Shared genetic background between cerebrospinal fluid biomarkers and risk for Alzheimer’s disease: A two-sample Mendelian randomisation study

Abstract Background: Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer’s disease (AD) is causal remains unclear. Recent failures to demonstrate the efficacy of several Aβ-modifying drugs may indicate a possibility that the observed association is not causal, which led to efforts to develop tau-directed treatments whose efficacy remains tentative. Methods: Herein, we conducted a two-sample Mendelian randomisation analysis to investigate shared genetic background between cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and risk for AD, and to find genetic evidence for causal association between these CSF biomarkers and risk for AD. We used summary statistics of genome-wide association study (GWAS) for CSF biomarkers (Aβ 1-42 , phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively-normal controls. We tested association between changes in the genetically-predicted CSF biomarkers and LOAD risk. Results: We found a decrease in the LOAD risk per one-standard deviation (SD) increase in the genetically-predicted CSF Aβ (odds ratio [OR], 2.87×10 -3 for AD; 95% confidence interval [CI], 1.54×10 -4 –0.05; p = 8.91×10 -5 ). Conversely, we observed an increase in the LOAD risk per one-SD increase in the genetically-predicted CSF p-tau (OR, 19.46; 95% CI, 1.50–2.52×10 2 ; p = 0.02) and t-tau (OR, 33.80; 95% CI, 1.57–7.29×10 2 ; p = 0.02). Conclusions: Our findings suggest a shared genetic background between the CSF biomarkers and LOAD risk. Although it requires validation by future studies including more genetic variants identified in large-scale GWASs for CSF biomarkers, our results suggest a causal association between CSF biomarkers and risk for LOAD Keywords: CSF biomarkers, Amyloid, Tau, Alzheimer’s disease

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Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study

Journal of Alzheimer s Disease ◽

10.3233/jad-200671 ◽

2021 ◽

pp. 1-11

Author(s):

Soyeon Kim ◽

Kiwon Kim ◽

Kwangsik Nho ◽

Woojae Myung ◽

Hong-Hee Won

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Genetic Background ◽

Mendelian Randomization ◽

Csf Biomarkers ◽

Tau Pathology ◽

T Tau ◽

Load Risk ◽

Shared Genetic

Background: Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer’s disease (LOAD) is causal remains unclear. Objective: We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD. Methods: We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aβ 1–42 [Aβ], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. Results: We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 2.87×10–3 for AD; 95%confidence interval [CI], 1.54×10–4 –0.05; p = 8.91×10–5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50–2.52×102; p = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57–7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). Conclusion: We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.

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Causal relationship of cerebrospinal fluid biomarkers with the risk of Alzheimer’s disease: A two-sample Mendelian randomization study

10.1101/719898 ◽

2019 ◽

Author(s):

Soyeon Kim ◽

Kiwon Kim ◽

Kwangsik Nho ◽

Woojae Myung ◽

Hong-Hee Won

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Beta ◽

Mendelian Randomization ◽

Csf Biomarkers ◽

Tau Pathology ◽

A Genome ◽

T Tau ◽

Load Risk

AbstractWhether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer’s disease (AD) is causal remains unclear. The recent failures to demonstrate the efficacy of several amyloid beta-modifying drugs may indicate the possibility that the observed association is not causal. These failures also led to efforts to develop tau-directed treatments whose efficacy is still tentative. Herein, we conducted a two-sample Mendelian randomization analysis to determine whether the relationship between the cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and the risk of AD is causal. We used the summary statistics of a genome-wide association study (GWAS) for CSF biomarkers (Aβ1-42, phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively normal controls. We tested the association between the change in the genetically predicted CSF biomarkers and LOAD risk. We found a modest decrease in the LOAD risk per one standard deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 0.63 for AD; 95% confidence interval [CI], 0.38-0.87; P = 0.02). In contrast, we observed a significant increase in the LOAD risk per one SD increase in the genetically predicted CSF p-tau (OR, 2.37; 95% CI, 1.46-3.28; P = 1.09×10−5). However, no causal association was observed of the CSF t-tau with the LOAD risk (OR, 1.15; 95% CI, 0.85-1.45; P = 0.29). Our findings need to be validated in future studies with more genetic variants identified in larger GWASs for CSF biomarkers.

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New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

Experimental & Molecular Medicine ◽

10.1038/s12276-020-0418-9 ◽

2020 ◽

Vol 52 (4) ◽

pp. 556-568 ◽

Cited By ~ 10

Author(s):

Sun Ah Park ◽

Song Mi Han ◽

Chae Eun Kim

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Treatment Response ◽

Amyloid Β ◽

Clinical Severity ◽

Intercellular Adhesion Molecule ◽

Csf Biomarkers ◽

Tau Pathology ◽

Protein Clearance ◽

New Biomarkers

Abstract Cerebrospinal fluid (CSF) biomarkers based on the core pathological proteins associated with Alzheimer’s disease (AD), i.e., amyloid-β (Aβ) and tau protein, are widely regarded as useful diagnostic biomarkers. However, a lack of biomarkers for monitoring the treatment response and indexing clinical severity has proven to be problematic in drug trials targeting Aβ. Therefore, new biomarkers are needed to track non-Aβ and non-tau pathology. Many proteins involved in the pathophysiological progression of AD have shown promise as new biomarkers. Neurodegeneration- and synapse-related biomarkers in CSF (e.g., neurofilament light polypeptide [NFL], neurogranin, and visinin-like protein 1) and blood (e.g., NFL) aid prediction of AD progress, as well as early diagnosis. Neuroinflammation, lipid dysmetabolism, and impaired protein clearance are considered important components of AD pathophysiology. Inflammation-related proteins in the CSF, such as progranulin, intercellular adhesion molecule 1, and chitinase-3-like protein 1 (YKL-40), are useful for the early detection of AD and can represent clinical severity. Several lipid metabolism-associated biomarkers and protein clearance-linked markers have also been suggested as candidate AD biomarkers. Combinations of subsets of new biomarkers enhance their utility in terms of broadly characterizing AD-associated pathological changes, thereby facilitating precise selection of susceptible patients and comprehensive monitoring of the treatment response. This approach could facilitate the development of effective treatments for AD.

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Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319266 ◽

2019 ◽

Vol 90 (7) ◽

pp. 740-746 ◽

Cited By ~ 7

Author(s):

Martha S Foiani ◽

Claudia Cicognola ◽

Natalia Ermann ◽

Ione O C Woollacott ◽

Carolin Heller ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Frontotemporal Dementia ◽

Neurodegenerative Disorder ◽

The Novel ◽

Tau Pathology ◽

Total Tau ◽

Significant Difference ◽

T Tau

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

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0057 Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment

SLEEP ◽

10.1093/sleep/zsaa056.055 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A23-A23

Author(s):

R Mehra ◽

R Bhambra ◽

J Bena ◽

L Bekris ◽

J Leverenz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Csf Biomarkers ◽

Significance Level ◽

Unit Increase ◽

T Tau ◽

Age And Sex

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A

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Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15606141 ◽

2015 ◽

Vol 36 (3) ◽

pp. 621-628 ◽

Cited By ~ 23

Author(s):

Sara Shams ◽

Tobias Granberg ◽

Juha Martola ◽

Xiaozhen Li ◽

Mana Shams ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Serum Albumin ◽

Amyloid Β ◽

Cerebral Microbleeds ◽

Csf Biomarkers ◽

Barrier Dysfunction ◽

T Tau

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p < 0.05). CSF/serum albumin ratios were high with multiple CMBs ( p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease ( p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

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Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Neurology ◽

10.1212/wnl.0000000000012513 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012513

Author(s):

Michel J. Grothe ◽

Alexis Moscoso ◽

Nicholas J. Ashton ◽

Thomas K. Karikari ◽

Juan Lantero-Rodriguez ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Braak Stage ◽

Neuritic Plaques ◽

Neurofilament Light ◽

T Tau

Objective:To study cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.Methods:We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).Results:All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Conclusions:Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of Evidence:This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.

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Usefulness of CSF Biomarkers in Predicting the Progression of Amnesic and Nonamnesic Mild Cognitive Impairment to Alzheimer’s Disease

Current Aging Science ◽

10.2174/1874609812666190112095430 ◽

2019 ◽

Vol 12 (1) ◽

pp. 35-42

Author(s):

Ricard L. Ortega ◽

Farida Dakterzada ◽

Alfonso Arias ◽

Ester Blasco ◽

Alba Naudí ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Csf Biomarkers ◽

Prodromal Phase ◽

Diagnosis And Prognosis ◽

Amnestic Mci ◽

Atypical Presentations ◽

T Tau

Objective: The aim of this study was to investigate the usefulness of Alzheimer’s disease Cerebrospinal Fluid (CSF) biomarkers in predicting the progression to dementia in patients with Mild Cognitive Impairment (MCI). Methods: One hundred and thirteen patients were consecutively recruited from April 2012 to April 2014. Measurement of CSF biomarkers (amyloid-β42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau)) and a neuropsychological evaluation were performed for all patients. We categorized patients with MCI as A+A- and N+N- based on the presence/absence of amyloid pathology and neurodegeneration, respectively. Results: Of 72 patients with MCI, 26 (36%) progressed to dementia. These patients had lower CSF Aβ42 levels and higher p-tau and t-tau levels at baseline. The proportion that progressed to dementia was 14.3% (2/14), 36.8% (7/19), 66.7% (4/6) and 75% (12/16) in the A-N-, A+N-, A-N+ (SNAP), and A+N+ patients, respectively (p < 0.05). There were significant differences in the probability of progression from amnestic MCI (aMCI) to AD between the A+N+ and A-N- patients (OR = 8.1, 95% CI 1.5-42.3, p = 0.001) but not between SNAP (OR = 7.3, 95% CI 0.9-61, p = 0.02) or A+N- (OR = 2.1, 95% CI 0.4 to 10.4, p = 0.15) patients compared to the A-N- subgroup. None of the biomarker profiles of the subgroups predicted the time until the progression to AD. Conclusion: The use of CSF AD biomarkers in clinical practice improves the certainty of diagnosis and prognosis of patients, especially in patients in the prodromal phase or in patients with atypical presentations.

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CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320826 ◽

2019 ◽

Vol 90 (10) ◽

pp. 1117-1123 ◽

Cited By ~ 12

Author(s):

Anna Jeppsson ◽

Carsten Wikkelsö ◽

Kaj Blennow ◽

Henrik Zetterberg ◽

Radu Constantinescu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Normal Pressure Hydrocephalus ◽

Neuronal Damage ◽

Amyloid Β ◽

Normal Pressure ◽

Idiopathic Normal Pressure Hydrocephalus ◽

Prediction Algorithm ◽

Csf Biomarkers ◽

T Tau

ObjectiveTo examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.MethodsThe study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).ResultsPatients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.ConclusionsThe combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

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Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology

Brain ◽

10.1093/brain/awz346 ◽

2019 ◽

Vol 143 (2) ◽

pp. 650-660 ◽

Cited By ~ 8

Author(s):

Kaj Blennow ◽

Chun Chen ◽

Claudia Cicognola ◽

Kristin R Wildsmith ◽

Paul T Manser ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Proteolytic Processing ◽

Tau Pathology ◽

Strong Negative Correlation ◽

Drug Candidates ◽

Tangle Pathology ◽

Tau Pet ◽

T Tau ◽

Fluid Biomarker

Abstract To date, there is no validated fluid biomarker for tau pathology in Alzheimer’s disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer’s disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer’s disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer’s disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer’s disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer’s disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer’s disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer’s disease and other tauopathies.

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