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Forest plots of beta coefficients of linear regression models for the main variables predicting plasma biomarker concentrations. Forest plot shows each regressors’ standardized β linear regression coefficient, with 95% confidence interval, predicting plasma biomarker concentrations. All variables were z-scored to enable them to be compared. All models were age- and sex-adjusted. Since the strongest predictor for plasma biomarkers was Aβ status, when the independent variable of interest was significant in age- and sex-adjusted models, a new model was calculated, further adjusting for Aβ status to see if the regressor remained significant. *Linear regression β coefficient remained significant after Aβ status adjustment. p-tau181, tau phosphorylated at threonine 181; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; Aβ status, CSF or amyloid-PET defined amyloid status; eGFR, estimated glomerular filtration rate; CCI, Charlson Comorbidity Index
Source publication
Plasma biomarkers have emerged as promising tools for identifying amyloid beta (Aβ) pathology. Before implementation in routine clinical practice, confounding factors modifying their concentration beyond neurodegenerative diseases should be identified. We studied the association of a comprehensive list of demographics, comorbidities, medication and...
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Citations
... Medical conditions such as reduced kidney function, diabetes, high blood pressure, and body mass may to some extent affect the BBMs, since these biomarkers are not limited to the central nervous system as in the case of the CSF. [27][28][29][30][31][32][33][34][35][36] This opens up a variety of potential effects on the BBMs that need to be explained and understood before clinical implementation. One potential confounder that needs to be understood is the effect of ethnicity and race. ...
INTRODUCTION
Blood‐based biomarkers have demonstrated high accuracy for identifying Alzheimer's disease (AD) pathology. However, the lack of representative cohorts creates a knowledge gap regarding their real‐world applicability. We examined the influence of ethnicity on the diagnostic accuracy of plasma tau phosphorylated at threonine 217 (p‐tau217) in identifying AD.
METHODS
A total of 1170 mixed memory clinic patients originating from 91 different countries were included. Cerebrospinal fluid or amyloid positron emission tomography supplemented the diagnostic evaluation for 539 patients. Plasma was analyzed for p‐tau217.
RESULTS
Plasma p‐tau217 concentrations did not differ between ethnic groups, and there was no influence of ethnicity on the diagnostic accuracy of plasma p‐tau217. Plasma p‐tau217 demonstrated strong discriminative ability for AD and AD‐pathology in our ethnically diverse cohort.
DISCUSSION
Our study suggests that ethnicity does not influence the diagnostic accuracy of plasma p‐tau217. Nonetheless, medical conditions influencing plasma biomarkers may disproportionally affect minoritized groups because of social determinants of health.
Highlights
Plasma tau phosphorylated at threonine 217 (p‐tau217) was highly accurate in the identification of Alzheimer's disease.
Geographic origin did not influence the precision of plasma p‐tau217.
Kidney function may influence p‐tau217 concentrations.
Representative inclusion in studies and trials should be a priority.
... Plasma NfL has also been associated with systemic factors such as body mass index (BMI) and cardiovascular disease 44 . Moreover, as suggested in previous studies, our ndings supports the association between NfL levels and systemic health markers including eGFR, albumin, and hemoglobin, all of which are known to in uence longevity 45 . This reinforces the idea that NfL serves as a broad indicator of overall health in the aging organism. ...
Blood-based neural biomarkers linked to systemic aging may provide insights into the biological endpoint of human lifespan. However, the key biomarker for predicting cognitive function and survival at extreme ages remains unclear. In this study, the relationship between neural biomarkers amyloid-β42/amyloid-β40 ratio (Aβ42/40), phosphorylated Tau181 (pTau181), and Neurofilament Light Chain (NfL), and cognitive function was examined in 495 centenarians. Longitudinal analysis was also performed on the same cohort. The results showed that NfL, a marker of non-specific axonal injury, was the strongest predictor of Mini-Mental State Examination (MMSE) scores (B [95% CI] = −2.28 [−3.72 – −0.85]) after adjusting for confounders. Higher NfL levels were also associated with increased mortality (HR [95% CI] = 2.82 [1.71 − 4.65]). These findings suggest NfL reflects neurodegeneration linked to late-life biological aging.
... After duplicate removal, a total of 3104 articles were retrieved; 3039 articles were excluded after title and abstract screening, and 55 were excluded after full-text reading (reasons for exclusions are reported in Fig. 1). Ten articles were thus included in the final qualitative assessment [25][26][27][28][29][30][31][32][33][34]. ...
... The other six studies investigated AD blood biomarkers [29][30][31][32][33][34]. They included between 360 [32] and 2366 participants [30], with mean/median age ranging from 66.5 to 76.4 years and a proportion of females from 43.9% to 61.7%. ...
... The other six studies investigated AD blood biomarkers [29][30][31][32][33][34]. They included between 360 [32] and 2366 participants [30], with mean/median age ranging from 66.5 to 76.4 years and a proportion of females from 43.9% to 61.7%. Five studies included participants with dementia [29,[31][32][33][34]. Five out of the six studies were population-based [29-31, 33, 34]. ...
Purpose
This systematic review aimed to summarize the evidence on the association between multimorbidity and fluid biomarkers of Alzheimer’s disease (AD).
Methods
We systematically searched PubMed, Web of Science, and Embase for studies investigating the association between multimorbidity—defined as the co-occurrence of multiple chronic conditions in the same individual—and levels of cerebrospinal fluid (CSF) or blood biomarkers of AD, focusing on the most established AD biomarkers (amyloid-beta, phosphorylated-tau, total-tau, neurofilament light chain, and glial fibrillary acidic protein). Studies were selected following PRISMA guidelines.
Results
Out of 3,104 records, we identified 10 cross-sectional studies. Four studies assessed CSF biomarkers in dementia-free participants with mean age between 61.8 and 66.6 years, yielding mixed findings with no consistent association between multimorbidity and CSF biomarkers. Six studies focused on blood biomarkers in participants with mean age ranging from 66.5 to 76.4 years, five of which included individuals with dementia. Most of these studies reported an association between multimorbidity and elevated blood biomarker levels.
Conclusions
This review suggests a significant association between multimorbidity and AD blood biomarkers in older populations, while the results on CSF are mixed and inconsistent. Further research is needed, particularly longitudinal studies assessing both CSF and blood biomarkers within the same populations.
... Recently published updated AD diagnostic criteria contemplate a biomarker-based AD diagnosis using only BBM, with the caveat that only those high-performing BBM with an accuracy > 90% should be used [7]. Plasma phosphorylated tau (p-tau) species increase along the AD continuum, are found in low concentrations in other neurodegenerative (frontotemporal dementia [FTD] or dementia with Lewy bodies [LBD]) or non-neurodegenerative etiologies of cognitive impairment and have demonstrated excellent performance in identifying patients with an underlying AD pathophysiological process in vivo [15][16][17][18][19][20][21][22][23][24][25]. Furthermore, plasma p-tau species have shown to systematically outperform other blood biomarkers, like glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and the amyloid beta 42/40 ratio (Aβ42/40), in discriminating CSF/amyloid PET-defined amyloid beta (Aβ) status both in cognitively unimpaired and impaired individuals [15,17,[19][20][21][22][23][24][26][27][28][29][30]. ...
... Plasma phosphorylated tau (p-tau) species increase along the AD continuum, are found in low concentrations in other neurodegenerative (frontotemporal dementia [FTD] or dementia with Lewy bodies [LBD]) or non-neurodegenerative etiologies of cognitive impairment and have demonstrated excellent performance in identifying patients with an underlying AD pathophysiological process in vivo [15][16][17][18][19][20][21][22][23][24][25]. Furthermore, plasma p-tau species have shown to systematically outperform other blood biomarkers, like glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and the amyloid beta 42/40 ratio (Aβ42/40), in discriminating CSF/amyloid PET-defined amyloid beta (Aβ) status both in cognitively unimpaired and impaired individuals [15,17,[19][20][21][22][23][24][26][27][28][29][30]. The p-tau181 epitope has been the most studied, owing to being commercially available for longer. ...
... Recent studies with in-house and commercial p-tau217 assays have demonstrated excellent performance in discriminating both Aβ and T status, even exceeding the former in direct comparisons [23,24,[31][32][33][34][35][36]. There is evidence that demographic and analytical factors [e.g., age, body mass index (BMI) or kidney function] may modify p-tau181 and p-tau217 levels, but the real impact of these factors on the diagnostic performance of these plasma biomarkers has been conflicting between studies [18,22,25,27,29,[36][37][38][39]. ...
Plasma tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217) have demonstrated high accuracy for Alzheimer’s disease (AD) diagnosis, defined by CSF/PET amyloid beta (Aβ) positivity, but most studies have been performed in research cohorts, limiting their generalizability. We studied plasma p-tau217 and p-tau181 for CSF Aβ status discrimination in a cohort of consecutive patients attending an academic memory clinic in Spain (July 2019–June 2024). All patients had CSF AD biomarkers performed as part of their routine clinical assessment. Aβ positivity was defined with a local cut-off of CSF Aβ1–42 < 600 pg/mL; in patients with borderline Aβ1–42 values or when there was a mismatch between the Aβ and the T status (T + if CSF p-tau181 ≥ 65 pg/mL), a ratio Aβ1–42/Aβ1–40 < 0.07 was used. Plasma p-tau217 and p-tau181 were measured retrospectively, from blood samples collected at first visit, with Fujirebio Lumipulse and Quanterix Simoa assays, respectively. We included 468 patients (mean age 67 years, 50% female, 61% Aβ positive). Plasma p-tau217 outperformed plasma p-tau181 in discriminating CSF Aβ status (AUC 0.95 vs 0.90, p = 0.005). A 97.5% sensitivity and specificity plasma p-tau217 algorithm, classifying patients into three groups of Aβ probability (Low, Intermediate and High), resulted in 67% of patients in the Low and High groups, having their Aβ status predicted (as negative and positive, respectively) with 96% accuracy. The remaining 33% in the Intermediate group were candidates to undergo CSF/PET testing. A model with a 10% variation in p-tau217 levels yielded small changes in accuracy (95%). In conclusion, plasma p-tau217 could have discriminated CSF Aβ status in two-thirds of patients with very high accuracy in a memory clinic cohort. These results support the implementation of plasma p-tau217 as an initial diagnostic tool in memory clinics for AD diagnosis, reducing the need for more invasive/expensive testing.
... Regarding other biomarkers, such as glial fibrillary acidic protein (GFAP), a marker of astroglial damage or activation [16], ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a marker for neuroaxonal integrity [17], and total TAU (tTAU), a marker for neurodegeneration [18], there have been only a few studies analyzing the impact of renal function on serum concentrations of these biomarkers. Various studies have shown, in line with the findings on NfL, an inverse correlation between eGFR and GFAP, suggesting that serum concentrations increase with impaired renal function [5,19]. In a different study, a moderate correlation between creatinine and tTAU was demonstrated, whereas this did not apply to GFAP or UCH-L1 [20]. ...
... However, after adjusting for age and BMI, the correlations were no longer significant, which aligns with the well-established understanding that age is the main factor influencing NfL concentrations [6,13] and supports the recommended use of z-scores for interpretation [25]. In contrast, our results are not consistent with previous studies that have reported correlations between eGFR and serum GFAP [5,19] or CSF NfL [7]. A potential explanation for this discrepancy could be the limited number of patients with pathological renal function in our cohort compared to other studies. ...
Impaired renal function can influence biomarker levels through mechanisms involving blood–brain barrier integrity and clearance pathways; however, the impact of variations within normal renal function remains unclear. The main aim of this study was to determine whether adjustment for the specific level of renal function is necessary when renal function remains within physiological levels. We studied n = 183 patients (NID n = 122; other neurological diseases n = 39; somatoform controls n = 22) who underwent lumbar puncture at University Hospital Frankfurt. Serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau protein (tTAU), and ubiquitin C-terminal hydrolase-L1 (UCHL1) were measured using the single molecule array (SIMOA) technique. Estimated glomerular filtration rate (eGFR) correlated negatively with CSF GFAP (r = −0.217, p = 0.004) and serum NfL (r = −0.164, p = 0.032). Patients with impaired renal function exhibited higher CSF NfL (p = 0.036) and CSF GFAP (p = 0.026) levels. However, these findings did not remain significant after adjusting for BMI and age. Importantly, in patients with normal renal function, no significant correlations with eGFR and biomarker levels were observed after adjustment. Our findings indicate that serum and CSF concentrations of NfL, GFAP, tTAU, and UCHL1 are not significantly affected by fluctuations in physiological kidney function but emphasize the importance of considering comorbidities in impaired renal function when interpreting biomarker levels.
... Positron Emission Tomography (PET) Imaging: PET imaging of amyloid and tau protein depositions offers detailed insights into the extent of neurodegenerative pathology. PET biomarkers, such as those assessing amyloid plaques and tau neurofibrillary tangles, complement plasma biomarkers by providing spatial and quantitative data on neurodegenerative changes, aiding in the prediction of cognitive trajectories in antipsychotic users (Sarto et al. 2024;Zeng et al. 2024). ...
... Elevated plasma NfL levels correlate with faster rates of memory decline, particularly in individuals on long-term antipsychotic treatment (Behzad et al. 2023). This marker is sensitive to both Alzheimer's and other neurodegenerative processes (Kivisäkk et al. 2023;Sarto et al. 2024). ...
... Studies recommend using multimodal approaches, integrating plasma Aβ42/40, p-tau, NfL, and GFAP levels with neuroimaging data (hippocampal volume and PET scans). This integrative strategy is particularly effective in clinical settings for monitoring antipsychotic users at risk of accelerated cognitive decline (Kivisäkk et al. 2023;Mendes et al. 2024;Sarto et al. 2024). ...
Psychotropic drugs are vital in psychiatry, aiding in the management of mental health disorders. Their use requires an understanding of their pharmacological properties, therapeutic applications, and potential side effects. Ongoing research aims to improve their efficacy and safety. Biomarkers play a crucial role in understanding and predicting memory decline in psychotropic drug users. A comprehensive understanding of biomarkers, including neuroimaging, biochemical, genetic, and cognitive assessments, is essential for developing targeted interventions and preventive strategies. In this narrative review, we performed a comprehensive search on PubMed and Google using review-specific terms. Clinicians should use a multifaceted approach, including neurotransmitter analysis, neurotrophic factors, miRNA profiling, and cognitive tasks for early intervention and personalized treatment. Anxiolytics' mechanisms involve various neurotransmitter systems and emerging targets. Research on biomarkers for memory decline in anxiolytic users can lead to early detection and intervention, enhancing clinical practices and aligning with precision medicine. Mood stabilizer users can benefit from early detection of memory decline through RNA, neurophysiological, and inflammatory biomarkers, promoting timely interventions. Performance-enhancing drugs may boost athletic performance in the short term, but their long-term health risks and ethical issues make their use problematic. Long-term use of psychotropic performance enhancers in athletes shows changes in biomarkers of cognitive decline, necessitating ongoing monitoring and intervention strategies. Understanding these genetic influences on memory decline helps pave the way for personalized approaches to prevent or mitigate cognitive deterioration, emphasizing the importance of genetic screening and early interventions based on an individual's genetic profile. Future research should focus on refining these biomarkers and protective measures against cognitive deterioration. Overall, a comprehensive understanding of biomarkers in psychotropic drug users is essential for developing targeted interventions and preventive strategies.
... kidney function) (66) could influence sex differences in the clearance and measurement of these biomarkers. For example, one study found that males have higher levels of p-tau181 and p-tau217 (38), which contrasts with the findings of some other studies (44,46). However, this difference was attenuated after excluding individuals with chronic kidney disease (38). ...
Ultrasensitive assays have been developed which enable biomarkers of Alzheimer's disease pathology and neurodegeneration to be measured in blood. These biomarkers can aid in diagnosis, and have been used to predict risk of cognitive decline and Alzheimer's disease. The ease and cost-effectiveness of blood collections means that these biomarkers could be applied more broadly in population-based screening, however it is critical to first understand what other factors could affect blood biomarker levels. The aim of this review was to determine the extent that sociodemographic, lifestyle and health factors have been associated with blood biomarkers of Alzheimer's disease and neuropathology. Of the 32 studies included in this review, all but one measured biomarker levels in plasma, and age and sex were the most commonly investigated factors. The most consistent significant findings were a positive association between age and neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), and females had higher GFAP than men. Apolipoprotein ε4 allele carriers had lower Aβ42 and Aβ42/40 ratio. Body mass index was negatively associated with GFAP and NfL, and chronic kidney disease with higher levels of all biomarkers. Too few studies have investigated other chronic health conditions and this requires further investigation. Given the potential for plasma biomarkers to enhance Alzheimer's disease diagnosis in primary care, it is important to understand how to interpret the biomarkers in light of factors that physiologically impact blood biomarker levels. This information will be critical for the establishment of reference ranges and thus the correct interpretation of these biomarkers in clinical screening.
... As we showed that NfL peaked after four weeks, the sampling time could have affected the prognostic value of NfL. Both sNfL and CSF NfL depend on age, but only sNfL on BMI [11,37,38]. When estimating the sNfL Z-scores, we adjusted for age, but because we did not have data on BMI, we could not control for this confounding factor. ...
Background
Elevated neurofilament light chain (NfL) levels are associated with worse prognosis in Guillain–Barré syndrome (GBS). Our objectives were to determine the utility of serum NfL (sNfL), cerebrospinal fluid (CSF)/serum NfL ratio and NfL index as prognostic and diagnostic biomarkers for GBS.
Methods
We measured NfL in serum and/or CSF obtained from 96 GBS patients between 1989 and 2014 in western Sweden. The sNfL Z-scores, NfL ratios and NfL indices were calculated. Outcome was determined with the GBS disability scale (GBSDS) at 3 and 12 months. NfL parameters in GBS were compared with healthy controls (HC), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).
Results
The sNfL Z-score was higher for GBSDS > 2 at 3 months (median [IQR], 3.5 ng/L [3.2–4.0], vs 2.6 [1.7–3.4], p = 0.008) and at 12 months (3.6 ng/L [3.5–3.8] vs 2.6 [1.8–3.5], p = 0.049). NfL ratio and index were not associated with outcome. The area under the curve (AUC) for sNfL Z-score was 0.76 (95% CI 0.58–0.93, p < 0.0001) for GBSDS > 2 at 3 months. NfL ratio and index were lower in GBS than HC, MS, and ALS. The AUC for the NfL ratio was 0.66 (95% CI 0.55–0.78, p = 0.0018) and for the NfL index 0.86 (95% CI 0.78–0.93, p < 0.0001).
Discussion
Our results confirm sNfL as prognostic biomarker for GBS and the precision was improved using the age-adjusted sNfL Z score. NfL index and Qalb are potential diagnostic biomarkers for GBS.
Ageing populations worldwide face increasing challenges of multimorbidity (that is, the co-occurrence of two or more chronic conditions). The combination of chronic kidney disease (CKD) and dementia occurs more frequently than it would by simple coincidence, owing to several underlying biological and clinical mechanisms. Population-based cohort studies are an important epidemiological tool and have contributed to improved understanding of these mechanisms. These mechanisms include uniquely shared haemodynamic features of vasculature, overlapping risk factor profiles, and direct neurotoxic effects of accumulating waste products due to poor kidney function. The effect of these pathways is suggested to differ across gender, relevant demographic subgroups, and populations from low- to middle-income countries. Yet, given their study design, population-based cohort studies also inherently face several methodological challenges. These challenges pertain to the use of biomarkers that do not always fully capture the structure and function of the kidney or the brain; bidirectionality across the pathways under study; and practical issues of proper causal inference in light of incomplete distinction between confounders, mediators and effect modifiers. This Review describes our current understanding of the link between CKD and dementia, with a focus on knowledge synthesized from population-based cohort studies. Methodological challenges and possible solutions will be described and directions for future research areas will be outlined.
Importance
Physical activity (PA) is a nonpharmacological intervention for dementia prevention. The association between PA and Alzheimer disease (AD) plasma biomarkers remains underexplored.
Objective
To investigate the associations among PA; plasma biomarkers, including β-amyloid 42/40 (Aβ42/40), phosphorylated-tau217 (ptau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL); and cognition.
Design, Setting, and Participants
This cross-sectional study included participants with and without cognitive impairment recruited from multiple memory clinics in South Korea between May 2019 and May 2022. Data were analyzed from June to December 2024.
Exposures
PA was assessed as metabolic equivalent task minutes per week using the International Physical Activity Questionnaire and categorized into quartiles from the lowest (Q1) to the highest (Q4).
Main Outcomes and Measures
Plasma Aβ42/40, ptau217, GFAP, and NfL were measured. Cognition was assessed using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB).
Results
Among 1144 participants (mean [SD] age 70.9 [8.7] years; 744 [65.0%] female), the highest PA quartile showed significantly lower ptau217 (estimate [SE], −0.14 [0.06]; P = .01) and NfL (estimate [SE], −0.12 [0.05]; P = .01) compared with the lowest quartile. Higher PA quartiles were associated with higher MMSE scores (estimate [SE]: Q2, 0.93 [0.31]; P = .003; Q3, 0.82 [0.32]; P = .009; Q4, 0.94 [0.32]; P = .004) and lower CDR-SB scores (estimate [SE]: Q2, –0.33 [0.16]; P = .04; Q3, –0.37 [0.16]; P = .02; Q4, –0.55 [0.16]; P = .001) after adjusting for age, sex, education years, and β-amyloid uptake. In subgroup analyses according to age and cognitive status, the associations of PA and plasma biomarkers with cognition were more pronounced in the older (age ≥65 years) and cognitively impaired groups compared with the younger and cognitively unimpaired groups.
Conclusions and Relevance
These findings suggest that PA may help delay cognitive decline by modulating neurodegeneration and AD-specific tau pathologies. However, the cross-sectional design limits causal inference, and longitudinal studies are needed to confirm and clarify these associations.
