Alzheimer’s disease biomarker profiling in a memory clinic cohort without common comorbidities

Abstract

AbstractBackgroundComorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to Alzheimer disease (AD) progression. However, their mechanistic contribution to pathology and neurodegeneration has not been clarified. The aim of this study was to investigate cerebrospinal fluid (CSF) levels of markers reflecting brain changes in synaptic integrity, inflammation, oxidative stress, glucose homeostasis and cholesterol metabolism in memory clinic patients without known AD comorbidities.MethodCSF samples from 90 memory clinic patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, were used to investigate 13 molecular markers representing key mechanisms underlying AD pathogenesis. Associations were analyzed by linear regression. Two‐step cluster analysis was used to determine patient clusters. Two key markers were analyzed by immunofluorescence staining in hippocampus from control and AD individuals.ResultCSF angiotensinogen, thioredoxin‐1, and interleukin‐15 had the most prominent associations with AD pathology, synaptic and axonal damage. SNAP‐25 and NFL were increased in MCI and AD cases. Grouping biomarkers by biological function, showed that inflammatory and survival components were associated with AD pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data‐driven analysis, two patient clusters were identified; cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared to cluster 2. Clinical groups were evenly distributed between the clusters. Analysis of post‐mortem hippocampal tissue, showed that, compared to non‐demented controls, angiotensinogen staining was higher in AD and co‐localized with phosphorylated‐tau.ConclusionThe identification of biomarker‐driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of AD and the importance of tailored prevention and treatment strategies.