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Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments. Longitudinal study of plasma biomarkers, in two independent cohorts, highlighted only p-tau217 as a surrogate marker of disease progression in early Alzheimer’s disease, supporting the development of new disease-modifying treatments.

INTRODUCTION Understanding longitudinal change in key plasma biomarkers will aid in detecting presymptomatic Alzheimer's disease (AD). METHODS Serial plasma samples from 424 Wisconsin Registry for Alzheimer's Prevention participants were analyzed for phosphorylated‐tau217 (p‐tau217; ALZpath) and other AD biomarkers, to study longitudinal trajectories in relation to disease, health factors, and cognitive decline. Of the participants, 18.6% with known amyloid status were amyloid positive (A+); 97.2% were cognitively unimpaired (CU). RESULTS In the CU, amyloid‐negative (A–) subset, plasma p‐tau217 levels increased modestly with age but were unaffected by body mass index and kidney function. In the whole sample, average p‐tau217 change rates were higher in those who were A+ (e.g., simple slopes(se) for A+ and A– at age 60 were 0.232(0.028) and 0.038(0.013))). High baseline p‐tau217 levels predicted faster preclinical cognitive decline. DISCUSSION p‐tau217 stands out among markers for its strong association with disease and cognitive decline, indicating its potential for early AD detection and monitoring progression. Highlights Phosphorylated‐tau217 (p‐tau217) trajectories were significantly different in people who were known to be amyloid positive. Subtle age‐related trajectories were seen for all the plasma markers in amyloid‐negative cognitively unimpaired. Kidney function and body mass index were not associated with plasma p‐tau217 trajectories. Higher plasma p‐tau217 was associated with faster preclinical cognitive decline.

INTRODUCTION Increasing evidence links amyloid beta (Aβ) aggregation with inflammation. This pilot study investigated the use of an immunoassay panel to map biomarker changes in patients with Alzheimer's disease (AD). Furthermore, we evaluated the stability of protein quantification after multiple freeze–thaw cycles (FTCs). METHODS The nucleic acid‐linked immuno‐sandwich assay (NULISA) inflammation panel measured 203 proteins in serum samples of individuals with (n = 31) and without (n = 31) AD pathology. Linear models, adjusted for age and sex, contrasted protein expression across groups. RESULTS After multiple‐testing adjustments, glial fibrillary acidic protein (p < 0.001) and S100A12 (p < 0.001) were significantly changed in the presence of AD pathology. Furthermore, they correlated with cerebrospinal fluid biomarkers (phosphorylated tau‐181 [p‐tau181], tau, and Aβ42). Additional markers were nominally changed between groups. Five FTCs caused minimal changes in measurements with the NULISA inflammation panel. DISCUSSION Monitoring of inflammation in AD, using the 200‐plex NULISA panel, demonstrates changes in peripherally circulating inflammation‐related proteins. Contrary to previous reports, FTCs had minimal impact on the quantification of inflammatory markers. Highlights The novel nucleic acid‐linked immuno‐sandwich assay (NULISA) inflammation panel, which includes 200 protein biomarkers, was used. The panel was used for the first time in serum from patients with Alzheimer's disease (AD). The protein S100A12 was identified as a potential biomarker for AD. Inflammation markers were stable in up to five freeze–thaw cycles.

Diagnosing Alzheimer’s disease (AD) in adults with Down syndrome (DS), a population with a high genetically determined risk of AD, remains challenging. In this large observational study including n  = 2329 samples from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) and euploid controls from the Sant Pau Initiative on Neurodegeneration (SPIN) with and without symptomatic AD, we investigate if the strong diagnostic performance of plasma p-tau217 observed in sporadic AD extends to the DS population. Plasma p-tau217 discriminated cognitively stable individuals with DS from those with AD dementia with an AUC of 0.96 (95% CI, 0.95-0.97), and from those with prodromal AD with an AUC of 0.90 (95% CI, 0.87-0.92). Amyloid β (Aβ) positive and Aβ negative individuals with DS were distinguished with an AUC of 0.95 (95% CI, 0.92-0.99). In this study, we demonstrate that plasma p-tau217 is highly accurate in detecting amyloid β positivity and predicting clinical progression in individuals with DS, outperforming other plasma biomarkers. These findings support its use as a reliable, noninvasive tool for early AD detection and management in individuals with DS. The authors show that phosphorylated tau 217 is an accurate blood-based biomarker to detect Alzheimer’s disease and predict disease progression in individuals with Down syndrome, supporting its use as a reliable, non-invasive tool for early diagnosis and care.

Plasma biomarkers have shown promising performance in research cohorts in discriminating between different stages of Alzheimer’s disease (AD). Studies in clinical populations are necessary to provide insights on the clinical utility of plasma biomarkers before their implementation in real-world settings. Here we investigated plasma biomarkers (glial fibrillary acidic protein (GFAP), tau phosphorylated at 181 and 231 (pTau181, pTau231), amyloid β (Aβ) 42/40 ratio, neurofilament light) in 126 patients (age = 65 ± 8) who were admitted to the Clinic for Cognitive Disorders, at Karolinska University Hospital. After extensive clinical assessment (including CSF analysis), patients were classified as: mild cognitive impairment (MCI) (n = 75), AD (n = 25), non-AD dementia (n = 16), no dementia (n = 9). To refine the diagnosis, patients were examined with [18F]flutemetamol PET (Aβ-PET). Aβ-PET images were visually rated for positivity/negativity and quantified in Centiloid. Accordingly, 68 Aβ+ and 54 Aβ– patients were identified. Plasma biomarkers were measured using single molecule arrays (SIMOA). Receiver-operated curve (ROC) analyses were performed to detect Aβ-PET+ using the different biomarkers. In the whole cohort, the Aβ-PET centiloid values correlated positively with plasma GFAP, pTau231, pTau181, and negatively with Aβ42/40 ratio. While in the whole MCI group, only GFAP was associated with Aβ PET centiloid. In ROC analyses, among the standalone biomarkers, GFAP showed the highest area under the curve discriminating Aβ+ and Aβ– compared to other plasma biomarkers. The combination of plasma biomarkers via regression was the most predictive of Aβ-PET, especially in the MCI group (prior to PET, n = 75) (sensitivity = 100%, specificity = 82%, negative predictive value = 100%). In our cohort of memory clinic patients (mainly MCI), the combination of plasma biomarkers was sensitive in ruling out Aβ-PET negative individuals, thus suggesting a potential role as rule-out tool in clinical practice.

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.

INTRODUCTION Recent advancements in immunological methods accurately quantify biofluid biomarkers for Alzheimer's disease (AD) pathology. Despite progress, more biomarkers, ideally in blood, are needed for effective disease monitoring for AD and other neurodegenerative proteinopathies. METHODS We used the Nucleic Acid Linked Immuno‐Sandwich Assay (NULISA) central nervous system panel for biomarker quantification in plasma, serum, and cerebrospinal fluid of patients with AD, mild cognitive impairment, Lewy body dementia, progranulin (GRN) mutation carriers. RESULTS NULISA identified phosphorylated tau217 and neurofilament light chain as the most deregulated biomarkers in the AD continuum and GRN mutation carriers, respectively. Importantly, numerous novel proteomic changes were observed in each disease endophenotype, which included synaptic processing, inflammation, microglial reactivity, TAR DNA‐binding protein 43, and α‐synuclein pathology. DISCUSSION We underline the potential of next‐generation biomarker identification tools to detect novel proteomic features that also incorporate established biomarkers. These findings highlight the importance of continued biomarker discovery to improve treatment decisions and help us better understand the complexities of neurodegenerative disorders. Highlights The, direct, or indirect, measures in blood that complement phosphorylated tau (p‐tau)217 for other proteinopathies or disease progression are urgently needed. Significant novel proteomic changes were observed in each disease endophenotype in plasma, serum, and cerebrospinal fluid, which included proteins involved in synaptic processing, inflammation, microglial reactivity, TAR DNA‐binding protein 43, and α‐synuclein pathology. Nucleic Acid Linked Immuno‐Sandwich Assay continued to unbiasely highlight p‐tau217 and neurofilament light chain as the most significantly deregulated blood biomarkers in the Alzheimer's disease continuum and progranulin mutation carriers, respectively.

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches. Synopsis Glia activation, inflammation, cell death pathways and neuronal pathologies are associated with disease progression in preclinical AD. Activation of glia cells and cell death pathways maintain a vicious cycle of neuroinflammation that drives disease progression. Protein CSF signatures of neuroinflammation, glia activation, cell death pathways and neuronal pathologies are increased in early Alzheimer’s disease. Glia activation and cell death pathways are associated with disease progression in preclinical Alzheimer’s disease. Activation of cell death pathways is a mediator of neuroinflammation and disease progression in early Alzheimer’s disease. Disturbed synaptic signalling is a mediator of neuroinflammation and cell death pathways in early Alzheimer’s disease. Glia activation, inflammation, cell death pathways and neuronal pathologies are associated with disease progression in preclinical AD. Activation of glia cells and cell death pathways maintain a vicious cycle of neuroinflammation that drives disease progression.

IntroductionAlexander disease (AxD) is a rare leukodystrophy caused by dominant gain-of-function mutations in the gene encoding the astrocyte intermediate filament, glial fibrillary acidic protein (GFAP). However, there is an urgent need for biomarkers to assist in monitoring not only the progression of disease but also the response to treatment. GFAP is the obvious candidate for such a biomarker, as it is measurable in body fluids that are readily accessible for biopsy, namely cerebrospinal fluid and blood. However, in the case of ASOs, the treatment that is furthest in development, GFAP is the target of therapy and presumably would go down independent of disease status. Hence, there is a critical need for biomarkers that are not directly affected by the treatment strategy.MethodsWe explored the potential utility of biomarkers currently being studied in other neurodegenerative diseases and injuries, specifically neurofilament light protein (NfL), phosphorylated forms of tau, and amyloid-β peptides (Aβ42/40).Results and ConclusionsHere, we report that GFAP is elevated in plasma of all age groups afflicted by AxD, including those with adult onset. NfL and p-tau are also elevated, but to a much lesser extent than GFAP. In contrast, the levels of Aß40 and Aß42 are not altered in AxD.

Background The APOE ε4 variant is the largest known genetic risk factor for late‐onset sporadic Alzheimer's disease (AD). Recent blood biomarker models include APOE ε4 status with plasma p‐tau217 for higher accuracy for AD pathology. Thus, protein assays that can accurately determine ε4 carriership simultaneously with plasma p‐tau217 would be advantageous for clinical use. This study aims to evaluate the concordance between the NULISA ApoE4 protein assay and conventional genetic testing for APOE measurement. Method We included two independent cohorts; cohort 1 (Translational Biomarker for Aging and Dementia Cohort [TRIAD]) consisted of 341 participants (mean [SD] age, 64.8[16.1] years; 213 females[62.4%]) and cohort 2 consisted of 38 participants (72.1[16.1] years; 21 females[55.2%]). APOE genotyping was determined by the TaqMan® SNP Genotyping Assay. In cohort 1, ApoE4 and p‐tau217 levels (NPQ) were quantified by the NULISAseq CNS disease panel from Alamar Biosciences. In cohort 2, ApoE4% (ApoE4/ApoEtotal) were quantified by a prototype singleplex assay from Alamar Biosciences Result In cohort 1, we included 341 participants with APOE genotyping (ε4 non‐carriers=221; ε4 carriers=120). ApoE4 NPQ values correctly identified 88.3% of carriers and 94.1% of non‐carriers (Figure 1A). Homozygous ε2 and ε4 carriers were entirely identified. Higher ApoE4 NPQ levels were observed in ε4/ε4 carriers (median [SD], 16.4[0.52]) compared to ε3/ε4 carriers (12.3[5.11]; P<0.0001) but an overlap remained. In these participants, the simultaneously measurement of NULISA plasma p‐tau217 was significantly increased in Aβ+ participants compared to Aβ‐ participants (AUC=0.941; P<0.0001). In cohort 2, we included 38 participants with APOE genotyping (ε3/ε3, n=26; ε3/ε4, n=9; ε4/ε4, n=6) and calculated the ApoE4% from a prototype singleplex NULISA method. Here, ε3/ε3 (0.03 [1.43]), ε3/ε4 (9.37 [1.61] and ε4/ε4 (41.9 [18.0]) individuals were classified with 100% accuracy (Figure 1B). Conclusion Our study assessed ApoE protein assays to determine APOE genotype. The ApoE4 assay within the NULISAseq CNS panel demonstrated high accuracy in distinguishing APOE ε4 carriers from non‐carriers, with some discordance. The reason for the discordance subject to further studies. However, ApoE4% quantification using a prototype singleplex assay distinguished ε4 homozygous, ε4 heterozygous, and non‐carriers with 100% accuracy. This pilot study demonstrates the ability to concurrently determine APOE status and p‐tau217 levels for more accurate diagnostic models of AD pathology.