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. 2025 Jul 1;8(7):e2519919.
doi: 10.1001/jamanetworkopen.2025.19919.

Cerebrospinal Fluid Amyloid and Tau Biomarker Changes Across the Alzheimer Disease Clinical Spectrum

Diederick M de Leeuw  1   2 , Calvin Trieu  1   2   3 , Ellen M Vromen  1   2 , Elena R Blujdea  3 , Inge M W Verberk  3 , Flora H Duits  1   2 , Charlotte E Teunissen  3 , Yolande A L Pijnenburg  1   2 , Wiesje M van der Flier  1   2 , Argonde C van Harten  1   2 , Pieter Jelle Visser  1   2   4   5 , Betty M Tijms  1   2
Affiliations

Cerebrospinal Fluid Amyloid and Tau Biomarker Changes Across the Alzheimer Disease Clinical Spectrum

Diederick M de Leeuw et al. JAMA Netw Open. .

Abstract

Importance: The trajectories of core Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers and the concurrent cognitive changes across the clinical spectrum remain unclear yet are important for clinical trial design.

Objective: To map longitudinal CSF amyloid, tau, and cognitive trajectories along the clinical spectrum of AD and amyloid-negative controls.

Design, setting, and participants: This longitudinal cohort study included participants with a minimum of 2 CSF samples from Alzheimer Centrum Amsterdam cohorts across the AD clinical spectrum (ie, abnormal amyloid levels at first visit, in different clinical stages) and cognitively normal controls with initially normal CSF markers from November 2003 to July 2019. The maximum follow-up period was 19.5 years (median [IQR], 2 [0-3] years). Data were analyzed from March 2024 to May 2025.

Exposures: AD biomarkers (ß-amyloid [Aß]1-42 to Aß1-40 ratio, total tau [t-tau], and phosphorylated tau [p-tau]) detected in serially collected CSF.

Main outcomes and measures: CSF AD biomarkers were measured with Lumipulse G600II. Cognition was measured using the Mini-Mental State Examination (MMSE) and delayed memory recall component of the of the Rey Auditory Verbal Learning Test. Analysis was conducted using linear mixed models, including random intercepts and slopes, adjusting for age, education level, and sex. Each model included an interaction term of time and clinical stage to study stage-specific slopes. Biomarker conversion rates per clinical stage were studied by comparing biomarker status between visits.

Results: The sample included 197 individuals (103 male [52.3%]), including 83 controls (mean [SD] age, 63 [8] years), 31 individuals with amyloid positivity who were cognitively unimpaired (mean [SD] age, 67 [9] years), 30 individuals with amyloid-positive mild cognitive impairment (MCI; mean [SD] age, 67 [7] years), and 53 individuals with amyloid-positive dementia (mean [SD] age, 65 [8] years). Aβ1-42/1-40 ratios decreased in controls (β [SE] = -8.55 × 10-4 [1.87 × 10-4]; P < .001) and the amyloid-positive cognitively unimpaired group (β [SE] = -1.05 × 10-3 [3.14 × 10-4]; P < .001), and remained low in amyloid-positive MCI and dementia groups. There were 10 controls (12.0%) who reached abnormal amyloid over a mean (SD) of 4.8 (3.4) years. In controls, CSF t-tau (β [SE] = 8.49 [2.55] pg/mL per year; P = .002) and p-tau (β [SE] = 1.36 [0.41] pg/mL per year; P = .001) levels increased over time, and levels also increased for those in the amyloid-positive cognitively unimpaired (t-tau: β [SE] = 17.24 [4.58] pg/mL per year; P < .001; p-tau: β [SE] = 3.10 [0.72] pg/mL per year; P < .001) and amyloid-positive MCI (t-tau: β [SE] = 30.80 [5.99] pg/mL per year; P < .001; p-tau: β [SE] = 4.40 [0.93] pg/mL per year; P < .001) groups, with t-tau increasing further in the dementia group (β [SE] = 24.97 [7.80] pg/mL per year; P = .002). Longitudinal increases in p-tau and t-tau were steeper in the amyloid-positive cognitively unimpaired and MCI groups than in controls, with 10 controls (12.0%) reaching abnormal p-tau and 12 controls (14.5%) reaching abnormal t-tau levels. Delayed recall declined most in the amyloid-positive cognitively unimpaired group (β [SE] = -0.31 [0.07]; P < .001) and was associated with CSF amyloid levels (β [SE] = 102.29 [47.30]; P = .03). MMSE scores declined most in individuals with amyloid-positive MCI (β [SE] = -1.25 [0.12]; P < .001) and dementia (β [SE] = -1.89 [0.13]; P < .001).

Conclusions and relevance: In this cohort study, CSF amyloid decreased toward abnormal levels in controls, declined further in the amyloid-positive cognitively unimpaired group , and was concurrent with decline of delayed recall; CSF amyloid stabilized in those with amyloid-positive MCI and dementia, while tau markers became increased (ie, more abnormal) in the amyloid-positive cognitively unimpaired and amyloid-positive MCI groups, suggesting that increase in CSF tau requires abnormal amyloid.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Verberk reported receiving consulting fees from Neurogen Biomarking paid directly to Amsterdam University Medical Center and speaker fees from Quanterix paid directly to Amsterdam University Medical Center outside the submitted work. Dr Teunissen reported receiving grants from the European Commission, Alzheimer Association, Horizon 2020, the European Union Joint Program-Neurodegenerative Disease Research, Alzheimer Nederland, Health-Holland, Alzheimer’s Drug Discovery Foundation, ZonMW, and the Micheal J Fox Foundation; having research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N Diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, and Vivoryon; being editor in chief of Alzheimer Research and Therapy; serving on editorial boards of Molecular Neurodegeneration, Alzheimer’s & Dementia, Neurology Neuroimmunology & Neuroinflammation, Medidact, and Neurologie (Springer); serving on the Committee to Define Guidelines for Cognitive Disturbances and the Committee for Acute Neurology in the Netherlands; and having consulting or speaker contracts with Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche, and Veravas outside the submitted work. Dr van der Flier reported receiving grants from ZonMW, Nederlandse Organisatie Voor Wetenschappelijk Onderzoek (Dutch Research Council), European Union Joint Program-Neurodgenerative Disease Research, European Union Innovative Health Innitiative (IHI), Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health-Holland, Topsector Life Sciences & Health (public-private partnerships allowance [grant No. LSHM20106]; all funding paid to Amsterdam University Medical Center), Stichting Dioraphte, Gieskes-Strijbis Fund, Stichting Equilibrio, Edwin Bouw Fund, Pasman Stichting, Philips, Biogen MA Inc, Novartis Nederland, Life Molecular Imaging, Avid Technology, Roche Nederland BV, Eli-Lilly Nederland, Fujifilm, Eisai, and Combinostics; and holding the Pasman chair (all funding paid to Amsterdam University Medical Center) outside the submitted work. Dr van der Flier also reported receiving grants from A Personalized Medicine Approach for Alzheimer's Disease, which is a public-private partnership receiving funding from ZonMW (grant No. 73305095007; all funding paid to Amsterdam University Medical Center) and TAP-Dementia, which receives funding from ZonMw (grant No. 10510032120003) and cofinancing from Avid Radiopharmaceuticals, Roche, and Amprion (all funding paid to Amsterdam University Medical Center) outside the submitted work. Dr van der Flier is the recipient of awards from the IHI (PROMINENT award No. 101112145 and AD-RIDDLE award No. 101132933), awards which are supported by the IHI Joint Undertaking (IHI JU); the IHI JU receives support from the European Union Horizon Europe Research and Innovation Programme and European Coordination Committee of the Radiological, Electromedical and Healthcare IT Industry, European Federation of Pharmaceutical Industries and Associations, EuropaBio, MedTech Europe and Vaccines Europe, Davos Alzheimer’s Collaborative, Combinostics Oy, Cambridge Cognition Ltd, C2N Diagnostics LLC, and neotiv GmbH (all funding paid to Amsterdam University Medical Center). Dr van der Flier also reported being an speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council (all funding paid to Amsterdam University Medical Center); being a consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai (all funding paid to Amsterdam University Medical Center); participating in advisory boards for Biogen MA Inc, Roche, and Eli Lilly; being a member of the steering committee of phase 3 studies for NovoNordisk (all funding paid to Amsterdam University Medical Center); being a member of the steering committee of PAVE and Think Brain Health; being a member of the Scientific Leadership Group of InRAD; being the associate editor of Alzheimer, Research & Therapy in 2020 and 2021; currently being associate editor at Brain; and being a member of the supervisory board (Raad van Toezicht) for the Trimbos Instituut outside the submitted work. Dr Harten reported receiving fees from Lilly and Eisai (paid to Amsterdam University Medical Center) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trajectories in Cognition Across the Alzheimer Disease Spectrum
A, Trajectories of Mini-Mental State Examination (MMSE) scores per cognitive stage. B, Delayed recall scores per cognitive stage. The thick line represents the slope, while the shaded area reflects the 95% CI. Lines with interconnected dots represent individual trajectories. Statistically significant differences in slopes are indicated. CU indicates cognitively unimpaired; MCI, mild cognitive impairment. aP < .001. bP = .005.
Figure 2.
Figure 2.. Cerebrospinal Fluid Biomarker Trajectories Across the Cognitive Spectrum
aP = .02. bP < .001. cP = .003. dP = .04.
See this image and copyright information in PMC

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