Protein biomarkers in biofluids are highly sensitive indicators of prodromal cognitive impairment yet remain limited for primary prevention. Lipids, essential to brain structure and function, offer un Show more
Protein biomarkers in biofluids are highly sensitive indicators of prodromal cognitive impairment yet remain limited for primary prevention. Lipids, essential to brain structure and function, offer untapped prognostic value. Here, we identify a lipidomic signature in serum from asymptomatic PSEN1-E280A mutation carriers aged 6-40 years, that differentiate carriers from non-carriers with an AUC 80-90%. Similarly, to symptomatic carriers (≥41 years; 93%) and sporadic AD cases (85%), using high-resolution mass spectrometry. Latent profile analysis revealed lipid-based signatures of dementia risk and resilience, shaped by genotype, sex, and APOE isoform, and supported by SIMOA protein biomarkers. Age-dependent dysregulation in sphingolipid and glycolipid metabolism was validated by enzymatic activity (TLC), glial phenotyping (flow cytometry), and gene expression (snRNAseq) in postmortem brain. Ganglioside clearance deficits emerged by age 6-12, followed by proinflammatory shifts from age 13 and p-tau217 elevation by age 20, with greater burden in females and APOE4 carriers. APOE3Ch individuals showed differential salvage pathways of ceramides and gangliosides. These findings position early lipid pathway dysregulation as a biological contributor to Alzheimer's pathogenesis and a potential therapeutic target for primary prevention. Show less
Proteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzhei Show more
Proteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction. In this study, we analyzed the relationship between BACE1 and SCD1 Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids. Show less