that end, we have engineered a δ homologue from the observed cognitive performance measures common to both projects [i.e. 'd:Texas Alzheimer's Research and Care Consortium to Alzheimer's Disease Neuroimaging Initiative' (dT2A)]. In this analysis, we confirm 13/22 serum proteins as partial mediators of age's effect on dementia severity as measured by dT2A in the Texas Alzheimer's Research and Care Consortium and then replicate 4/13 in the Alzheimer's Disease Neuroimaging Initiative's plasma data. The replicated mediators of age-specific effects on dementia severity are adiponectin, follicle-stimulating hormone, pancreatic polypeptide and resistin. In their aggregate, the 13 confirmed age-specific mediators suggest that 'cognitive frailty' pays a role in dementia severity as measured by δ. We provide both discriminant and concordant support for that hypothesis. Weight, calculated low-density lipoprotein and body mass index are partial mediators of age's effect in the Texas Alzheimer's Research and Care Consortium. Biomarkers related to other disease processes (e.g. cerebrospinal fluid Alzheimer's disease-specific biomarkers in the Alzheimer's Disease Neuroimaging Initiative) are not. It now appears that dementia severity is the sum of multiple independent processes impacting δ. Each may have a unique set of mediating biomarkers. Age's unique effect appears to be at least partially mediated through proteins related to frailty. Age-specific mediation effects can be replicated across cohorts and biofluids. These proteins may offer targets for the remediation of age-specific cognitive decline (aka 'senility'), help distinguish it from other determinants of dementia severity and/or provide clues to the biology of Aging Proper.

Keywords: aging; cognition; dementia; g; intelligence.

Graphical abstract

Figure 1

Fully adjusted MIMIC mediation model of serum resistin as a mediator of age’s unique association with the latent dT2A homologue in TARCC. Age’s association with the bifactor dT2A δ homologue is being partially mediated by serum resistin in TARCC’s NHW sample (N = 2251) independently of age’s direct effects on individual cognitive performance measures. Gender had no significant independent association with dT2A and was omitted from the model. AGE is correlated to EDUC, APOE4, GENDER and GDS (paths not shown). EDUC is also correlated with e8. Statistically significant structural paths of interest are in bold. Animals = animal naming; BNT = Boston Naming Test; CHI SQ = chi square; CD40 = cluster of differentiation 40; CFI = comparative fit index; EDUC = education (years); FIB = fibrinogen; FRTN = ferritin; HCC4 = human C–C motif chemokine-4; IADL = instrumental activities of daily living; IgE = immunoglobulin E; LMI = Wechsler Logical Memory immediate recall; LMII = Wechsler Logical Memory delayed recall; MIP-1a = macrophage inflammatory protein 1 alpha; MIP-1b = macrophage inflammatory protein 1 beta; MMSE = Mini–Mental State Examination; PAP = prostatic acid phosphatase; RMSEA = root-mean-square evaluative assessment; Trails B = Trail-Making Test Part B.

Figure 2

Fully adjusted MIMIC mediation model of plasma resistin as a mediator of age’s unique association with the latent dT2A homologue in in ADNI. Age’s association with the bifactor dT2A δ homologue is being partially mediated by plasma resistin in ADNI’s NHW sample (N = 1668) independently of age’s direct effects on individual cognitive performance measures. AGE is correlated to EDUC, APOE4, GENDER and GDS (paths not shown). EDUC is also correlated with e8. Statistically significant structural paths of interest are in bold. Animals = animal naming; BNT = Boston Naming Test; CHI SQ = chi square; CD40 = cluster of differentiation 40; CFI = comparative fit index; EDUC = education (years); FAQ = Functional Abilities Questionnaire; FIB = fibrinogen; FRTN = ferritin; HCC4 = human C–C motif chemokine-4; IgE = immunoglobulin E; LMI = Wechsler Logical Memory immediate recall; LMII = Wechsler Logical Memory delayed recall; MIP-1a = macrophage inflammatory protein 1 alpha; MIP-1b = macrophage inflammatory protein 1 beta; MMSE = Mini–Mental State Examination; PAP = prostatic acid phosphatase; RMSEA = root-mean-square evaluative assessment; Trails B = Trail-Making Test Part B.