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The role of microglia in tau accumulation is currently unclear but could provide an important insight into the mechanisms underlying Alzheimer’s disease (AD)1. Here, we measured the microglial marker soluble TREM2 and the disease-associated microglial activation stage 2 markers AXL, MERTK, GAS6, LPL, CST7, SPP1 and CSF1 in nondemented individuals from the Swedish BioFINDER-2 cohort who underwent longitudinal tau-positron emission tomography (PET), amyloid-PET and global cognitive assessment. To assess whether baseline microglial markers had an effect on AD-related changes, we studied three sub-groups of individuals: 121 with evidence of amyloid-PET pathology (A+), 64 with additional evidence of tau-PET pathology (A+T+) and 159 without amyloid- or tau-PET pathology (A−T−). Our results showed that increased levels of TREM2 were associated with slower amyloid accumulation in A+ individuals in addition to slower tau deposition and cognitive decline in A+T+ subjects. Similarly, higher levels of AXL, MERTK, GAS6, LPL, CST7 and CSF1 predicted slower tau accumulation and/or cognitive decline in the A+T+ group. These findings have important implications for future therapeutic strategies aiming to boost microglial protective functions in AD.

Background Alzheimer’s disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement. Methods We developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer’s disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer’s disease from non-AD (p n = 165) and BioFINDER-2 cohorts (n = 563), consisting of patients across the full Alzheimer’s disease continuum, including also young controls ( Results Increased levels of all phosphorylated epitopes were found in Alzheimer’s disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer’s disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC = 98.73%, fold change = 7.64; BioFINDER-2: AUC = 91.89%, fold change = 10.65), pT217 (TRIAD: AUC = 99.71%, fold change = 6.33; BioFINDER-2: AUC = 98.12%, fold change = 8.83) and pT205 (TRIAD: AUC = 99.07%, fold change = 5.34; BioFINDER-2: AUC = 93.51%, fold change = 3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC = 83.26, fold change = 2.39; BioFINDER-2: AUC = 91.05%, fold change = 3.29), pT231 (TRIAD: AUC = 86.25, fold change = 3.80; BioFINDER-2: AUC = 78.69%, fold change = 3.65) and pT205 (TRIAD: AUC = 71.58, fold change = 1.51; BioFINDER-2: AUC = 71.11%, fold change = 1.70). Conclusions While an increase was found for all pTau species examined, the highest fold change in Alzheimer’s disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates.

PURPOSE: To compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer’s Disease (AD) Research Framework derived from [(18)F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181). METHODS: We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL). RESULTS: FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. CONCLUSION: The choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.

We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice. This study shows that combinations of blood-based biomarkers can be used to predict cognitive decline and dementia due to Alzheimer’s disease in patients with mild cognitive impairment. Biomarkers for tau and neurodegeneration provided accurate prognosis of decline and conversion over four years.

Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer’s disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87–0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94–0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials. Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.

Biomarkers have revolutionized scientific research on neurodegenerative diseases, in particular Alzheimer’s disease, transformed drug trial design, and are also increasingly improving patient management in clinical practice. A few key cerebrospinal fluid biomarkers have been robustly associated with neurodegenerative diseases. Several novel biomarkers are very promising, especially blood-based markers. However, many biomarker findings have had low reproducibility despite initial promising results. In this perspective, we identify possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases, with a focus on Alzheimer’s disease. We suggest guidelines for researchers and journal editors, with the aim to improve reproducibility of findings., Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.

Background The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer’s disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer’s Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [18F]flortaucipir, and more accurately identifies individuals with abnormally increased [18F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [18F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [18F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD., Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the AD brain. Here the authors demonstrate that CSF p-tau217 shows better performance as an AD biomarker than p-tau181.

The independent effects of different brain pathologies on age-dependent cognitive decline are unclear. We examined this in 300 cognitively unimpaired elderly individuals from the BioFINDER study. Using cognition as outcome we studied the effects of cerebrospinal fluid biomarkers for amyloid-β (Aβ42/40), neuroinflammation (YKL-40), and neurodegeneration and tau pathology (T-tau and P-tau) as well as MRI measures of white-matter lesions, hippocampal volume (HV), and regional cortical thickness. We found that Aβ positivity and HV were independently associated with memory. Results differed depending on age, with memory being associated with HV (but not Aβ) in older participants (73.3–88.4 years), and with Aβ (but not HV) in relatively younger participants (65.2–73.2 years). This indicates that Aβ and atrophy are independent contributors to memory variability in cognitively healthy elderly and that Aβ mainly affects memory in younger elderly individuals. With advancing age, the effect of brain atrophy overshadows the effect of Aβ on memory function.

A new study has found that levels of primary fatty amides in plasma correlate with amyloid-β pathology and other Alzheimer disease (AD)-related phenomena. In addition to identifying potential plasma biomarkers for AD, the findings suggest new avenues for investigation into the early stages of AD.

Proteolytic degradation of amyloid β (Aβ) peptides has been intensely studied due to the central role of Aβ in Alzheimer’s disease (AD) pathogenesis. While several enzymes have been shown to degrade Aβ peptides, the main pathway of Aβ degradation in vivo is unknown. Cerebrospinal fluid (CSF) Aβ42 is reduced in AD, reflecting aggregation and deposition in the brain, but low CSF Aβ42 is, for unknown reasons, also found in some inflammatory brain disorders such as bacterial meningitis. Using 18O-labeling mass spectrometry and immune-affinity purification, we examined endogenous proteolytic processing of Aβ in human CSF. The Aβ peptide profile was stable in CSF samples from healthy controls but in CSF samples from patients with bacterial meningitis, showing increased leukocyte cell count, 18O-labeling mass spectrometry identified proteolytic activities degrading Aβ into several short fragments, including abundant Aβ1–19 and 1–20. After antibiotic treatment, no degradation of Aβ was detected. In vitro experiments located the source of the proteolytic activity to blood components, including leukocytes and erythrocytes, with insulin-degrading enzyme as the likely protease. A recombinant version of the mid-domain anti-Aβ antibody solanezumab was found to inhibit insulin-degrading enzyme-mediated Aβ degradation. 18O labeling-mass spectrometry can be used to detect endogenous proteolytic activity in human CSF. Using this technique, we found an enzymatic activity that was identified as insulin-degrading enzyme that cleaves Aβ in the mid-domain of the peptide, and could be inhibited by a recombinant version of the mid-domain anti-Aβ antibody solanezumab.

Increased APP (amyloid precursor protein) processing causes β-amyloid (Aβ) accumulation in autosomal dominant Alzheimer's disease (AD), but it is unclear if it also affects sporadic Aβ accumulation. We tested healthy controls and patients with mild cognitive symptoms (N=331) in the BioFINDER study, using cerebrospinal fluid (CSF) Aβ40 as a surrogate for amyloidogenic APP processing. We find that levels of brain Aβ fibrils (measured by 18F-flutemetamol PET) are independently associated with high CSF Aβ40 (P, Autosomal dominant Alzheimer's disease is thought to be caused by increased amyloidogenic APP processing. Mattson et al. show that association between brain Aβ and cerobrospinal fluid Aβ40 levels is stronger in APOE ɛ4 negative people, suggesting that increased processing may also underlie sporadic disease.

Niemann-Pick type C (NPC) is a progressive neurodegenerative lysosomal disease with altered cellular lipid trafficking. The metabolism of amyloid-β (Aβ) - previously mainly studied in Alzheimer's disease - has been suggested to be altered in NPC. Here we aimed to perform a detailed characterization of metabolic products from the amyloid precursor protein (APP) in NPC models and patients. We used multiple analytical technologies, including immunoassays and immunoprecipitation followed by mass spectrometry (IP-MS) to characterize Aβ peptides and soluble APP fragments (sAPP-α/β) in cell media from pharmacologically (U18666A) and genetically (NPC1 ( -/- ) ) induced NPC cell models, and cerebrospinal fluid (CSF) from NPC cats and human patients. The pattern of Aβ peptides and sAPP-α/β fragments in cell media was differently affected by NPC-phenotype induced by U18666A treatment and by NPC1 ( -/- ) genotype. U18666A treatment increased the secreted media levels of sAPP-α, AβX-40 and AβX-42 and reduced the levels of sAPP-β, Aβ1-40 and Aβ1-42, while IP-MS showed increased relative levels of Aβ5-38 and Aβ5-40 in response to treatment. NPC1 ( -/- ) cells had reduced media levels of sAPP-α and Aβ1-16, and increased levels of sAPP-β. NPC cats had altered CSF distribution of Aβ peptides compared with normal cats. Cats treated with the potential disease-modifying compound 2-hydroxypropyl-β-cyclodextrin had increased relative levels of short Aβ peptides including Aβ1-16 compared with untreated cats. NPC patients receiving β-cyclodextrin had reduced levels over time of CSF Aβ1-42, AβX-38, AβX-40, AβX-42 and sAPP-β, as well as reduced levels of the axonal damage markers tau and phosphorylated tau. We conclude that NPC models have altered Aβ metabolism, but with differences across experimental systems, suggesting that NPC1-loss of function, such as in NPC1 ( -/- ) cells, or NPC1-dysfunction, seen in NPC patients and cats as well as in U18666A-treated cells, may cause subtle but different effects on APP degradation pathways. The preliminary findings from NPC cats suggest that treatment with cyclodextrin may have an impact on APP processing pathways. CSF Aβ, sAPP and tau biomarkers were dynamically altered over time in human NPC patients.

Activated microglial cells, which are the resident macrophages of the central nervous system, surround amyloid β-plaques in Alzheimer's disease (AD) brains. Inflammation including microglial activation may contribute in AD pathogenesis, and biomarkers for this process may thus be of value to study AD pathogenesis and might facilitate development of therapies targeting these cells. We therefore examined cerebrospinal fluid (CSF) biomarkers in patients with AD, other dementias, mild cognitive impairment and in healthy controls. Samples were analyzed for markers with known association to macrophage activity, including chitotriosidase, YKL-40 (CHI3L1, HC gp-39) and chemokine CC motif ligand 2 (CCL2, MCP1). Patients with AD had higher chitotriosidase activity than controls and patients with stable mild cognitive impairment, consistent with the presence of activated microglial cells in AD brains, but with large overlaps between groups. CCL2 and YKL-40 concentrations did not differ among groups. Microglial markers are unlikely to be useful for AD diagnosis, but might be useful for identification of distinct subgroups of patients, and for the development and implementation of drugs targeting microglial pathology.

Introduction The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. However, in the elderly, AD pathology is likely to occur together with subcortical axonal degeneration on the basis of cerebrovascular disease. Therefore, we hypothesized that biomarkers for AD and subcortical axonal degeneration would correlate in patients undergoing testing for dementia biomarkers, particularly in older age groups. Methods We performed correlation and cluster analyses of cerebrospinal fluid (CSF) biomarker data from 5,542 CSF samples analyzed in our routine clinical neurochemistry laboratory in 2010 through 2012 for the established CSF AD biomarkers total tau (T-tau), phosphorylated-tau (P-tau), amyloid β1-42 (Aβ42), and for neurofilament light (NFL), which is a protein expressed in large-caliber myelinated axons, the CSF levels of which correlate with subcortical axonal injury. Results Aβ42, T-tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low Aβ42/P-tau ratio (suggesting AD pathology) had high levels of NFL. High levels of NFL also correlated with the presence of an AD biomarker pattern defined by Aβ42/P-tau and T-tau. Only 29% of those with an AD biomarker signature had normal NFL levels. Age was a possible confounding factor for the associations between NFL and established AD biomarkers, but in a logistic regression analysis, both age and NFL independently predicted the AD biomarker pattern. Conclusions The association between an AD-like signature using the established biomarkers Aβ42, T-tau, and P-tau with increased levels of NFL provides in vivo evidence of an association between AD and subcortical axonal degeneration in this uniquely large dataset of CSF samples tested for dementia biomarkers.

In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.