Relation between cardiovascular health and Alzheimer: unraveling the role of lipid metabolism and related proteins through DIA-PASEF

Dementia of the Alzheimer's type (DAT) is the most common cause of dementia worldwide. Cardiovascular risk factors and established cardiovascular disease (CVD) are known to increase the risk of suffering DAT, although the molecular mechanisms involved in that relationship remain unclear. Here, we set out to define specific proteomic and metabolomic profiles of CVD in patients with DAT to better understand the relationship between these conditions, to unravel the mechanisms underlying the high risk of developing DAT in CVD patients and to define new markers of early phases of this disease.

Plasma samples from patients with DAT alone, or patients with DAT and CVD, were analyzed through a multiomics approach that centered on DIA-PASEF technology, and that integrated the proteomics and metabolomics datasets using the OmicsNet web-based tool. ABCA1 and APOH were identified in this way as potential biomarkers for the combined condition, as verified through immunoblotting in an independent cohort with two additional study groups: controls and patients with CVD alone.

The metabolomics results showed an enrichment in lipids and lipid-like molecules, especially in fatty acids and sterol lipids. Similarly, the most significant cluster identified in the proteomics study was formed by 5 proteins related to lipoprotein and cholesterol metabolism, including ABCA1 and APOH. After integration and functional enrichment according to the KEGG database, we found glycerolipid metabolism, fatty acid degradation and sphingolipid metabolism to be among the most significant functions. Finally, differential expression of ABCA1 and APOH was verified through immunodetection, with higher levels in patients with DAT and CVD, and positively correlated with phospho-Tau (181), a classical hallmark of DAT.

Different molecular profiles appear to exist in patients with DAT, with and without CVD. Alterations can be detected in both diseases but such dysregulation is exacerbated in patients in which DAT and CVD co-exist. This information may help to define new biomarkers like ABCA1 and APOH that identify patients with cardiovascular dysfunction that are at high risk of developing DAT. Such markers will allow more personalized patient interventions to be selected, a further step towards precision medicine for individuals whose molecular profiles might indicate a distinct response to the same management strategies.