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 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: 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.

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. 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. 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). 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.

Plasma biomarkers of Alzheimer’s disease (AD), especially p-tau217, are promising tools to identify subjects with amyloid deposition in the brain, de

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.

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. 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. 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). In amyloid-negative cognitively unimpaired subjects, ApoE4 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.