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.

Cerebral Blood Flow in Alzheimer's Disease: A Meta-Analysis on Transcranial Doppler Investigations.

BACKGROUND: Cerebrovascular hemodynamic impairment has been reported in Alzheimer's disease (AD). We performed a systematic review and meta-analysis to investigate changes in cerebral blood flow (CBF) in AD patients. METHODS: Data were obtained by searching MEDLINE and Scopus for all investigations published between 1 January 2011 and 1 November 2021, comparing the cerebrovascular hemodynamic between AD patients and cognately healthy age-matched controls, using transcranial Doppler (TCD) ultrasound. RESULTS: Twelve studies, based on 685 patients [395 with AD and 290 age-matched cognitively healthy controls, with a mean age of 71.5 and 72.1 years, respectively] were included in the analysis. A random effect model revealed that AD patients, in the proximal segments of the middle cerebral artery (MCA), have a significantly lower CBF velocity, compared to controls (MD: -7.80 cm/s, 95%CI: -10.78 to -5.13, p < 0.0001, I2 = 71.0%). Due to a significant Egger's test (t = 3.12, p = 0.008), a trim-and-fill analysis was performed, confirming the difference (MD: -11.05 cm/s, 95%CI: -12.28 to -9.82, p < 0.0001). Meta-regression analysis demonstrated that the mean CBF at the proximal MCA was directly correlated with arterial hypertension (p = 0.03) and MMSE score (p < 0.001), but inversely correlated with age (p = 0.01). In AD patients, the pulsatility index was significantly higher compared to controls (MD: 0.16, 95%CI: 0.07 to 0.25, p < 0.0001, I2: 84.5%), while the breath-holding index test results were significant lower (MD: -1.72, 95%CI: -2.53 to -0.91, p < 0.001, I2: 85.4%). CONCLUSIONS: AD patients have a significant impairment in relation to their cerebrovascular perfusion, suggesting that cerebrovascular hemodynamic deterioration, evaluated using TCD, may be a useful diagnostic tool.

Variability in Alzheimer's disease mortality from European vital statistics, 2012-2020.

OBJECTIVE: Data regarding the trends in Alzheimer's disease (AD) mortality in the modern European Union (EU-27) member states are lacking. We assess the sex- and age-specific trends in AD mortality in the EU-27 member states between years 2012 and 2020. METHODS: Data on cause-specific deaths and population numbers by sex for each country of the EU-27 were retrieved through publicly available European Statistical Office (EUROSTAT) dataset from 2012 to 2020. AD-related deaths were ascertained when the ICD-10 code G30 was listed as the primary cause of death in the medical death certificate. To calculate annual trends, we assessed the average annual percent change (AAPC) with relative 95% confidence intervals (CIs) using Joinpoint regression. RESULTS: During the study period, 751,493 deaths (1.7%, 233,271 males and 518,222 females) occurred in the EU-27 because of AD. Trends in the proportion of AD-related deaths per 1000 total deaths slightly increased from 16.8% to 17.5% (p for trend <0.001). The age-adjusted mortality rate was higher in women over the entire study period. Joinpoint regression analysis revealed a stagnation in age-adjusted AD-related mortality from 2012 to 2020 among EU-27 Member States (AAMR: -0.1% [95% CI: -1.8-1.79], p = 0.94). Stratification by Country showed relevant regional disparities, especially in the Northern and Eastern EU-27 member states. CONCLUSIONS: Over the last decade, the age-adjusted AD-related mortality rate has plateaued in EU-27. Important disparities still exist between Western and Eastern European countries.

Acetyl-cholinesterase-inhibitors reconsidered. A narrative review of post-marketing studies on Alzheimer's disease.

The real efficacy of Acetyl-cholinesterase-inhibitors (AChEI) has been questioned. In this narrative review we evaluated their effect on cognitive decline, measured by Mini Mental State Examination (MMSE), and on total mortality rates in patients with Alzheimer's disease (AD) recruited into post-marketing open/non-randomized/retrospective studies. In AD patients treated with AChEI, the mean MMSE loss ranged from 0.2 to 1.37 points/years, compared with 1.07-3.4 points/years in non-treated patients. Six studies also reported data about survival; a reduction in total mortality relative risk between 27% and 42% was observed, over a period of 2-8 years. The type of studies and the use of MMSE to assess cognitive decline, may have introduced several biases. However, the clinical effects of AChEI seem to be of the same order of magnitude as the drugs currently used in most common chronic disorders, as regards progression of the disease and total mortality. In the absence of long-term randomized trials on "standard" unselected AD outpatients, open/retrospective studies and health databases represent the best available evidence on the possible effect of AChEI in the real-word setting. Our data support the clinical benefit of AChEI in older patients affected by AD.

Serum zonulin levels are increased in Alzheimer's disease but not in vascular dementia.

BACKGROUND: Zonulin is involved in the integrity and functioning of both intestinal-epithelial barrier and blood-brain barrier (BBB) by regulating tight junction molecular assembly. AIM: Since changes in microbiota and BBB may play a role in neurodegenerative disorders, we aimed to determine whether serum zonulin levels change in older patients affected by different types of dementia or mild cognitive impairment (MCI). METHODS: We evaluated serum zonulin levels in patients with late-onset AD (LOAD), vascular dementia (VAD), MIXED (AD + VAD) dementia, amnestic MCI, and in healthy controls. RESULTS: Compared with controls, serum zonulin increased in LOAD, MIXED dementia, and aMCI but not in VAD, independent of potential confounders (ANCOVA p = 0.01; LOAD vs controls, p = 0.01; MIXED vs. controls, p = 0.003; aMCI vs. controls, p = 0.04). Notably, aMCI converting to dementia showed significantly higher levels of zonulin compared with stable aMCI (p = 0.04). Serum zonulin inversely correlated with the standardized Mini-Mental State Examination (MMSE) score (p < 0.05), regardless of potential confounders. DISCUSSION: We found increased serum zonulin levels in patients with aMCI, LOAD and MIXED dementia, but not in VAD; moreover, zonulin levels were higher in aMCI converting to AD compared with stable ones. CONCLUSIONS: Our findings suggest that a dysregulation of intestinal-epithelial barrier and/or BBB may be an early specific event in AD-related neurodegeneration.

Paraoxonase 1 activity in patients with Alzheimer disease: Systematic review and meta-analysis.

Cumulating evidence links environmental toxicants, such as organophosphate (OP) pesticides, to the pathogenesis of Alzheimer's disease (AD). The calcium-dependent Paraoxonase 1 (PON1) can neutralize these toxicants with good catalytic efficiency, thus protecting from OP-induced biological damage. Although different previous studies have already partially described an association between PON1 activity and AD, this intriguing relationship has not yet been comprehensively examined. To fill this gap, we performed a meta-analysis of existing data comparing the PON1 arylesterase activity in AD and healthy subjects from the general population. Data were obtained by searching MEDLINE, Embase and CENTRAL, Google Scholar, and SCOPUS electronic databases for all studies published at any time up to February 2023, reporting and comparing the PON1- paraoxonase activity between AD patients and controls. Seven studies, based on 615 subjects (281 AD and 356 controls) met the inclusion criteria and were included into the final analysis. A random effect model revealed that PON1 arylesterase activity was significantly lower in the AD group compared to controls, exhibiting low level of heterogeneity (SMD = - 1.62, 95% CI = -2.65 to -0.58, p = 0.0021, I2 = 12%). These findings suggest that PON1 activity might be reduced in AD reflecting a major susceptibility to OPs neurotoxicity. Further studies should be conducted to definitely ascertain this link and to establish the cause-effect relationship between PON1 reduction and AD onset.

Frontier on Alzheimer's Disease.

Although substantial progress has been made in the last two decades, there are still important unfilled gaps in the understanding of the pathomechanism of Alzheimer's disease (AD) [...].

Cholesterol efflux capacity is increased in subjects with familial hypercholesterolemia in a retrospective case-control study.

Familial Hypercholesterolemia (FH) is characterized by an increase in Low-Density Lipoprotein Cholesterol (LDL-C) and by premature Cardiovascular Disease (CVD). However, it remains to be fully elucidated if FH impairs cholesterol efflux capacity (CEC), and whether CEC is related to lipoprotein subfraction distribution. This study aimed at comparing FH patients and age, sex and BMI matched controls in terms of LDL and HDL subfraction distribution as well as CEC. Forty FH patients and 80 controls, matched for age, sex and BMI, were enrolled in this case-control study. LDL and HDL subfractions were analyzed using the Quantimetrix Lipoprint System. CEC was evaluated as aq-CEC and ABCA1-CEC. FH subjects showed a significantly higher concentration of all LDL subfractions, and a shift from large to small HDL subfraction pattern relative to controls. FH subjects with previous CVD event had smaller LDL lipoproteins than controls and FH subjects without previous CVD event. Both aq-CEC and ABCA1-CEC were increased in FH patients with respect to controls. To conclude, FH subjects had a metabolic profile characterized not only by higher LDL-C but also by shift from large to small HDL subfraction phenotype. However, FH subjects showed an increase CEC than controls.

Interleukin-18 Is a Potential Biomarker Linking Dietary Fatty Acid Quality and Insulin Resistance: Results from a Cross-Sectional Study in Northern Italy.

Dietary lipids are pivotal in modulating metabolic inflammation. Among the inflammatory mediators characterizing metabolic inflammation, interleukin 18 (IL-18) has been consistently associated with obesity and insulin resistance. This study aims to evaluate whether the quality of lipid intake impacts upon IL-18 plasma levels and the implications on insulin resistance computed by the homeostatic model assessment for insulin resistance (HOMA-IR). Using a cross-sectional design, this study confirmed that IL-18 correlated positively with insulin resistance and individuals with a HOMA-IR ≥ 2.5 displayed higher circulating IL-18 levels compared with their insulin-sensitive counterparts. In terms of the effect of the quality of dietary lipids on IL-18 circulating levels, the ratio between monounsaturated, omega-3, polyunsaturated and saturated fatty acids as well as the intake of eicosapentaenoic and docosahexaenoic acids correlated negatively with IL-18. Despite this, IL-18 circulating levels, but not dietary fatty acid quality, predicted insulin resistance. Nevertheless, the ratio between omega 3 and saturated fatty acids was a predictor of IL-18 plasma levels. Thus, the downregulation of IL-18 may underpin, at least partially, the beneficial metabolic effects of substituting omega 3 for saturated fatty acids with this cytokine potentially representing a biomarker linking dietary lipids and metabolic outcomes.

Lipoprotein-Associated Phospholipase A2 Activity as Potential Biomarker of Vascular Dementia.

A wealth of evidence suggests that Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a relevant role in atherogenesis and inflammation, which in turn are associated with the risk of developing dementia. The aim of this study was to evaluate whether serum Lp-PLA2 activity might be an early and/or late biomarker for different forms of dementia. Serum Lp-PLA2 activity was assessed in older patients with mild cognitive impairment (MCI, n = 166; median clinical follow-up = 29 months), Late-Onset Alzheimer's disease (LOAD, n = 176), vascular dementia (VAD, n = 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) (n = 136), other dementia subtypes (n = 45), and cognitively normal controls (n = 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA, p = 0.028). Similarly, Lp-PLA2 activity was greater in MCI converting to VAD compared with those that did not or did convert to the other types of dementia (ANOVA, p = 0.011). After adjusting for potential confounders, high levels of Lp-PLA2 activity were associated with the diagnosis of VAD (O.R. = 2.38, 95% C.I. = 1.06-5.10), but not with other types of dementia. Our data suggest that increased serum Lp-PLA2 activity may represent a potential biomarker for the diagnosis of VAD.

A Nutraceutical Compound Containing a Low Dose of Monacolin K, Polymethoxyflavones, Phenolic Acids, Flavonoids, and Hydroxytyrosol Improves HDL Functionality.

BACKGROUND: In earlier studies, it has been observed that 8-week treatment with a novel nutraceutical compound (NC) containing low monacolin K dose, polymethoxyflavones, phenolic acids, flavonoids, and hydroxytyrosol improves lipid profile and endothelial function and reduces the level of oxidized low-density lipoprotein (oxLDL). We hypothesize that this effect might be, at least in part, explained by positive modulation exerted by the NC on the atheroprotective function of high-density lipoprotein (HDL). AIM: This study aimed to evaluate whether the NC could influence determinants of HDL function. METHODS: Forty-five subjects with low-moderate dyslipidaemia were enrolled and treated for 8 weeks with the NC, followed by 4 weeks of washout. Blood samples were collected at every time point to evaluate changes in lipid profile, endothelial function, oxLDL, and markers of HDL function, such as the anti-oxidant activities of paraoxonase-1, glutathione peroxidase-3 (Gpx3), lipoprotein-phospholipase A2 (Lp-PLA2), and pro-oxidant activity of myeloperoxidase (MPO). RESULTS: Although the concentration of HDL-C did not change, the activity of Lp-PLA2 significantly decreased upon treatment (-11.6%, p<0.001) and returned to baseline level 4 weeks after the end of treatment. In contrast, Gpx3 increased after treatment (+5%, p<0.01) and remained unvaried after 4 weeks. Both MPO activity and concentration significantly decreased after the washout period (-33 and 32%, p<0.001). CONCLUSION: For the first time, it was found that the administration of an NC with beneficial effects on lipid homeostasis also positively impacts HDL function by improving the balance between protective and damaging determinants. Further investigation is required to corroborate our findings.

Irisin Attenuates Muscle Impairment during Bed Rest through Muscle-Adipose Tissue Crosstalk.

The detrimental effect of physical inactivity on muscle characteristics are well known. Irisin, an exercise-induced myokine cleaved from membrane protein fibronectin type III domain-containing protein-5 (FNDC5), mediates at least partially the metabolic benefits of exercise. This study aimed to assess the interplay between prolonged inactivity, circulating irisin, muscle performance, muscle fibers characteristics, as well as the FNDC5 gene expression (FNDC5ge) in muscle and adipose tissue among healthy subjects. Twenty-three healthy volunteers were tested before and after 14 days of Bed Rest, (BR). Post-BR circulating levels of irisin significantly increased, whereas body composition, muscle performance, and muscle fiber characteristics deteriorated. Among the subjects achieving the highest post-BR increase of irisin, the lowest reduction in maximal voluntary contraction and specific force of Fiber Slow/1, the highest increase of FNDC5ge in adipose tissue, and no variation of FNDC5ge in skeletal muscle were recorded. Subjects who had the highest FNDC5ge in adipose tissue but not in muscle tissue showed the highest circulating irisin levels and could better withstand the harmful effect of BR.

COVID-19 patients with acute pulmonary embolism have a higher mortality risk: systematic review and meta-analysis based on Italian cohorts.

BACKGROUND: Acute pulmonary embolism has been recognized as a frequent complication of COVID-19 infection influencing the clinical course and outcomes of these patients. OBJECTIVES: We performed a systematic review and meta-analysis to evaluate the mortality risk in COVID-19 Italian patients complicated by acute pulmonary embolism in the short-term period. METHODS: The study was performed in accordance with the Preferred Report Items for Systematic Reviews and Meta-analyses guidelines. PubMed-MEDLINE and Scopus databases were systematically searched for articles, published in the English language and enrolling Italian cohorts with confirmed COVID-19 infection from inception through 20 October 2021. Mortality risk data were pooled using the Mantel-Haenszel random effects models with odds ratio as the effect measure with 95% confidence interval. Heterogeneity among studies was assessed using Higgins and Thomson I2 statistic. RESULTS: Eight investigations enrolling 1.681 patients (mean age 64.9 years, 1125 males) met the inclusion criteria and were considered for the analysis. A random-effect model showed that acute pulmonary embolism was present in 19.0% of Italian patients with COVID-19 infection. Moreover, these patients were at higher mortality risk compared with those without (odds ratio: 1.76, 95% confidence interval: 1.26-2.47, P  = 0.001, I2  = 0%). Sensitivity analysis confirmed yielded results. CONCLUSION: In Italian patients with COVID-19 infection, acute pulmonary embolism was present in about one out of five and significantly associated with a higher mortality risk in the short-term period. The identification of acute pulmonary embolism in these patients remains critical to promptly identify vulnerable populations who would require prioritization in treatment and prevention and close monitoring.

Acetyl-cholinesterase-inhibitors slow cognitive decline and decrease overall mortality in older patients with dementia.

We evaluated the effect of Acetyl-cholinesterase-inhibitors (AChEIs) on cognitive decline and overall survival in a large sample of older patients with late onset Alzheimer's disease (LOAD), vascular dementia (VD) or Lewy body disease (LBD) from a real world setting. Patients with dementia enrolled between 2005 and 2020 by the "Alzheimer's Disease Research Centers" were analysed; the mean follow-up period was 7.9 years. A 1:1 propensity score matching was performed generating a cohort of 1.572 patients (786 treated [AChEIs +] and 786 not treated [AChEIs-] with AChEIs. The MMSE score was almost stable during the first 6 years of follow up in AChEIs + and then declined, while in AChEIs- it progressively declined so that at the end of follow-up (13.6 years) the average decrease in MMSE was 10.8 points in AChEIs- compared with 5.4 points in AChEIs + (p < 0.001). This trend was driven by LOAD (Δ-MMSE:-10.8 vs. -5.7 points; p < 0.001), although a similar effect was observed in VD (Δ-MMSE:-11.6 vs. -8.8; p < 0.001). No effect on cognitive status was found in LBD. At multivariate Cox regression analysis (adjusted for age, gender, dependency level and depression) a strong association between AChEIs therapy and lower all-cause mortality was observed (H.R.:0.59; 95%CI: 0.53-0.66); this was confirmed also in analyses separately conducted in LOAD, VD and LBD. Among older people with dementia, treatment with AChEIs was associated with a slower cognitive decline and with reduced mortality, after a mean follow-up of almost eight years. Our data support the effectiveness of AChEIs in older patients affected by these types of dementia.

Dementia and Related Comorbidity: Analysis of 2 Years of Admissions to Italian Hospitals.

BACKGROUND: The aim of the present study was to examine the prevalence of dementia, related comorbidities, and mortality rates in hospitalized elderly patients in Italy. METHODS: Data were obtained from the Italian Ministry of Health and included all discharge records from Italian hospitals concerning subjects aged 65 years or above admitted to acute Internal Medicine during 2 years (n=3,695,278 admissions). Discharge diagnoses were re-classified into 24 clusters, each including homogeneous diseases by the ICD-9-CM code classification. Dementia was identified by the presence of ICD-9-CM codes 290, 294, or 331 series. RESULTS: Patients with dementia represented 7.5% of the sample; compared with those without dementia, they were older and more often female, had a greater length of hospital stay and higher mortality rate. Besides delirium [odds ratio (OR): 54.20], enthesopaties (OR: 2.19), diseases of fluids and electrolytes (OR:1.96), diseases of arteries (OR: 1.69), skin diseases (OR: 1.64), and pneumonia and pleurisy (OR: 1.53) were the diseases more strongly associated with the diagnosis of dementia, independent of other clusters, age, sex, and length of stay. CONCLUSIONS: Some comorbidities are specifically associated with the diagnosis of dementia among hospitalized elderly patients. Overall, these comorbidities describe the typical clinical profile of the patient with advanced dementia and could be treated in the context of the primary care, since they do not require specific skills belonging to hospital settings.

Paraoxonase-1 (PON-1) Arylesterase Activity Levels in Patients with Coronary Artery Disease: A Meta-Analysis.

Aim: To review and compare the PON-1 arylesterase activity between coronary artery disease (CAD) and non-CAD patients. Methods: Data were obtained by searching MEDLINE and Scopus for all investigations published between January 1, 2000 and March 1, 2021 comparing PON-1 arylesterase activity between CAD and controls. Results: Twenty studies, based on 5417 patients, met the inclusion criteria and were included in the analysis. A random effect model revealed that PON-1 arylesterase activity was significantly lower in the CAD group compared to controls (SMD = -0.587, 95%CI = -0.776 to -0.339, p < 0.0001, I 2 = 92.3%). In CAD patients, the PON-1 arylesterase activity was significantly higher among CAD patients without diabetes mellitus (DM) compared to those with diabetes (SMD: 0.235, 95% CI: 0.014 to 0.456, p = 0.03, I 2 = 0%). Conclusions: PON-1 activity is significantly lower in CAD patients, and those without DM presented a significantly higher PON-1 arylesterase activity.

Biological Response of Irisin Induced by Different Types of Exercise in Obese Subjects: A Non-Inferiority Controlled Randomized Study.

Background: Weight loss through physical exercise is warranted among obese individuals. Recently, a greater benefit in cardiorespiratory fitness was achievable with high-intensity interval training (HIIT) as compared with moderate intensity continuous training. The beneficial effect of training on CV health might be related to a specific modulation of circulating irisin, an adypo-myokine implicated in the regulation of energy expenditure. Methods: The present study investigates the circulating plasma levels of irisin at baseline and in response to 12-week of training program either with HIIT or moderate-intensity continuous training (MICT) among young female and male obese subjects. Clinical, anthropometric, and training characteristics for each participant were available. A sex-disaggregated data for circulating plasma levels of irisin pre- and post-training are provided as well as an adjusted multivariate linear regression model to identify the determinants of post-training irisin levels. Results: Data from a total of 32 obese healthy individuals (47% female, mean age 38.7 years, mean BMI 35.6 kg/m2), randomized in a 1:1 manner to HIIT or MICT were analyzed. Circulating plasma levels of irisin similarly and significantly decreased in both MICT and HIIT interventional groups. Females had higher post-exercise irisin levels than males (6.32 [5.51-6.75] vs. 4.97 [4.57-5.72] µg/mL, p = 0.001). When stratified by an interventional group, a statistically significant difference was observed only for the MICT group (male, 4.76 [4.20-5.45] µg/mL vs. female 6.48 [4.88-6.84] µg/mL p = 0.03). The circulating post-training level of irisin was independently associated with post-training fat-free mass (ß -0.34, 95% confidence interval, CI -0.062, -0.006, p = 0.019) in a model adjusted confounders. When female sex was added into the adjusted model, it was retained as the only factor independently associated with irisin levels (ß 1.22, 95% CI, 0.50, 1.93, p = 0.002). Conclusions: In obese healthy subjects, circulating irisin levels were reduced in response to 12-weeks of exercise involving either HIIT or MICT. A sex-specific differences in circulating irisin levels at baseline and as biological response to chronic exercise was described. Sex-specific biological response of irisin to exercise should be further explored to tailor sex-specific training approaches for improving the cardiovascular health of obese healthy subjects.

Increased Serum Beta-Secretase 1 Activity is an Early Marker of Alzheimer's Disease.

BACKGROUND: Beta-site APP cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid-ß (Aß) plaques formation. BACE1 activity is increased in brains of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and plasma levels of BACE1 appears to reflect those in the brains. OBJECTIVE: In this work, we investigated the role of serum BACE1 activity as biomarker for AD, estimating the diagnostic accuracy of the assay and assessing the correlation of BACE1 activity with levels of Aß1 - 40, Aß1 - 42, and Aß40/42 ratio in serum, known biomarkers of brain amyloidosis. METHODS: Serum BACE1 activity and levels of Aß1 - 40, Aß1 - 42, were assessed in 31 AD, 28 MCI, diagnosed as AD at follow-up (MCI-AD), and 30 controls. The BACE1 analysis was performed with a luciferase assay, where interpolation of relative fluorescence units with a standard curve of concentration reveals BACE1 activity. Serum levels of Aß1 - 40, Aß1 - 42 were measured with the ultrasensitive Single Molecule Array technology. RESULTS: BACE1 was increased (higher than 60%) in AD and MCI-AD: a cut-off of 11.04 kU/L discriminated patients with high sensitivity (98.31%) and specificity (100%). Diagnostic accuracy was higher for BACE1 than Aß40/42 ratio. High BACE1 levels were associated with worse cognitive performance and earlier disease onset, which was anticipated by 8 years in patients with BACE1 values above the median value (> 16.67 kU/L). CONCLUSION: Our results provide new evidence supporting serum/plasma BACE1 activity as an early biomarker of AD.