Plasma BACE1 Research Articles

Influencing factors of plasma BACE1 and its relationship with plasma Aβ: A cross-sectional study of a cognitively normal population of Shunyi cohort (P10-6.009)

<h3>Objective:</h3> The aim of this study was to firstly describe the concentration and activity of plasma BACE1 in a community cohort of China, and to explore its influencing factors and its relationship with plasma Aβ. <h3>Background:</h3> BACE1, as the rate-limiting step in the Aβ production, is considered as a candidate biomarker of Alzheimer’s disease (AD) and is also involved in the disruption of cerebral vessels. <h3>Design/Methods:</h3> 887 cognitively healthy subjects form Shunyi cohort were included in this cross-sectional study. We used linear regression analysis to investigate the relationship between the concentration and activity of plasma BACE1 with common AD and vascular disease risk factors, with plasma Aβ42 and Aβ40 concentrations. <h3>Results:</h3> The concentration of BACE1 in present study was 4.46(2.89–6.93) ng/ml and the activity was 344.19(249.7–437.41) RFU/min. After adjusting for age, sex, ApoE4 allele, increasing age [β (SE) =0.05 (0.02), p=0.021] and increasing systolic blood pressure [β (SE) =0.03 (0.01), p=0.015] were positively correlated with lnBACE1 activity. lnhsCRP[β (SE) =0.07 (0.02), p=0.001] and lnTNF-α[β (SE) =0.24 (0.08), p=0.002] were positively correlated with lnBACE1 activity. The concentration of lnBACE1 was negatively correlated with the concentration of Aβ42[β (SE) =−0.86 (0.28), p=0.003] and Aβ40[β (SE) =−15.6 (2.13), p &lt; 0.001], while was positively associated with Aβ42/40 [β (SE) =0.10 (0.02), p &lt; 0.001]. There was no significant correlation between lnBACE1 activity and Aβ concentration. <h3>Conclusions:</h3> BACE1 activity but not concentration increased with age. Control of systolic blood pressure, screening and intervention of systemic inflammation may reduce BACE1 activity in cognitively normal population. Decreased plasma Aβ42 and Aβ40 concentrations and elevated Aβ42/40 may reflect the early state of cognitive decline caused by neurodegenerative and vascular diseases. <b>Disclosure:</b> Ziang Pan has nothing to disclose. Dr. Gao has nothing to disclose. Ding-Ding Zhang has nothing to disclose. Ming Yao has nothing to disclose. Jun Ni has nothing to disclose. Lixin Zhou has nothing to disclose. Dr. Shen has nothing to disclose. Yi-Cheng Zhu has nothing to disclose.

Bilateral Hippocampal Volume Mediated the Relationship Between Plasma BACE1 Concentration and Memory Function in the Early Stage of Alzheimer's Disease: A Cross-Sectional Study.

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme in the formation of amyloid-β (Aβ) protein. Increasing evidence suggests that BACE1 concentration is a potential biomarker for Alzheimer's disease (AD). To evaluate the correlations between plasma BACE1 concentration, cognition, and hippocampal volume at different stages of the AD continuum. Plasma BACE1 concentrations were measured in 32 patients with probable dementia due to AD (ADD), 48 patients with mild cognitive impairment (MCI) due to AD, and 40 cognitively unimpaired (CU) individuals. Memory function was evaluated using the auditory verbal learning test (AVLT), and voxel-based morphometry was used to analyze bilateral hippocampal volumes. Correlation and mediation analyses were performed to investigate the associations between plasma BACE1 concentration, cognition, and hippocampal atrophy. The MCI and ADD groups exhibited elevated BACE1 concentrations compared with the CU group after adjusting for age, sex, and apolipoprotein E (APOE) genotype. Increased BACE1 concentration was found in AD continuum patients who were APOE ɛ4 carriers (p < 0.05). BACE1 concentration was negatively associated with the scores of the subitems of the AVLT and hippocampal volume (p < 0.05, false discovery rate correction) in the MCI group. Moreover, bilateral hippocampal volume mediated the relationship between BACE1 concentration and recognition in the MCI group. BACE1 expression increased in the AD continuum, and bilateral hippocampal volume mediated the effect of BACE1 concentration on memory function in patients with MCI. Research has indicated that the plasma BACE1 concentration might be a biomarker at the early stage of AD.

Plasma β-secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD.

Increased β-secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidβ(Αβ) accumulation in cognitively healthy individuals with subjective memory complaint (SMC). In 302 individuals from the same cohort, we investigated the cross-sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t-tau and Neurofilament light chain (NfL), fluorodeoxyglucose-positron emission tomography (FDG-PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex). We report a positive longitudinal correlation of BACE1 with both NfL and t-tau, as well as a correlation between annual BACE1 changes and bi-annual reduction of BF volume. We show a positive association between BACE1 and FDG-PET signal at baseline. The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration.

Increased β-site APP cleaving enzyme 1-mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment.

Patients with type 2 diabetes mellitus (T2DM) are at a high risk of cognitive impairment, with insulin resistance playing a pivotal role. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is considered a predictor of Alzheimer's disease. However, the potential roles of BACE1 in insulin resistance and the risk of cognitive impairment in T2DM remain unclear. We measured plasma BACE1 levels, BACE1 cleavage activities for Swedish mutant amyloid precursor protein (APPsw) and insulin receptor β subunit (INSR-β), and soluble INSR (sINSR) levels in a clinical cohort study. T2DM patients with or without cognitive impairment exhibited elevated plasma BACE1 levels and BACE1 enzymatic activities for APPsw and INSR-β, and sINSR levels. Moreover, the glycemic status correlated with elevated BACE1 levels and BACE1-mediated INSR cleavage, which was associated with insulin resistance. The elevated BACE1 levels in T2DM may contribute to increasing the cognitive impairment risk through both amyloidogenesis and insulin resistance.

Relationship Between Alzheimer's Disease and Retinal Choroidal Thickness: A Cross-Sectional Study.

The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81±81.30) μm versus (233.79±38.29) μm, p < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (β=-0.772, p = 0.000) and age (β=-0.176, p = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR = 0.984, 95% CI: 0.972-0.997). There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression.

Plasma Aβ in cerebral microbleeds‐positive subjects with cognitive impairment

AbstractBackgroundCerebral amyloid angiopathy (CAA) is strongly related to Alzheimer’s disease (AD). Accumulation of amyloid affects pathophysiology of parenchyma and vessels in amyloidosis. Continuum of amyloid pathology may result in complicated clinical symptoms due to overlap of vascular and neurodegenerative factors during amyloidosis. MRI can detect hemosiderin deposits as cerebral microbleeds (CMBs) and cortical superficial siderosis. CMBs may be involved in amyloid pathology in AD and mixed dementia. Here, we analyzed relationship of these cerebrovascular changes to plasma Aβ42 and Aβ40 levels.MethodAge‐matched subjects with cognitive impairment were classified into CMBs‐positive, ‐suspective and ‐negative groups by MRI. Plasma Aβ42, Aβ40, BACE1 levels were determined by ELISA (ADx, Euroimun).ResultThere is no significant changes of MMSE score and hippocampal atrophy among the CMBs groups. CMBs‐positive subjects showed lower Aβ42 levels and higher Aβ40/42 ratio in plasma. Plasma BACE1 levels showed no significant change in CMBs‐positive subjects.ConclusionCMBs, plasma Aβ42 and Aβ40/42 ratio may be potential biomarkers for amyloid pathology in cognitive impairment.

Correlation of Serum BACE1 With Emergence Delirium in Postoperative Patients: A Preliminary Study.

Background: The mechanism underlying delirium, a common acute fluctuating mental state, may be related to the activation of a neuroinflammatory response. In this study, we attempted to investigate whether plasma inflammatory response markers, vascular and cerebrovascular injury-related markers, and neurodegeneration-associated markers were associated with emergence delirium (ED).Methods: Patients aged 50 years or above who underwent elective laparoscopic surgery under general anesthesia were included in this study. Delirium was assessed postoperatively with the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scale. Plasma samples were collected from ED patients and non-ED patients to test concentrations of inflammation markers, including interleukin 6 (IL-6), chitinase 3-like 1 (CHI3L1), S100 calcium-binding protein B (S100B), lipoprotein-associated phospholipase-A2 (Lp-PLA2), and macrophage migration inhibitory factor (MIF); vascular and cerebrovascular injury-related markers, including intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1); and neurodegeneration-associated markers, including alpha-synuclein (α-Syn) and β-secretase 1 (BACE1). Binary logistic regression analysis was performed to analyze the relationship between biomarkers and ED, and receiver operating characteristic (ROC) curves were used to analyze the diagnostic value of biomarkers.Results: A total of 104 patients were included in this study, with an average age of 63.69 ± 7.21. IL-6 (OR = 2.73, 95% CI: 1.66–6.44, P = 0.022), S100B (OR = 4.74, 95% CI: 1.88–11.95, P = 0.001), and BACE1 (OR = 6.54, 95% CI: 2.57–16.65, P < 0.000) were independent biological indicators for the occurrence of ED.CHI3L1, Lp-PLA2, MIF, ICAM-1, VCAM-1, and α-Syn were unrelated to ED. Plasma BACE1 level had a possible diagnostic value for ED [area under curve (AUC) = 0.75, 95% CI: 0.66–0.85], whereas plasma IL-6 (AUC = 0.62, 95% CI: 0.51–0.73) and S100B (AUC = 0.65, 95% CI: 0.54–0.76) levels had little diagnostic value for distinguishing ED vs. non-ED.Conclusion: Higher levels of systemic inflammation marker IL-6, cerebral inflammation marker S100B, and neurodegeneration-associated marker BACE1 are related to ED. Plasma BACE1 may be a potential diagnostic biomarker for ED.

BACE1 and Other Alzheimer's-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer's Disease Patients from Cognitively-Impaired Neurosyphilis Patients.

Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer's disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1-40 (Aβ40), Aβ42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

Associations of Plasma BACE1 Level and BACE1 C786G Gene Polymorphism with Cognitive Functions in Patients with Type 2 Diabetes: A Cross- Sectional Study.

β-Site APP-cleaving enzyme 1 (BACE1) is a key enzyme involved in the pathophysiology of Type 2 Diabetes Mellitus (T2DM) and Mild Cognitive Impairment (MCI). We aimed to investigate the potential associations of plasma BACE1 levels and BACE1 gene polymorphism with different cognitive performances in T2DM patients with MCI. The recruited 186 T2DM subjects were divided into 92 MCI group and 94 healthy-cognition controls, according to the Montreal Cognitive Assessment (MoCA) scores. Sociodemographic characteristics, clinical parameters and neuropsychological tests were assessed. BACE1 C786G gene polymorphism and plasma BACE1 level were determined. Compared to controls, MCI patients exhibited higher plasma BACE1 levels. Plasma BACE1 levels were negatively associated with MoCA, Clock Drawing Test and Logical Memory Test scores, whereas positively associated with Trail Making Test-B time in the MCI group (all p<0.05), after adjusting fasting blood glucose, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance by C-peptide. Multivariable logistic regression analysis showed a significant trend towards increased MCI risk with high plasma BACE1 level in T2DM patients (OR = 1.492, p = 0.027). The plasma BACE1 levels of GG and GC genotypes were obviously higher than that of CC genotype in T2DM-MCI patients (p = 0.035; p = 0.026, respectively). Increased plasma BACE1 levels were associated with poor overall cognition functions, especially visuospatial abilities, visual/logical memory and executive functions in T2DM-MCI patients. Additionally, elevated plasma BACE1 level was a risk factor for MCI in T2DM patients, and might be influenced by BACE1 C786G gene mutations.

Sex differences in circulating neuregulin1-β1 and β-secretase 1 expression in childhood-onset schizophrenia

ObjectiveEarly-onset schizophrenia is a severe and rare form of schizophrenia that is clinically and neurobiologically continuous with the adult form of schizophrenia. Neuregulin1 (NRG1)-mediated signaling is crucial for early neurodevelopment, which exerts its function by limited β-secretase 1 (BACE1) proteolysis processing. However, circulating neuregulin1-β1 (NRG1-β1), an isoform of NRG1, and its cleavage enzyme BACE1 have not been studied in early-onset patients with schizophrenia. MethodsIn this study, we collected plasma and clinical information from 71 young patients (7 ≤ age years ≤20) with schizophrenia and 53 age- and sex-matched healthy controls. Immunoassay was used to test levels of circulating NRG1-β1 and BACE1 expression. We further analyzed the relationship of disease-onset age and gender with NRG1-β1 and BACE1 levels. ResultsWe found that circulating plasma levels of NRG1-β1 were significantly decreased in young patients with early-onset schizophrenia. In males with childhood onset schizophrenia (COS), NRG1-β1 was reduced and was inversely correlated with positive symptom of PANSS; moreover, these male patients with higher plasma BACE1 levels showed more severe general symptoms of PANSS and defective social functioning; whereas, no aforementioned results were found in adolescent-onset schizophrenia (AOS). Notably, young female patients with COS and AOS had no significant change in NRG1-β1 and BACE1, which demonstrated a sex-dependent effect in early-onset schizophrenia. ConclusionOur results suggest that decreased levels of NRG1-β1 and its cleavage enzyme BACE1 contribute to increased risk of etiology of schizophrenia. Synthetic biomarkers may have clinical applications for the early diagnosis of male COS.

Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD

IntroductionSuccessful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)–targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. MethodsWe investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-β (Aβ) deposition, using positron emission tomography global standard uptake value ratios. ResultsBaseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aβ–positron emission tomography global standard uptake value ratios. DiscussionOur results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aβ production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

Effects of vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer’s disease: a randomised, double-blind, placebo-controlled trial

ObjectiveOur study aimed to assess the effect of a 12-month vitamin D supplementation on cognitive function and amyloid beta (Aβ)-related biomarkers in subjects with Alzheimer’s disease (AD).Methods This was a...

SEXUAL DIMORPHISM IN PLASMA BETA-SECRETASE 1 CONCENTRATIONS IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR AD: CROSS-SECTIONAL AND LONGITUDINAL STUDIES

The development of effective disease-modifying treatments for early Alzheimer's disease (AD) and targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted requires biomarker-drug co-development strategies, including the validation and qualification of accessible and non-invasive biological markers for different contexts of use. Cross-sectional and longitudinal studies demonstrated that plasma and cerebrospinal fluid (CSF) concentrations of BACE1 closely correlate with each other. We conducted both cross-sectional and longitudinal explorative studies in a cohort of individuals with subjective memory complaint (SMC), a condition at risk for AD, to investigate whether key biological factors such as sex, APOE ε4allele, and age affect plasma BACE1 concentrations. SMC individuals were recruited from the “INveStIGation of AlzHeimer's PredicTors in Subjective Memory Complainers” (INSIGHT-preAD) study, a university-based cohort which is part of the Alzheimer Precision Medicine Initiative (APMI) and its Cohort Program (APMI-CP). In the cross-sectional analysis, we found that baseline plasma BACE1 concentrations were highly significantly increased in females compared to males (p<0.001). Women showed a highly significantly increased plasma BACE1 concentrations compared to men, at all the three investigated time intervals (p<0.001). No difference regarding the longitudinal trajectories of plasma BACE1 concentrations was found between women and men. There was no significant effect of age and APOE ε4carrier status neither on overall BACE1 concentrations nor on BACE1 concentrations evolution. There was a highly significant decrease in plasma BACE1 concentrations in the whole sample of SMC individuals over time (p<0.001). We did not find any significant impact of two-way interactions between age and sex, age and APOE ε4 allele, sex and APOE ε4 allele on BACE1 plasma concentrations either at baseline or longitudinally. Thus, we demonstrate that the impact of a sexual-dimorphism on plasma BACE1 concentrations is irrespective of age and time. Evidence of the potential impact of a sexual dimorphism on the concentration and activity of BACE1 may be a relevant missing design component contributing to the failure of negative clinical BACE1 inhibitor therapy trial outcomes. Our results indicate that the impact of a sexual dimorphism on plasma BACE1 should be considered in further biomarker validation and qualification studies and in clinical BACE1 trials.

Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

BACE1 levels are increased in plasma of Alzheimer's disease patients compared with matched cognitively healthy controls.

BACE1 is the secretase that acts in Aβ production in Alzheimer's disease (AD). We investigated mRNA expression in total blood and the levels of plasma protein BACE1 in AD patients compared with cognitively healthy subjects. Probable AD (n = 47) and non-AD control group (n = 32) were evaluated for mRNA expression for BACE1 using reverse transcription-qPCR. A subsample of n = 21 AD and n = 20 non-AD had plasma BACE1 levels analyzed, using ELISA. No differences were found on BACE1 mRNA between groups. However, higher levels of BACE1 were detected in plasma of AD patients. Blood-based diagnostic tools are desired to improve AD diagnosis. BACE1 plasma levels could provide an additional diagnostic tool for AD in association with neuropsychological tests.

The feasibility of utilizing plasma MiRNA107 and BACE1 messenger RNA gene expression for clinical diagnosis of amnestic mild cognitive impairment.

To investigate the relationship between microRNA107 (miRNA107) and BACE1 messenger RNA (mRNA) gene expressions in plasma and their diagnostic capability to distinguish subjects with amnestic mild cognitive impairment from healthy controls. We recruited 97 patients with Alzheimer's disease according to diagnostic criteria of DSM-IV and National Institute of Neurologic and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association, 116 subjects with amnestic mild cognitive impairment, and 81 healthy controls from January 2012 to December 2012. The real-time PCR was used to quantify miRNA107 and BACE1 mRNA. The power of classification accuracies between patients with amnestic mild cognitive impairment and healthy controls was performed using linear discriminate analysis single or combining both the expression miRNA107 and BACE1 mRNA. For patients with Alzheimer's disease, the miRNA107 expressions in plasma and cerebral spinal fluid were correlated (Pearson correlation = 0.665, P = .034). There were statistically significant correlations between plasma miRNA107 and BACE1 mRNA gene expression in Alzheimer's disease, amnestic mild cognitive impairment, and healthy control groups (r value = -0.316 [P = .002], -0.615 [P < .001], and -0.367 [P = .001], respectively). The overall classification accuracy of miRNA107 to discriminate between patients with amnestic mild cognitive impairment and healthy controls was 91.9%, with sensitivity of 98.3% and specificity of 82.7%. The miRNA107 expression in plasma has a high capability to discriminate between patients with amnestic mild cognitive impairment and healthy controls. ClinicalTrials.gov identifier: NCT01819545.

Characterization of plasma β‐secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease

Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho-thr181 tau consistently differentiate between Alzheimer's disease (AD) and age-matched control subjects. In contrast, CSF β-site APP-cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age-matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1-specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ-secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age-matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies.