Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Dementia: A Pilot Study.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a ß-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

PON1 and PON3 in Alzheimer's Disease: Similar Functions but Different Roles.

Paraoxonase 1 (PON1) and Paraoxonase 3 (PON3) are enzymes located on the surface of high-density lipoprotein (HDL) and share similar antioxidant properties, possibly modulated by other proteins such as Myeloperoxidase (MPO), which drives the shift from functional to dysfunctional HDL. PON1 has been extensively studied in relation to Alzheimer's Disease (AD), but the role of PON3 remains unknown. To fill this knowledge gap, the study analyzed PON3 protein levels and PON1-arylesterase activity in 99 AD patients, 100 patients with mild cognitive impairment (MCI), and 79 cognitively normal controls. The results showed that serum PON3 levels remained unchanged across all groups. In contrast, serum arylesterase activity was significantly reduced in both AD and MCI patients compared to controls (p < 0.001 for both comparisons). Surprisingly, there was no correlation between arylesterase activity and MPO protein concentration or activity. However, PON3 was found to have a significant positive correlation with both MPO concentration (r = 0.507, p < 0.0001) and MPO activity (r = 0.264, p < 0.01). In conclusion, we demonstrated for the first time that PON1 and PON3 have distinct relationships with AD, with only PON1 showing a decrease in activity in this disease, while PON3 levels remained unchanged. Another noteworthy finding was the selective correlation between PON3 and MPO, which may suggest a preferential physical association of PON3 with dysfunctional HDL.

High plasma homocysteine levels predict the progression from mild cognitive impairment to dementia.

High levels of blood homocysteine (HCy), a well-known cardiovascular risk factor and promoter of oxidative stress, have been associated with the incidence of cognitive impairment and dementia. Nonetheless, contrasting data are still present on its involvement in the progression from Mild Cognitive Impairment (MCI) to overt dementia. In this study we aimed to observe whether blood HCy level are associated with the evolution from MCI, divided into amnestic MCI (aMCI) and non-amnestic MCI (naMCI), to dementia. Blood HCy was measured in 311 MCI subjects (aMCI: 64%, naMCI: 36%) followed-up for a median of 33 months (range 10-155 months). At follow-up, 137 individuals converted to dementia (naMCI, n = 34; aMCI, n = 103). Based on HCy distribution, subjects in the highest tertile had a greater risk to convert to dementia compared to tertile I (Hazard Ratio (95% confidence interval): 2.25 (1.05-4.86); p = 0.04). aMCI subjects did not show increased risk to convert to dementia with increasing HCy concentration, but was significant in naMCI (p = 0.04). We observed a non-significant increase in the risk of progression to dementia from naMCI/low HCy (reference group, HCy cutoff value = 16 µmol/L) to naMCI/high HCy, but it was significant from aMCI/low HCy (HR: 2.73; 95%CI: 1.06-7.0; p:0.03), to aMCI/high HCy (HR: 3.24; 95%CI: 1.17-8.47; p:0.02). Our results suggest that HCy levels are associated with the progression from MCI to dementia. This association seems significant only for the naMCI group, indirectly supporting the notion that hyperhomocysteinemia damages the nervous system through its role as a vascular risk factor.