Plasma S100β is a predictor for pathology and cognitive decline in Alzheimer's disease.

Blood-brain barrier dysfunction is one characteristic of Alzheimer's disease (AD) and is recognized as both a cause and consequence of the pathological cascade leading to cognitive decline. The goal of this study was to assess markers for barrier dysfunction in postmortem tissue samples from research participants who were either cognitively normal individuals (CNI) or diagnosed with AD at the time of autopsy and determine to what extent these markers are associated with AD neuropathologic changes (ADNC) and cognitive impairment. We used postmortem brain tissue and plasma samples from 19 participants: 9 CNI and 10 AD dementia patients who had come to autopsy from the University of Kentucky AD Research Center (UK-ADRC) community-based cohort; all cases with dementia had confirmed severe ADNC. Plasma samples were obtained within 2 years of autopsy. Aβ40, Aβ42, and tau levels in brain tissue samples were quantified by ELISA. Cortical brain sections were cleared using the X-CLARITY™ system and immunostained for neurovascular unit-related proteins. Brain slices were then imaged using confocal microscopy and analyzed for microvascular diameters and immunoreactivity coverage using Fiji/ImageJ. Isolated human brain microvessels were assayed for tight-junction protein expression using the JESS™ automated Western blot system. S100 calcium-binding protein B (S100β), matrix metalloproteinase (MMP)-2, MMP-9, and neuron-specific enolase (NSE) levels in plasma were quantified by ELISA. All outcomes were assessed for linear associations with global cognitive function (MMSE, CDR) and cerebral atrophy scores by Pearson, polyserial, or polychoric correlation, as appropriate, along with generalized linear modeling or generalized linear mixed-level modeling. As expected, we detected elevated Aβ and tau pathology in brain tissue sections from AD patients compared to CNI. However, we found no differences in microvascular diameters in cleared AD and CNI brain tissue sections. We also observed no differences in claudin-5 protein levels in capillaries isolated from AD and CNI tissue samples. Plasma biomarker analysis showed that AD patients had 12.4-fold higher S100β plasma levels, twofold lower NSE plasma levels, 2.4-fold higher MMP-9 plasma levels, and 1.2-fold lower MMP-2 plasma levels than CNI. Data analysis revealed that elevated S100β plasma levels were predictive of AD pathology and cognitive impairment. Our data suggest that among different markers relevant to barrier dysfunction, plasma S100β is the most promising diagnostic biomarker for ADNC. Further investigation is necessary to assess how plasma S100β levels relate to these changes and whether they may predict clinical outcomes, particularly in the prodromal and early stages of AD.

Nehra G ，Maloney BJ ，Smith RR ，Chumboatong W ，Abner EL ，Nelson PT ，Bauer B ，Hartz AMS ... -  《Fluids and Barriers of the CNS》

The impact of kidney function on Alzheimer's disease blood biomarkers: implications for predicting amyloid-β positivity.

Impaired kidney function has a potential confounding effect on blood biomarker levels, including biomarkers for Alzheimer's disease (AD). Given the imminent use of certain blood biomarkers in the routine diagnostic work-up of patients with suspected AD, knowledge on the potential impact of comorbidities on the utility of blood biomarkers is important. We aimed to evaluate the association between kidney function, assessed through estimated glomerular filtration rate (eGFR) calculated from plasma creatinine and AD blood biomarkers, as well as their influence over predicting Aβ-positivity. We included 242 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, comprising cognitively unimpaired individuals (CU; n = 124), mild cognitive impairment (MCI; n = 58), AD dementia (n = 34), and non-AD dementia (n = 26) patients all characterized by [18F] AZD-4694. Plasma samples were analyzed for Aβ42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), tau phosphorylated at threonine 181 (p-tau181), 217 (p-tau217), 231 (p-tau231) and N-terminal containing tau fragments (NTA-tau) using Simoa technology. Kidney function was assessed by eGFR in mL/min/1.73 m2, based on plasma creatinine levels, age, and sex. Participants were also stratified according to their eGFR-indexed stages of chronic kidney disease (CKD). We evaluated the association between eGFR and blood biomarker levels with linear models and assessed whether eGFR provided added predictive value to determine Aβ-positivity with logistic regression models. Biomarker concentrations were highest in individuals with CKD stage 3, followed by stages 2 and 1, but differences were only significant for NfL, Aβ42, and Aβ40 (not Aβ42/Aβ40). All investigated biomarkers showed significant associations with eGFR except plasma NTA-tau, with stronger relationships observed for Aβ40 and NfL. However, after adjusting for either age, sex or Aβ-PET SUVr, the association with eGFR was no longer significant for all biomarkers except Aβ40, Aβ42, NfL, and GFAP. When evaluating whether accounting for kidney function could lead to improved prediction of Aβ-positivity, we observed no improvements in model fit (Akaike Information Criterion, AIC) or in discriminative performance (AUC) by adding eGFR to a base model including each plasma biomarker, age, and sex. While covariates like age and sex improved model fit, eGFR contributed minimally, and there were no significant differences in clinical discrimination based on AUC values. We found that kidney function seems to be associated with AD blood biomarker concentrations. However, these associations did not remain significant after adjusting for age and sex, except for Aβ40, Aβ42, NfL, and GFAP. While covariates such as age and sex improved prediction of Aβ-positivity, including eGFR in the models did not lead to improved prediction for any biomarker. Our findings indicate that renal function, within the normal to mild impairment range, does not seem to have a clinically relevant impact when using highly accurate blood biomarkers, such as p-tau217, in a biomarker-supported diagnosis.

Arslan B ，Brum WS ，Pola I ，Therriault J ，Rahmouni N ，Stevenson J ，Servaes S ，Tan K ，Vitali P ，Montembeault M ，Klostranec J ，Macedo AC ，Tissot C ，Gauthier S ，Lantero-Rodriguez J ，Zimmer ER ，Blennow K ，Zetterberg H ，Rosa-Neto P ，Benedet AL ，Ashton NJ ... -  《Alzheimers Research & Therapy》

Predicting Longitudinal Cognitive Decline and Alzheimer's Conversion in Mild Cognitive Impairment Patients Based on Plasma Biomarkers.

Park MK ，Ahn J ，Kim YJ ，Lee JW ，Lee JC ，Hwang SJ ，Kim KC ... -  《Cells》

Informing etiological heterogeneity of mild cognitive impairment and risk for progression to dementia with plasma p-tau217.

Asken BM ，Cid REC ，Crocco EA ，Armstrong MJ ，Levy SA ，Arias F ，Rosselli M ，Uribe IV ，Barker WW ，Matusz EF ，DeSimone JC ，Wang WE ，Fiala J ，Marsiske MM ，DeKosky ST ，Vaillancourt DE ，Duara R ，Loewenstein DA ，Smith GE ... -  《-》

Multiomics Blood-Based Biomarkers Predict Alzheimer's Predementia with High Specificity in a Multicentric Cohort Study.

Souchet B ，Michaïl A ，Heuillet M ，Dupuy-Gayral A ，Haudebourg E ，Pech C ，Berthemy AA ，Autelitano F ，Billoir B ，Domoto-Reilly K ，Fowler C ，Grabowski T ，Jayadev S ，Masters CL ，Braudeau J ... -  《-》