These findings highlight the complementary roles of CSF and plasma tau biomarkers in tracking disease progression: CSF biomarkers capture early pathological changes, whereas plasma biomarkers more effectively reflect disease progression within symptomatic stages.
Abstract
Summary Background Nearly all individuals with Down syndrome (DS) develop Alzheimer’s disease (AD) dementia, primarily due to overexpression of the APP gene. Although specific cerebrospinal fluid (CSF) and plasma tau biomarkers have been investigated in DS-AD, how different tau species change in the DS-AD continuum in comparison to sporadic AD remains uncertain. Methods In this cross-sectional study, we analysed CSF and plasma tau biomarkers in 461 samples from the DABNI and SPIN cohorts, including individuals with DS, cognitively normal euploid participants, and patients with sporadic AD. Biomarker differences were assessed using linear regression with Tukey post hoc comparisons. LOESS modelling was applied to estimate the age at which tau biomarkers became abnormal. Findings We analysed 461 participants from the DABNI and SPIN cohorts. Both CSF and plasma tau biomarkers increased during the asymptomatic stages of DS and in euploid controls, coinciding with Aβ positivity; across the DS clinical spectrum the largest increases were observed for CSF NTA-tau (fold-change [fc] = 6.46–6.94), CSF p-tau217 (fc = 6.43–6.74) and plasma p-tau217 (fc = 4.63–6.54) (linear regression adjusted for age, sex and APOE-ε4 with Tukey post-hoc tests; all p < 0.001). During the dementia stages, CSF tau biomarkers showed only modest further increases (no CSF biomarker differed between pDS and dDS; all p ≥ 0.268), whereas plasma tau biomarkers retained a broader dynamic range across symptomatic phases (pDS vs dDS: plasma p-tau217 p = 0.001, p-tau181 p = 0.002, p-tau231 p = 0.004). Plasma p-tau217 showed the highest diagnostic accuracy, with areas under the curve (AUC) of 0.91–0.97 for biological categorisations and numerically higher values than CSF in symptomatic stages (pDS vs dDS: plasma p-tau217 AUC = 0.69 [95% CI 0.58–0.80] vs CSF p-tau217 AUC = 0.53 [95% CI 0.41–0.65]; DeLong test p = 0.019). In LOESS analyses, tau biomarkers diverged from age-matched controls in the late 30s to early 40s (e.g., plasma p-tau217 ≈ 37.3 years, CSF p-tau181 ≈ 38.1 years) and reached abnormality (+2 SD) over an approximately 20-year span between the fourth and sixth decades, outlining differential but temporally compressed increases. Finally, during symptomatic stages, tau biomarker levels remained stable in DS-AD, in contrast to sporadic AD, where levels declined with advancing age. Interpretation These findings highlight the complementary roles of CSF and plasma tau biomarkers in tracking disease progression: CSF biomarkers capture early pathological changes, whereas plasma biomarkers more effectively reflect disease progression within symptomatic stages. Furthermore, tau biomarkers might support disease staging and monitor clinical progression in DS-AD, but with the need to adapt biomarker frameworks to this specific population. Funding La Caixa Foundation, Instituto de Salud Carlos III, Generalitat de Catalunya, National Institute on Ageing, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer’s Association, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer’s Society.
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Keun You Kim, Hyunsun Ham, E. Yoon et al.· The journal of prevention of...· 0 citations
Among soluble tau biomarkers, tau phosphorylation at position T205 (p-tau205) has been suggested to distinctly emergence across Alzheimer's disease (AD) continuum compared to other p-tau and non-phosphorylated tau forms, and a moderate relationship with both amyloid-β and tau aggregated pathologies. To evaluate this and further expand the characterization of this biomarker, we measured cerebrospinal fluid (CSF) p-tau205 using an in-house developed immunoassay in a total of 2069 samples from the BioFINDER-2 (n = 1364) and BioFINDER-1 (n = 705) cohorts. These two cohorts spanned the full AD continuum and were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, baseline p-tau205 levels correlated with Aβ-PET (R² = 0.28), tau-PET (medial temporal: R2 = 0.35, neocortical: R² = 0.29), cortical atrophy (R² = 0.15) and cognition (MMSE, R² = 0.15). Baseline p-tau205 predicted subsequent Aβ accumulation (R² = 0.44) and tau-accumulation measured by PET (R² = 0.33). Longitudinal p-tau205 levels increased more steeply longitudinally in Aβ-positive than Aβ-negative participants (β[95%CI] = 0.16[0.12-0.21], p < 0.001). Longitudinal p-tau205 changes were associated with cortical thinning (R² = 0.32) and cognitive decline (R² ≥ 0.41). When incorporating Aβ42/40, p-tau217 and p-tau205 into a conceptual CSF-based staging model, the final p-tau205-positive stage showed the strongest association with cortical atrophy, cognitive impairment, and risk of progression to dementia (HR = 6.40[4.28-9.59]). These findings support CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging.
J. Lantero‐Rodriguez, S. Janelidze, S. Palmqvist et al.· Molecular Psychiatry· 0 citations
Increased serum p-tau217 and decreased ApoE levels were significantly associated with greater AD severity, suggesting that both biomarkers may serve as complementary noninvasive indicators of disease severity in Alzheimer’s disease.
Ahmed Kadom Kalaf, Khawla A. Shemran, Waleed Azeez AlAmeedy· International Journal of Nut...· 0 citations
The introduction of blood-based biomarkers (BBMs) for Alzheimer’s disease (AD) represents one of the most transformative advances in neurodegenerative disease research over the past decade. 1,2 For the first time, biological evidence of AD pathology can be obtained through a minimally invasive, scalable blood test, opening new opportunities for early diagnosis, patient triage, and implementation of disease-modifying therapies. 3 Among the available biomarkers, phosphorylated tau (p-tau) species, particularly plasma p-tau217, have consistently shown excellent diagnostic performance across the AD continuum, recently culminating in regulatory approval of plasma p-tau217-based assays in both the USA and Europe. 4–6 Despite this remarkable clinical success, a fundamental paradox remains. Plasma tau biomarkers work
Lucilla Parnetti, L. Gaetani· EBioMedicine· 0 citations
Complement-mediated neuroinflammation has been implicated in Alzheimer’s disease (AD), but its role during the pre-symptomatic phase of the disease remains unclear. In the PREVENT-AD cohort of cognitively unimpaired individuals at increased familial risk of AD, we investigated whether CSF complement proteins relate to early AD pathology and synaptic dysfunction, then assessed our results’ reproducibility across the clinical AD spectrum. Baseline CSF C1q, C3, C3b, and Factor H were measured in relation to CSF AD biomarkers, synaptic proteins, cognition, MRI volumetry, and amyloid and tau PET. Key findings were then examined in 708 participants from ADNI spanning cognitively normal, mild cognitive impairment (MCI), and dementia stages of AD. In PREVENT-AD, C1q was positively associated with CSF P-tau181, T-tau, and multiple synaptic markers including ADAM23, GAP43, SNAP25, and SYT1. Factor H showed similarly strong positive associations with P-tau181, T-tau, ADAM22, ADAM23, GAP43, and SYT1. By contrast, C3 showed minimal associations, while C3b displayed weaker positive relationships with P-tau181, T-tau, ADAM22, and ADAM23. Complement proteins were not robustly associated with amyloid or tau PET, and only C1q related to lower global cognitive performance. In ADNI, C1q emerged as the most consistent analyte, showing positive associations with tau, neurofilament light, and synaptic markers across all diagnostic groups. C3 exhibited predominantly negative associations, whereas C3b and Factor H showed stage-dependent relationships, particularly with evident neurodegeneration and synaptic injury in symptomatic individuals. These findings identify complement dysregulation, especially involving C1q, as an early correlate of tau-linked synaptic pathology, and support a role for complement activation in the AD molecular cascade.
J. Loncke, M. Savard, C. Picard et al.· bioRxiv· 0 citations
Structural brain changes during the earliest asymptomatic stages of Alzheimer’s disease (AD) remain poorly understood. Previous research in preclinical AD shows heterogeneous findings, reporting both subtle neuronal loss and paradoxical increases in grey matter (GM) volume. This study applies an extensive cerebrospinal fluid (CSF) biomarker panel to better understand the biological processes underlying longitudinal GM changes in cognitively unimpaired (CU) adults, spanning the amyloid/tau (AT) continuum.
We analysed data from 627 CU individuals from three longitudinal cohorts (ALFA+, Wisconsin ADRC, WRAP), with repeated MRI (3.5 ± 0.9 years) and baseline CSF biomarkers from the NeuroToolKit panel (Roche Diagnostics). Using non-negative matrix factorization, we decomposed the CSF biomarker levels into six latent components, reflecting amyloid-β (Aβ) pathology, tau-related pathophysiology with synaptic injury, neuroaxonal injury, microglial reactivity, astrocytic reactivity, and cytokine signalling. We tested associations between component weights and voxel-wise longitudinal GM volume changes using single-component and a joint-all components model. Analyses were performed across the full sample and stratified by AT status. Associations with longitudinal cognitive performance (PACC) were assessed using linear mixed-effects models.
The Aβ pathology component was the strongest and most widespread predictor of longitudinal GM atrophy, predominantly in temporal and frontal regions, also when controlling for tau pathophysiology, neuroaxonal injury, or neuroinflammatory components. Higher Aβ pathology scores were also associated with cognitive decline. The component capturing tau-related pathophysiology and synaptic injury initially associated with GM loss but lost significance after accounting for other biomarker components. In contrast, components reflecting microglial reactivity, astrocytic reactivity, and cytokine signalling were associated with longitudinal GM volume increases, with effects varying by AT stage.
In this large longitudinal sample of asymptomatic individuals, the Aβ-dominant biomarker component showed the strongest association with longitudinal GM atrophy and cognitive decline, beyond the effects of tau pathophysiology and neuroaxonal injury. While glial and inflammatory processes may contribute to transient GM increases in preclinical AD. A better understanding of these dynamic relationships between structural brain changes and various biological pathways at the earliest stages of AD is crucial to inform the development of interventions before irreversible neurodegeneration occurs.
W. Pelkmans, R. Cacciaglia, Michalis Kassinopoulos et al.· Molecular Neurodegeneration· 0 citations
