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Background The arrival of new disease-modifying treatments for Alzheimer’s disease (AD) requires the identification of subjects at risk in a simple, inexpensive, and non-invasive way. With tools allowing an adequate screening, it would be possible to optimize the use of these treatments. Plasma markers of AD are very promising, but it is necessary to prove that alterations in their levels are related to alterations in gold standard markers such as cerebrospinal fluid or PET imaging. With this research, we want to evaluate the performance of plasma Aβ40, Aβ42, and p-tau181 to detect the pathological changes in CSF using the automated Lumipulse platform. Methods Both plasma and CSF Aβ40, Aβ42, and p-tau181 have been evaluated in a group of 208 cognitively unimpaired subjects with a 30.3% of ApoE 4 carriers. We have correlated plasma and CSF values of each biomarker. Then, we have also assessed the differences in plasma marker values according to amyloid status (A − / +), AD status (considering AD + subjects to those A + plus Tau +), and ATN group defined by CSF. Finally, ROC curves have been performed, and the area under the curve has been measured using amyloid status and AD status as an outcome and different combinations of plasma markers as predictors. Results Aβ42, amyloid ratio, p-tau181, and p-tau181/Aβ42 ratio correlated significantly between plasma and CSF. For these markers, the levels were significantly different in the A + / − , AD + / − , and ATN groups. Amyloid ratio predicts amyloid and AD pathology in CSF with an AUC of 0.89. Conclusions Plasma biomarkers of AD using the automated Lumipulse platform show good diagnostic performance in detecting Alzheimer’s pathology in cognitively unimpaired subjects.

INTRODUCTION The role of neuroinflammation in preclinical Alzheimer's disease (AD) remains unclear. METHODS We assessed changes in microglial and astrocytic biomarkers in a well‐characterized cohort of 211 cognitively unimpaired individuals. Structural equation modeling was used to simultaneously assess all relationships among microglial and astrocytic responses and AD pathological events. RESULTS Plasma glial fibrillary acidic protein (GFAP) and cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were increased in preclinical AD. Plasma GFAP showed an inverse bidirectional relationship with CSF amyloid beta (Aβ)42/40. CSF sTREM2 directly influenced CSF phosphorylated tau‐181 (p‐tau181) and neurogranin, and correlated with CSF S100 calcium‐binding protein beta (S100β). CSF chitinase‐3‐like protein 1 (YKL‐40) mediated the association between CSF p‐tau181 and total tau (t‐tau), whereas CSF S100β and neurofilament light showed mutual influence. DISCUSSION Our findings suggest that microglial and astrocyte reactivity, measured through fluid biomarkers, occur early and impact the amyloid cascade on the preclinical Alzheimer´s continuum. Specifically, GFAP influences amyloid accumulation, sTREM2 promotes tau pathology, and YKL‐40 and S100β contribute to the progression of downstream neurodegenerative changes. Highlights Preclinical Alzheimer's disease (AD) showed increased levels of plasma glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) compared to cerebrospinal fluid (CSF) in healthy subjects. Higher plasma GFAP levels was directly associated with lower CSF amyloid beta (Aβ)42/Aβ40. Higher CSF sTREM2 concentrations increased CSF phosphorylated tau‐181. Chitinase‐3‐like protein 1 (YKL‐40) mediated tau‐induced neurodegeneration. S100 calcium‐binding protein beta (S100β) was directly linked to higher neurofilament light (NfL) and showed a mutual relationship with sTREM2.

Background Plasma biomarkers for Alzheimer's disease (AD) are a promising tool for accessible and accurate biological diagnostics. However, data in clinical practice are needed to better understand their diagnostic and prognostic ability in memory unit patients. Methods We analyzed plasma phosphorylated tau at threonine 217 (p-tau217) and neuroflament light chain (NfL) levels and AD cerebrospinal fluid (CSF) biomarkers in a group of 493 subjects using the Lumipulse G600II platform. The sample includes 340 patients from our memory unit (142 dementia, 186 mild cognitive impairment, and 12 with subjective complaints) and 153 cognitively unimpaired volunteers. We have correlated plasma and CSF biomarkers; we have analyzed plasma biomarker levels as a function of clinical diagnosis, cognitive status and amyloid status. We have also studied the ability of p-tau217 to discriminate between amyloid-positive and -negative subjects according to CSF using receiver operating characteristic curves. Results Plasma p-tau217 correlated significantly with CSF Aβ42/Aβ40 (Rho = -0.75; p -value < 0.001), p-tau181 ( r  = 0.66; p -value < 0.001), and t-tau ( r  = 0.59; p -value < 0.001). Plasma NfL correlated with CSF NfL ( r  = 0.48; p -value < 0.001). By clinical diagnosis, plasma p-tau217 levels showed to be higher in AD patients than in healthy controls (difference = 0.63 pg/ml; p -value < 0.001), FTD (difference = 0.60 pg/ml; p -value < 0.001), and nondegenerative dementias (difference = 0.61 pg/ml; p -value < 0.001). Plasma p-tau217 showed an area under the curve of 0.95 to discriminate between A + and A- subjects (95%CI 0.93–0.97). Conclusion Plasma p-tau217 shows excellent results for detecting amyloid pathology at brain level in a clinical setting with an AUC of 0.95. It is a highly specific marker of AD and increases progressively along the disease continuum . Using plasma p-tau217 as an initial diagnostic tool with cut-offs at sensitivities and specificities of 95 or 97.5% could save between 57.4–84.8% of LP/PETs with diagnostic accuracies of 95–97%. Plasma NfL increases progressively at different cognitive stages.

Background The advent of Alzheimer’s disease-modifying drugs requires accurate biological diagnosis to identify candidates for these therapies. So far, the most promising single plasma biomarker is phosphorylated tau at threonine 217 (p-tau217). To understand its biological features, it is essential to know its longitudinal trajectory and factors influencing it in cognitively unimpaired subjects with no brain pathology. Methods We analyzed longitudinal plasma p-tau217 values (mean follow-up time = 768.3 days) in a cohort of 209 healthy volunteers. We have studied factors associated with plasma p-tau217 changes by using different linear mixed-effects models. Results In amyloid-negative cognitively healthy subjects ( n  = 151) carriers of ApoE ε4 allele had significantly higher p-tau217 values than non-carriers (0.85 pg/mL; p-value < 0.001) and also a greater rate of change (0.01 pg/mL/year; p-value < 0.001). In the overall sample, including subjects with amyloid and tau pathology we have seen that amyloid positive subjects had higher predicted baseline plasma p-tau217 values than amyloid negative subjects (0.16 pg/mL; p-value < 0.001) and a greater rate of change (0.00004 pg/mL/day; p-value < 0.001). Subjects considered tau positive also showed a greater rate of change of p-tau217 with respect to tau negative (0.00005 pg/mL/day; p-value < 0.001). A + T + N + participants showed a higher baseline p-tau217 levels than A-T-N- subjects (0.2 pg/mL; p-value < 0.001) and also a greater rate of change (0.00006 pg/mL/day; p-value = 0.002). ApoE ε4 carriers had a greater rate of change than non-carriers (0.00003 pg/mL/day; p-value = 0.03). Conclusion In amyloid-negative cognitively unimpaired subjects, ApoE 4 status influenced both baseline levels and rate of change of plasma p-tau217. Other factors such as age, sex or glomerular filtration rate have not shown significant influence on plasma p-tau217 levels in this group.

Plasma biomarkers for Alzheimer’s disease (AD) are a promising tool that may help in early diagnosis. However, their levels may be influenced by physiological parameters and comorbidities that should be considered before they can be used at the population level. For this purpose, we assessed the influences of different comorbidities on AD plasma markers in 208 cognitively unimpaired subjects. We analyzed both plasma and cerebrospinal fluid levels of Aβ40, Aβ42, and p-tau181 using the fully automated Lumipulse platform. The relationships between the different plasma markers and physiological variables were studied using linear regression models. The mean differences in plasma markers according to comorbidity groups were also studied. The glomerular filtration rate showed an influence on plasma Aβ40 and Aβ42 levels but not on the Aβ42/Aβ40 ratio. The amyloid ratio was significantly lower in diabetic and hypertensive subjects, and the mean p-tau181 levels were higher in hypertensive subjects. The glomerular filtration rate may have an inverse relationship on plasma Aβ40 and Aβ42 levels but not on the amyloid ratio, suggesting that the latter is a more stable marker to use in the general population. Cardiovascular risk factors might have a long-term effect on the amyloid ratio and plasma levels of p-tau181.

IntroductionAs Hearing loss and dementia affect people with the same profile, several epidemiological studies have evaluated their relationship. However, the link between age-related hearing loss and Alzheimer’s disease is still unclear.MethodsWe selected subjects with no history of exposure to loud noises, blasts, head trauma with hearing loss, or sudden sensorineural hearing loss from a cohort intended to study preclinical phases of Alzheimer’s disease. Participants are volunteers over 55 years without cognitive impairment. We correlated the results of an objective auditory evaluation with brain amyloid and p-tau181 levels and with the outcomes of a comprehensive neuropsychological assessment.ResultsFifty-five subjects at different stages of the Alzheimer's disease continuum were evaluated. There were no statistically significant correlations between amyloid-β and p-tau levels and any of the objective auditory measures. A weak but significant correlation was found between amyloid-β values and the Hearing Handicap Inventory for the Elderly. The neuropsychological domains more correlated to hearing loss were executive function and processing speed.DiscussionAge-related hearing loss is not linked to any pathological markers of Alzheimer's disease nor to neuropsychological domains typically affected in this disease. The Hearing Handicap Inventory for the Elderly has an important component of subjectivity and further studies are needed to explore its relationship with amyloid-β levels.

Background The arrival of new disease-modifying treatments for Alzheimer's disease (AD) requires the identification of subjects at risk in a simple, inexpensive, and non-invasive way. With tools allowing an adequate screening, it would be possible to optimize the use of these treatments. Plasma markers of AD are very promising, but it is necessary to prove that alterations in their levels are related to alterations in gold standard markers such as cerebrospinal fluid or PET imaging. With this research, we want to evaluate the performance of plasma A[beta]40, A[beta]42, and p-tau181 to detect the pathological changes in CSF using the automated Lumipulse platform. Methods Both plasma and CSF A[beta]40, A[beta]42, and p-tau181 have been evaluated in a group of 208 cognitively unimpaired subjects with a 30.3% of ApoE4 carriers. We have correlated plasma and CSF values of each biomarker. Then, we have also assessed the differences in plasma marker values according to amyloid status (A - / +), AD status (considering AD + subjects to those A + plus Tau +), and ATN group defined by CSF. Finally, ROC curves have been performed, and the area under the curve has been measured using amyloid status and AD status as an outcome and different combinations of plasma markers as predictors. Results A[beta]42, amyloid ratio, p-tau181, and p-tau181/A[beta]42 ratio correlated significantly between plasma and CSF. For these markers, the levels were significantly different in the A + / - , AD + / - , and ATN groups. Amyloid ratio predicts amyloid and AD pathology in CSF with an AUC of 0.89. Conclusions Plasma biomarkers of AD using the automated Lumipulse platform show good diagnostic performance in detecting Alzheimer's pathology in cognitively unimpaired subjects. Keywords: Alzheimer's disease, Plasma biomarkers, Early diagnosis, Screening, Validation, Lumipulse