Clinical validation of the Lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer’s disease

Abstract Background Ongoing efforts within the Alzheimer’s disease (AD) field have focused on improving the intra- and inter-laboratory variability for cerebrospinal fluid (CSF) biomarkers. Fully automated assays offer the possibility to eliminate sample manipulation steps and are expected to contribute to this improvement. Recently, fully automated chemiluminescence enzyme immunoassays for the quantification of all four AD biomarkers in CSF became available. The aims of this study were to (i) evaluate the analytical performance of the Lumipulse G β-Amyloid 1-42 (restandardized to Certified Reference Materials), β-Amyloid 1-40, total Tau, and pTau 181 assays on the fully automated LUMIPULSE G600II; (ii) compare CSF biomarker results of the Lumipulse G assays with the established manual ELISA assays (INNOTEST®) from the same company (Fujirebio); and (iii) establish cut-off values and the clinical performance of the Lumipulse G assays for AD diagnosis. Methods Intra- and inter-assay variation was assessed in CSF samples with low, medium, and high concentrations of each parameter. Method comparison and clinical evaluation were performed on 40 neurological controls (NC) and 80 patients with a diagnosis of probable AD supported by a follow-up ≥ 3 years and/or positive amyloid PET imaging. A small validation cohort of 10 NC and 20 AD patients was also included to validate the cut-off values obtained on the training cohort. Results The maximal observed intra-assay and inter-assay coefficients of variation (CVs) were 3.25% and 5.50%, respectively. Method comparisons revealed correlation coefficients ranging from 0.89 (for Aβ40) to 0.98 (for t-Tau), with those for Aβ42 (0.93) and p-Tau (0.94) in-between. ROC curve analysis showed area under the curve values consistently above 0.85 for individual biomarkers other than Aβ40, and with the Aβ42/40, Aβ42/t-Tau, and Aβ42/p-Tau ratios outperforming Aβ42. Validation of the cut-off values in the independent cohort showed a sensitivity ranging from 75 to 95% and a specificity of 100%. The overall percentage of agreement between Lumipulse and INNOTEST was very high (> 87.5%). Conclusions The Lumipulse G assays show a very good analytical performance that makes them well-suited for CSF clinical routine measurements. The good clinical concordance between the Lumipulse G and INNOTEST assays facilitates the implementation of the new method in routine practice.

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Clinical utility of Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer’s Disease in Korea

10.21203/rs.3.rs-25971/v1 ◽

2020 ◽

Author(s):

Jongmin Lee ◽

Hyemin Jang ◽

Sung Hoon Kang ◽

Jaeho Kim ◽

Ji-Sun Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Clinical Utility ◽

Medical Center ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Characteristic Analysis ◽

Csf Biomarker ◽

T Tau

Abstract Background Cerebrospinal fluid (CSF) biomarkers are increasingly used in clinical practice for the diagnosis of Alzheimer’s disease (AD). We aimed to 1) determine cutoff values of CSF biomarkers for AD, 2) investigate their clinical utility by estimating a concordance with amyloid positron emission tomography (PET), and 3) apply AT (amyloid/tau) classification based on CSF results. Methods We performed CSF analysis in 51 normal controls (NC), 23 amnestic mild cognitive impairment (aMCI) and 65 AD dementia (ADD) patients at the Samsung Medical Center in Korea. We tried to develop cutoff of CSF biomarkers for differentiating ADD from NC using receiver operating characteristic analysis. We also investigated a concordance between CSF and amyloid PET results and applied AT classification scheme based on CSF biomarker abnormalities to characterize our participants. Results CSF Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) significantly differ across the three groups. The area under curve for the differentiation between NC and ADD was highest in t-tau/Aβ42(0.994) followed by p-tau/Aβ42(0.963), Aβ42(0.960) and t-tau (0.918). The concordance rate between CSF Aβ42 and amyloid PET results was 92%. Finally, AT classification based on CSF biomarker abnormalities led to a majority of NC categorized into A-T-(72%), aMCI as A + T-(52%)/A + T+(30%), and AD as A + T+(56%)/A + T-(41%). Conclusion CSF biomarkers had high sensitivity and specificity in differentiating ADD from NC and were as accurate as amyloid PET. The AT group distribution was comparable to those of previous studies, which may serve to predict the prognosis more accurately than amyloid PET alone in the future.

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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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Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

Brain Sciences ◽

10.3390/brainsci11101258 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1258

Author(s):

George P. Paraskevas ◽

Elisabeth Kapaki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Small Vessel Disease ◽

Lewy Bodies ◽

Plaque Burden ◽

Csf Biomarkers ◽

Β Amyloid ◽

Disease Modifying

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations.

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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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Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer’s Disease Spectrum: Who Really Deserves an A+?

Journal of Alzheimer s Disease ◽

10.3233/jad-210593 ◽

2021 ◽

pp. 1-12

Author(s):

Luca Sacchi ◽

Tiziana Carandini ◽

Giorgio Giulio Fumagalli ◽

Anna Margherita Pietroboni ◽

Valeria Elisa Contarino ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Amyloid Β ◽

Standardized Uptake Value ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Linear Regression Models ◽

Csf Analysis ◽

Disease Spectrum

Background: Association between cerebrospinal fluid (CSF)-amyloid-β (Aβ)42 and amyloid-PET measures is inconstant across the Alzheimer’s disease (AD) spectrum. However, they are considered interchangeable, along with Aβ 42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). Objective: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. Methods: We include ed 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aβ 42 within a 365-days interval. Thresholds used for dichotomization were: Aβ 42 < 640 pg/mL (Aβ 42+); pTau > 61 pg/mL (pTau+); and Aβ 42/40 < 0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). Results: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93–0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p = 0.0063) and Aβ 42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = –0.56, p = 0.0058; rho = –0.52, p = 0.0117 respectively). No correlations between CSF-Aβ 42 and global SUVRs were observed. In subregion analysis, both pTau and Aβ 42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2 = 0.55–0.59, p < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aβ 42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aβ 42 or using Aβ 42/40, instead of Aβ 42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. Conclusion: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aβ 42/40 and secondarily pTau rather than Aβ 42 levels.

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Associations of Green Tea Consumption and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE Study

Journal of Alzheimer s Disease ◽

10.3233/jad-200410 ◽

2020 ◽

Vol 77 (1) ◽

pp. 411-421

Author(s):

Ya-Hui Ma ◽

Jia-Huan Wu ◽

Wei Xu ◽

Xue-Ning Shen ◽

Hui-Fu Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Green Tea ◽

Interaction Effects ◽

Csf Biomarkers ◽

Tea Consumption ◽

And Gender ◽

T Tau ◽

Cognitively Intact

Background: Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer’s disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. Objective: This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. Methods: Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOE ɛ4 status and gender using a two-way analysis of covariance. Results: Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p = 0.041) but not with the levels of CSF amyloid-β 42 (Aβ42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p = 0.007) and CSF t-tau/Aβ42 (p = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOE ɛ4 and gender. Conclusion: Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies.

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Obstructive sleep apnea and longitudinal Alzheimer’s disease biomarker changes

SLEEP ◽

10.1093/sleep/zsz048 ◽

2019 ◽

Vol 42 (6) ◽

Cited By ~ 31

Author(s):

Omonigho M Bubu ◽

Elizabeth Pirraglia ◽

Andreia G Andrade ◽

Ram A Sharma ◽

Sandra Gimenez-Badia ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Obstructive Sleep Apnea ◽

Cognitive Impairment ◽

Sleep Apnea ◽

Rate Of Change ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Obstructive Sleep ◽

T Tau

Abstract Study Objectives To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aβ42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) elderly. Methods Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aβ42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA. Results In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B = .06, 95% CI = .02, .11 and B = .08, 95% CI = .05, .12, respectively) and decrease in CSF Aβ42 levels (B = −2.71, 95% CI = −3.11, −2.35 and B = −2.62, 95% CI = −3.23, −2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA− participants. No significant variations in the biomarker changes over time were seen in the AD group. Conclusions In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

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Relationship Between General Cognition, Visual Assessed Cortical Atrophy, and Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease: A Cross-Sectional Study from a Chinese PUMCH Cohort

Journal of Alzheimer s Disease ◽

10.3233/jad-210344 ◽

2021 ◽

pp. 1-10

Author(s):

Chenhui Mao ◽

Longze Sha ◽

Jie Li ◽

Xinying Huang ◽

Shanshan Chu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Rating Scales ◽

Mmse Score ◽

Cortical Atrophy ◽

Csf Biomarkers ◽

Cortical Region ◽

Cross Sectional ◽

T Tau

Background: Cerebrospinal fluid (CSF) biomarkers are widely accepted as manifestations of Alzheimer’s disease (AD) pathogenesis and incorporated into biological definition of AD. However, the correlations between CSF and other biomarkers such as neuroimaging and neuropsychiatric evaluation are complicated and inconsistent. Objective: We aimed to better interpreting CSF biomarkers results accompanying with other indexes in improving accurate diagnosis of AD. Methods: 112 AD patients and 30 cognitive normal controls were selected. Commercial accessible ELISA kits were introduced for measurement of CSF t-tau, p-tau181, Aβ 1–42, and NfL based on standard protocol. MRI examinations were performed using a 3-T MRI scanner and visual rating scales including medial temporal atrophy score and Koedam’s scale were used to evaluate medial temporal atrophy and posterior region atrophy. Results: CSF biomarkers’ profile including decreased concentration of Aβ 1–42, increased concentration of t-tau, p-tau181, t-tau/Aβ 1–42, and NfL were diagnostic between AD and control. CSF biomarkers profile was not influenced by the APOE genotype. Increased concentration of t-tau and NfL, as well as ratio of t-tau/Aβ 1–42 were related to decrease of Mini-Mental State Examination (MMSE) score while concentration of Aβ 1–42 not. Visual assessed cortical atrophy was related to MMSE score, but most of the CSF biomarkers were not related to atrophy, except that increased concentration of p-tau181 was significantly associated with atrophy of posterior cortical region. Conclusion: Our results supported CSF biomarkers were helpful in diagnosis of AD. However, CSF biomarkers were cross-sectional reflection of pathogenesis, which did not correlate well with clinical progression. CSF biomarkers should be interpreted in combination with MRI and cognitive evaluation in clinical use.

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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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