Plasma proteins, cognitive decline, and 20‐year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies

Abstract

Introduction: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. Methods:In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years.

Immune system and blood-brain barrier-wide biomarker analyses provide causal evidence for autoimmunity in dementia

“…94 Immune system and BBB search terms were identified using identifiers of cell types, receptors, proteins, metabolites, and genes. The identifiers were searched from several publications 3, 4, 6, 23, 36, 38, 40, 95, 96 and from Uniprot 97 with search terms “immune” and “blood brain barrier”. Outcomes included all cohorts with following diseases: all types of Alzheimer’s disease, Parkinson’s disease, vascular dementia, frontotemporal dementia, dementia in general, and progression of dementia.…”

“…Plasma protein measurements in Whitehall II study were available for 6,235 individuals of whom 310 developed dementia and the methods have been describe before ( SMethods ). 6, 99, 100 In brief, the plasma proteins were measured using the SomaScan version 4.0 and 4.1 assays. 6, 101, 102 The assays were validated against external reference population and protein-specific conversion coefficients were used to balance the technical differences between versions 4.0 and 4.1.…”

“…6, 99, 100 In brief, the plasma proteins were measured using the SomaScan version 4.0 and 4.1 assays. 6, 101, 102 The assays were validated against external reference population and protein-specific conversion coefficients were used to balance the technical differences between versions 4.0 and 4.1. Using DNA extracted from whole blood, a standard PCR assay determined APOE genotype using the salting out method.…”

“…The plasma proteins were measured using the SomaScan version 4.0 and 4.1 assays. 4, 16, 17 The assays were validated against external reference population and protein-specific conversion coefficients were used to balance the technical differences between versions 4.0 and 4.1. The analyses used plasma samples measured in 1995/1997 and stored in 0.25 mL aliquots at −80◦C.…”

“…1, 4 Because of the crosstalk between the central and peripheral immune system and BBB, the causal factors linking inflammation to dementias may originate from any of these systems. Chronic peripheral inflammation, from low-grade systemic inflammation 5, 6 and infections, 7 can disrupt BBB so that it allows neurotoxic and pro-inflammatory plasma components and pathogens to enter CNS. 4 Dysfunctional BBB may also promote peripherally driven neuroinflammation by increasing endothelial adhesion molecules and chemokines and migration of peripheral leukocytes to CNS.…”