Alzheimer’s disease (AD) is the most common cause of dementia in people above age 65. Platelet studies with ADAM10 have shown that its expression is reduced in AD patients. The aim of this research was to compare the platelet levels of ADAM10 protein in two Brazilian elderly groups, considering the stages of the disease. The SDS-PAGE technique followed by Western blotting was used. Data were analyzed using comparison, correlation and association statistical methods. The results showed reduced platelet ADAM10 levels in AD elderly compared to non-AD subjects. The disease progression intensified this reduction. ADAM10 was the only statistically significant variable (p = 0.01) to increase the AD occurrence probability. The cutoff value of 0.4212 in the receiver operating characteristic curve captured sensitivity and specificity of 70 and 80.77%, respectively. Together with other clinical criteria, ADAM10 seems to be a relevant biomarker tool for early and accurate AD diagnosis.

ABSTRACT. In July 2019, a group of multidisciplinary dementia researchers from Brazil and the United Kingdom (UK) met in the city of Belo Horizonte, Minas Gerais, Brazil, to discuss and propose solutions to current challenges faced in the diagnosis, public perception and care of dementia. Here we summarize the outcomes from the workshop addressing challenges in diagnosis. Brazil faces a major problem in dementia underdiagnosis, particularly involving the population in an adverse socioeconomic context. There is poor availability of resources and specialists, and the knowledge of general practitioners and other healthcare professionals is far from satisfactory. Low education level is a further obstacle in diagnosing dementia, as the most commonly used screening tests are not designed to evaluate this population. Patients and their families must overcome the stigma of a diagnosis of dementia, which is still prevalent in Brazil and increases the burden of this condition. Whilst the UK has greater resources, dedicated memory services and a National Dementia Strategy plan, the National Health Service (NHS) has limited funding. Therefore, some challenges regarding diagnosis are common across both countries. The authors suggest possible solutions to confront these, with the goal of improving assessment and recognition of dementia and reducing misdiagnosis.

The clinical diagnosis of Alzheimer's disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process. Abnormalities in amyloid-beta precursor protein (APP) metabolism and in the level of APP secretases have been demonstrated in platelets, and to a lesser extent in leukocytes, of AD patients, with conflicting results. The aim of the present study was to compare the protein level of the APP secretases A-disintegrin and metalloprotease 10 (ADAM10), Beta-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PSEN1) in platelets and leukocytes from 20 non-medicated older adults with AD and 20 healthy elders, and to determine the potential use of these biomarkers to discriminate cases of AD from controls. The protein levels of all APP secretases were significantly higher in platelets compared to leukocytes. We found statistically a significant decrease in ADAM10 (52.5%, p < 0.0001) and PSEN1 (32%, p = 0.02) in platelets from AD patients compared to controls, but not in leukocytes. Combining all three secretases to generate receiver-operating characteristic (ROC) curves, we found a good discriminatory effect (AD vs. controls) when using platelets (the area under the curve-AUC-0.90, sensitivity 88.9%, specificity 66.7%, p = 0.003), but not in leukocytes (AUC 0.65, sensitivity 77.8%, specificity 50.0%, p = 0.2). Our findings indicate that platelets represent a better biological matrix than leukocytes to address the peripheral level of APP secretases. In addition, combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls.

Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.

Background: Down syndrome (DS) is associated with a high prevalence of cognitive impairment and dementia in middle age and older adults. Given the presence of common neuropathological findings and similar pathogenic mechanisms, dementia in DS is regarded as a form of genetically determined, early-onset AD. The clinical characterization of cognitive decline in persons with DS is a difficult task, due to the presence intellectual disability and pre-existing cognitive impairment. Subtle changes that occur at early stages of the dementing process may not be perceived clinically, given that most cognitive screening tests are not sensitive enough to detect them. Therefore, biological markers will provide support to the diagnosis of DS-related cognitive impairment and dementia, particularly at early stages of this process. Objective: To perform a systematic review of the literature on AD-related biomarkers in DS. Method: We searched PubMed, Web of Science and Cochrane Library for scientific papers published between 2008 and 2018 using as primary mesh terms ‘Down’, ‘Alzheimer’, ‘biomarker’. Results: 79 studies were retrieved, and 39 were considered eligible for inclusion in the systematic review: 14 post-mortem studies, 10 neuroimaging, 4 addressing cerebrospinal fluid biomarkers, and 11 on peripheral markers. Conclusion: There is consistent growth in the number of publication in this field over the past years. Studies in DS-related dementia tend to incorporate many of the diagnostic technologies that have been more extensively studied and validated in AD. In many instances, the study of CNS and peripheral biomarkers reinforces the presence of AD pathology in DS.

Background The clinical diagnosis of Alzheimer’s disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process as Mild Cognitive Impairment (MCI). Beta‐amyloid peptide (Aβ) accumulation is one of the hallmarks of AD. It is well‐known that the main mechanism of Aβ production, whose accumulation is one of the hallmarks of AD, is from abnormalities in amyloid‐beta precursor protein (APP) metabolism. APP is an integral transmembrane protein widely expressed in neuronal and peripheral tissues and the enzymatic machinery needed to process APP in neurons is also present in platelets. The aim of the present study was to compare the protein level of APP to discriminate cases of AD and MCI from controls. Method The APP protein levels were measured in platelets from non‐medicated older adults with AD (n=10), MCI (n=17) and healthy elders (n=12) by western blotting. The densitometries of 130kDa and 110kDa were used to estimate the levels of APP and APP–ratio. Each sample was analyzed in duplicate and for normalization of platelet assay values we used β‐actin as loading (internal) control. All statistical analyses were performed with the aid of the software Statistical Package for the Social Sciences (SPSS) ‐ version 14. Differences in sociodemographic characteristics and platelets APP concentrations at baseline were analyzed using the Kruskal‐Wallis. Result There was no difference regarding gender distribution or age among the three groups (p=0.310 and p=0.088, respectively). We found a down expression of 110kDa‐APP‐fragment in AD compared to MCI and controls. In contrast, there was no difference nor in 130kDa‐APP‐fragment (p=0.212) either APPratio (p=0.736). Conclusion Our findings indicate that 110kDa‐APP‐fragment is down regulated in AD and may be a marker of altered APP metabolism in platelets since MCI state when compared to controls.

Background The cerebrospinal fluid (CSF) is reputed as the best humoral matrix to address Alzheimer´s disease (AD) biomarkers. AD‐related CSF biomarkers are largely related to intracerebral amyloidosis, and have proved useful for diagnostic purposes and prediction of dementia in high‐risk populations. Lower CSF concentrations of Aβ1‐42 have been consistently reported in AD. However, results with peripheral biomarkers have so far yielded less consistent results. Platelets are the main peripheral source of amyloid precursor protein (APP) and contain the enzymatic machinery required for its proteolytic metabolism. Previous studies have shown that platelet APP ratio (130/110 kDa sAPP) is reduced in AD. Method We enrolled 66 older adults (26 with AD and 40 cognitively unimpaired subjects). The expression of 110‐ and 130kDA secreted APP peptides (sAPP) was determined in platelets by Western blotting using 22C11 monoclonal antibody, to determine APP ratio (rAPP). CSF concentrations of Aβ1‐42 were determined by a multiplexed method using commercial kits (Innobia AlzBio3). Result There were no statistically significant differences in age (p=0.67) or gender distribution (χ2=0.155; p=0.69) across groups. Compared to controls, AD patients had lower mean platelet rAPP (AD: 1.26, SD0.5; controls: 2.07, SD0.93; p<0.001) and CSF Aβ1‐42 concentrations (AD: 319.04, SD146.7; controls: 450.84, SD 109.9; p=0.001). We also found positive correlations between platelet rAPP and CSF Aβ1‐42 (Spearman’s Rho=0.40; p=0.01). Conclusion Our findings confirm that platelet rAPP and CSF Aβ1‐42 are reduced in AD. We further show that these two parameters are correlated, indicating that platelet rAPP may be regarded as a surrogate marker of intracerebral accumulation of amyloid‐beta.

Background Down syndrome (DS) is associated with high prevalence of dementia, with onset in late adulthood. Given the pathological similarities, dementia in DS is regarded as a variant of early‐onset Alzheimer’s disease (AD). The genetic causality of dementia in DS is attributed to the overexpression of the amyloid precursor protein (APP) gene located on chromosome 21. Abnormalities in the regulation of APP metabolism cause the overproduction of the amyloid‐beta peptide (Aβ) and subsequent effects on the amyloid cascade, which ultimately lead to the formation of neuritic plaques and neurofibrillary tangles. To compare protein levels of secreted APP metabolites (sAPP) and APP‐secretases (ADAM10, BACE1, PSEN1) in platelets from adults and elders with DS compared to controls, and to determine whether these findings correlate with global cognitive state. Method The study group comprises 21 aging adults with DS, and the comparison group comprises a similar number of age/gender‐matched healthy subjects with normal karyotype (controls). DS subjects were subdivided according to age stratification (20‐34 years, n=8; 35‐49 years, n=4; ≥50 years, n=9). Global cognitive state of participants was ascertained with the CAMCOG schedule (controls) or its adapted version for DS (CAMCOG‐DS). Protein levels of APP‐related biomarkers were determined by Western Blotting. Result CAMCOG‐DS scores were significantly different in DS subgroups (clinical evidence of cognitive impairment/dementia, DSd; normal cognitive function, DSnc). DSd subjects achieving lower scores (43.8, SD20.7) than DSnc (66.4, SD16.1) p=0.001. Low levels of APP130 have been found among DS as age increased (1.71, SD0.99; 0.76, SD0.46; 0.48, SD0.16, respectively; p=0,013), and higher BACE1 levels was found between aged 35‐49 years old DS (0.44, SD0.77) compared with aged 20‐34 years old DS (0.70, DS0.20), p=0,048. No statistically significant differences were found in platelet levels of ADAM10. Conclusion In this preliminary analysis, APP‐related platelet biomarkers was able to show significant differences among DS age groups.