Multiomics machine learning identifies inflammation molecular pathways in prodromal Alzheimer’s Disease

Abstract

Mild Cognitive Impairment (MCI) is a phase that can precede Alzheimer's Disease (AD). To better understand the molecular mechanisms underlying conversion from MCI to AD, we proposed a multiomics machine learning pipeline (four algorithms) to identify key pathways. Data consisted of metabolites (n=540) and proteins (n=3630) measured in blood plasma coupled with standard clinical tests (n=26). The cohort comprised 230 controls, 386 MCI participants and 184 AD-type dementia participants. Multiclass models showed that oleamide, MMSE and the priority language Z-score were the most relevant variables. Oleamide was increased in the MCI group and further increased in converters (both P<0.0001). In-vitro disease-associated microglia were able to synthesize oleamide and excrete it in vesicles. MCI conversion models showed pTau, tTau and JPH3, CFP, synuclein and PI15 proteins as the most relevant. This study uncovered molecular pathways in MCI conversion involved in inflammation (oleamide, CFP), neuronal regulation (JPH3, SNCA) and protein degradation (PI15).

A UHPLC–MS/MS method for determination of N-acylethanolamines in cerebrospinal fluid

“…Alzheimer’s disease (AD) can exhibit elevated levels of oleamide within blood and blood exosomes [35,36]. Additionally post-mortem analysis of AD brains have revealed significant alterations in the composition and signaling of the ECS [27].…”

“…The first hypotheses suggests that when microglia, the immune cells of the brain, become activated by a toxin such as amyloid/tau in the case of AD, eCBs are subsequently released. These eCBs are then transported within the extracellular vesicles to neighboring neurons where they potentially modulate their cellular activity [35]. This modulation could be related to sedative effects or sleep-inducing effects, one of the known protective functions of eCBs, maybe preventing hyperactivity damage to neurons [37].…”

“…On the other hand, the biosynthesis of oleamide is primarily localized within the brain microglia [34], and there is limited data available regarding its synthesis beyond the CNS. Oleamide is detectable in human plasma and notably individuals diagnosed with Alzheimer's disease (AD) can exhibit elevated levels of oleamide within blood and blood exosomes [35,36]. Additionally post-mortem analysis of AD brains have revealed significant alterations in the composition and signaling of the ECS [27].…”