Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study

Wolf, Frank de; Ghanbari, Mohsen; Licher, Silvan; McRae-McKee, Kevin; Gras, Luuk; Weverling, Gerrit Jan; Wermeling, Paulien R.; Sedaghat, Sanaz; Ikram, Mohammad Kamran; Waziry, Reem; Koudstaal, Wouter; Klap, J.M.; Kostense, Stefan; Hofman, Albert; Anderson, Roy M.; Goudsmit, Jaap; Ikram, M. Arfan

doi:10.1093/brain/awaa054

Cited by 222 publications

(254 citation statements)

References 45 publications

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“…The reason may be attributed to different study population and different follow-up time. Most of previous studies observed marked cognitive decline (clinical progression to MCI) or the incidence of dementia for a long follow-up time in old and high-risk dementia populations (Yaffe, 2011;Gabelle et al, 2013;Verberk et al, 2018;de Wolf et al, 2020). In our study, we just observed 2-year MMSE change in a cognitively normal population with middle and old age.…”

Section: Discussionsupporting

confidence: 41%

Non-linear Relationship Between Plasma Amyloid-β 40 Level and Cognitive Decline in a Cognitively Normal Population

Gao

Shang

Chen

et al. 2020

Front. Aging Neurosci.

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Objectives: Recent studies regarding the relationships between plasma amyloid-β (Aβ) levels and cognitive performance had inconsistent results. In this study, we aimed to characterize the relationship between cognitive decline and plasma Aβ levels in a largesample cognitively normal population. Methods: This population-based, prospective cohort study included 1,240 participants with normal cognition. The Mini-Mental State Examination (MMSE) was used to assess cognitive function at baseline and 2 years later. Restricted cubic splines, multivariate logistic regression, and multivariate linear regression models were used to evaluate the type of relationship between cognitive decline during the 2-year follow-up period and plasma Aβ levels (Aβ 40 , Aβ 42 , and Aβ 42/40). Results: Participants with moderate Aβ 40 levels had the highest risk of cognitive decline during a 2-year follow-up relative to individuals with low Aβ 40 [odds ratio (OR): 0.60, 95% confidence interval (CI): 0.45-0.81, p < 0.001] or high Aβ 40 (OR: 0.65, 95% CI: 0.49-0.87, p = 0.004) levels. The association between Aβ 40 and cognitive decline did not depend on sex, education level, or APOE ε4 status. There was an interaction found between age (≤ 65 and > 65 years) and Aβ 40 (p for interaction = 0.021). In individuals older than 65 years, there was a positive linear relationship between plasma Aβ 40 and cognitive decline (OR: 1.02, 95% CI: 1.00-1.04, p = 0.027). For participants ≤ 65 years old, the lower Aβ 40 and higher Aβ 40 groups had a lower risk of cognitive decline than the medium Aβ 40 group (OR: 0.69, 95% CI: 0.50-0.94, p = 0.02; OR: 0.63, 95% CI: 0.45-0.86, p = 0.004). None of relationship between plasma Aβ 42 , Aβ 42/40 and cognitive decline was found during a 2-year follow-up. Conclusion: The relationship between plasma Aβ 40 and cognitive decline was not linear, but an inverted-U shape in a cognitively normal population. The underlying mechanism requires further investigation.

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Section: Discussionsupporting

confidence: 41%

Non-linear Relationship Between Plasma Amyloid-β 40 Level and Cognitive Decline in a Cognitively Normal Population

Gao

Shang

Chen

et al. 2020

Front. Aging Neurosci.

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“…Whereas there is good agreement that NfL is elevated in both AD and other neurodegenerative diseases, 43,49 measurement of tau in plasma has yielded conflicting results. 18,24,50 This is probably due to the molecular complexity of extracellular tau 12,13,[30][31][32] and use of assays that measure different populations of tau. 11,31 We recently developed an ultra-sensitive immunoassay, which detects forms of tau captured by the mid-region antibody BT2 (amino acids 194-198) and detected with the N-terminal antibody Tau12 (amino acids 6-13).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent longitudinal population-based study found no association between Quanterix assay measured plasma tau and AD dementia risk. 24 Differences between results obtained with distinct assays highlight the importance of the diversity of molecular forms of tau detected when different mAbs are used. The Quanterix assay uses a combination of an N-terminal mAb (residues 16-24) and a mid-region mAb (residues 218-222), 18 and thus requires a minimal tau sequence spanning residues 16 to 222.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17][18][19][20][21] Some studies found that tau in plasma was increased in AD, 16,19,22,23 whereas others found no significant change. 19,24 The Quanterix Human Tau kit (erroneously referred to as "total tau") has been the most widely applied assay used to measure tau in plasma. 18,19,23,25,26 Results suggest that the Quanterix assay measures forms of tau in plasma that tend to be increased in AD, but that differences between AD and controls is of limited diagnostic value.…”

mentioning

confidence: 99%

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Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

Mengel

Bateman

Glynn

et al. 2020

Annals of Neurology

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Objective There is an urgent need for sensitive, widely available, blood‐based screening tests to identify presymptomatic individuals destined to develop Alzheimer's disease (AD). We investigated whether tau detected in plasma by our in‐house NT1 assay is specifically altered in AD, and when applied to patients with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) can serve to predict progression to AD dementia. The predictive value of NT1 versus tau measured using assays from Quanterix and Roche, and the specificity of NT1 for AD versus a nonspecific marker of neurodegeneration (neurofilament light [NfL]) were also examined. Methods NT1 tau and NfL were measured in plasma from prospectively followed patients with SCD or MCI who remained cognitively stable, converted to AD dementia, or converted to non‐AD dementias, and in cognitively unimpaired participants. Tau was measured using Quanterix and Roche assays in baseline subjects with SCD and MCI. Results Plasma NT1 tau was specifically elevated in AD, but not in non‐AD dementia compared with controls, whereas NfL was increased in both AD and non‐AD dementias. Baseline specimens from individuals who had SCD or MCI revealed that NT1 tau, but not tau measured using Quanterix or Roche assays, is elevated in subjects who progress to AD dementia. As expected, baseline plasma NfL is elevated in those who progress to AD and non‐AD dementias. Interpretation Plasma NT1 tau is a specific marker of AD, which is elevated early in disease and may prove useful as a first round screen to identify individuals at risk of developing AD. ANN NEUROL 2020;88:878–892

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“…However, no study has been performed to examine this association in an older population. Meanwhile, a recent research by de Wolf et al [8] has reported that adults with both low plasma Aβ 42 and high NfL levels demonstrated a higher risk of developing dementia or AD than those with one biomarker condition (i.e. low Aβ 42 or high NfL).…”

Section: Introductionmentioning

confidence: 99%

Plasma Aβ and neurofilament light chain are associated with cognitive and physical function decline in non-dementia older adults

He¹,

Barreto

Aggarwal

et al. 2020

Alz Res Therapy

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Background Cognition is closely associated with physical function. Although high brain amyloid-β (Aβ) deposition and neurofilament light chain (NfL) are associated with cognitive and gait speed decline, relationships of combined plasma Aβ and NfL profiles with cognitive and physical functions in older adults remain unknown. The research aim of this study was to investigate the prospective associations of combined plasma Aβ and NfL profiles with cognitive and physical functions in older adults. Methods Participants (n = 452, aged 76 ± 5 years) who had both plasma Aβ and NfL data collected from the Multidomain Alzheimer’s Preventive Trial (MAPT, May 2008 to April 2016) were included in the current study. These participants were from four MAPT groups (multidomain interventions [physical activity and nutritional counselling, and cognitive training], omega-3 supplementation, multidomain plus omega-3 supplementation and control group) and had received a 3-year intervention, followed by a 2-year observational follow-up. Cognitive function was evaluated as Mini-Mental State Examination and composite cognitive score (CCS, a mean Z-score combining four cognitive tests). Physical function was evaluated as gait speed (4-m usual-pace walk test) and chair-stand time (5-time maximal chair-stand test). Cognitive and physical function data measured at the time of and after blood Aβ and NfL tests were used for analysis. Participants with plasma Aβ42/Aβ40 ratios lower than 0.107 and NfL levels greater than 93.04 pg/ml were classified as Aβ+ and NfL+. Multivariable regressions and mixed-effects linear models were used for the analysis. Results At the cross-sectional level, no significant association was found between Aβ+NfL+ and cognitive or physical function after controlling for age, sex, body mass index, education level and MAPT group. Evaluating longitudinal changes, participants with Aβ+NfL+ had greater annual declines in the CCS (β = − 0.11, 95%CI [− 0.17, − 0.05]) and gait speed (β = − 0.03, 95%CI [− 0.05, − 0.005]). After adjusting for APOE ɛ4 genotype, Aβ+NfL+ was associated with a greater decline only in the CCS (β = − 0.09, 95%CI [− 0.15, − 0.02]). Conclusions Combined low plasma Aβ42/Aβ40 ratio and high plasma NfL level was associated with greater declines in cognition and gait speed over time, providing further evidence of the links between cognitive and physical function. Trial registration www.clinicaltrials.gov [NCT00672685].

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Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study

Cited by 222 publications

References 45 publications

Non-linear Relationship Between Plasma Amyloid-β 40 Level and Cognitive Decline in a Cognitively Normal Population

Non-linear Relationship Between Plasma Amyloid-β 40 Level and Cognitive Decline in a Cognitively Normal Population

Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

Plasma Aβ and neurofilament light chain are associated with cognitive and physical function decline in non-dementia older adults

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