Cerebrospinal fluid biomarkers for Alzheimer's disease

Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease diagnosis, with p-tau217 considered to have the most utility. However, the availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests.

Objective: To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts.

Design, setting, and participants: This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023.

Exposures: Magnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay).

Main outcomes and measures: Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status.

Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signals. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity.

Conclusions and Relevance: This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage ¹⁾

Platelets may serve as a perfect peripheral source for exploring diagnostic biomarkers for Alzheimer's disease (AD); however, the molecular linkage between platelet and the brain is missing. To find the common altered and driving molecules in both brain and the platelet, Yu et al. performed an integrated analysis of our platelet omics and brain omics reported in the literature and analyzed their correlations with AD-specific pathology and cognitive impairment. By integrating the gene and protein expression profiles from 269 AD patients, they deduced that 239 differentially expressed proteins (DEPs) appeared in both the brain and the platelet, and 70.3% of them had consistent changes. Further analysis demonstrated that the altered brain and peripheral regulations were pinpointed into 10 imbalanced pathways. They also found that 117 DEPs, including ADAM10, were closely associated with the AD-specific β-amyloid and tau pathologies; and the changes of IDH3B and RTN1 had a potential diagnostic value for cognitive impairment analyzed by machine learning. Finally, we identified that HMOX2 and SERPINA3 could serve as driving molecules in neurodegeneration, and they were increased and decreased in AD patients, respectively. Together, this integrated brain and platelet omics provide a valuable resource for establishing efficient peripheral diagnostic biomarkers and potential therapeutic targets for AD. ²⁾.

Astrocytic contributions to Alzheimer's disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early feature of Alzheimer's disease, potentially providing a promising target for preclinical Alzheimer's Disease diagnosis and Alzheimer's Disease treatment. Several in vivo Alzheimer's Disease biomarkers already exist, but presently there is a paucity of specific and sensitive in vivo astrocyte biomarkers that can accurately measure preclinical AD. Measuring monoamine oxidase-B with neuroimaging and glial fibrillary acidic protein from bodily fluids are biomarkers that are currently available. Developing novel, more specific, and sensitive astrocyte biomarkers will make it possible to pharmaceutically target chemical pathways that preserve beneficial astrocytic functions in response to AD pathology ³⁾

CSF Aβ40, Aβ42, total tau, and phosphorylated tau are the most sensitive biomarkers for Alzheimer's disease diagnosis and prediction of onset of AD from mild cognitive impairment (MCI).

Patients at memory clinics of Japan were classified into three categories, consisting of AD (n = 61), mild cognitive impairment (MCI) (n = 42), and cognitively normal (CN) (n = 23), with MMSE scores of 20.4 ± 4.2, 26.9 ± 1.7, and 29.0 ± 1.6, respectively. In each category, CSF protein levels were highly correlated with each other. In cognitively normal (CN) subjects, increased CSF protein levels correlated well with those of AD markers, including amyloid beta and tau protein, whereas in MCI and AD subjects, correlations declined with AD markers except p-tau. Future follow-up on each clinical subject may provide a clue that the CSF proteins would be AD-related biomarkers ⁴⁾.

Benedet et al. suggest that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD ⁵⁾.

Current diagnosis of Alzheimer's disease relies largely on documenting mild cognitive impairment, at which point, Alzheimer's has already caused severe brain damage.

Several potential biomarkers are being studied for their ability to indicate early stages of Alzheimer's disease. Examples being studied include beta-amyloid and tau protein levels in cerebrospinal fluid (CSF) and brain changes detectable by imaging. Recent research suggests that these indicators may change at different stages of the disease process.

There are currently no validated biomarkers for Alzheimer's disease, but researchers are investigating several promising candidates, including brain imaging, proteins in CSF, blood and urine tests, and genetic risk profiling.

Research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status.

In the last 20 years, research focused on developing retinal imaging as a source of potential Alzheimer's disease biomarkers and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study ⁶⁾.

Amyloid beta in Alzheimer's disease.

Astrocyte Biomarkers in Alzheimer's Disease.

Plasma p-tau181

Serum total and free T3 and CSF total T3 levels are significantly lower in AD patients compared to controls. The temporality of changes in thyroid hormone levels and AD development should be illustrated by further longitudinal studies ⁷⁾

¹⁾

Ashton NJ, Brum WS, Di Molfetta G, Benedet AL, Arslan B, Jonaitis E, Langhough RE, Cody K, Wilson R, Carlsson CM, Vanmechelen E, Montoliu-Gaya L, Lantero-Rodriguez J, Rahmouni N, Tissot C, Stevenson J, Servaes S, Therriault J, Pascoal T, Lleó A, Alcolea D, Fortea J, Rosa-Neto P, Johnson S, Jeromin A, Blennow K, Zetterberg H. Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology. JAMA Neurol. 2024 Jan 22. doi: 10.1001/jamaneurol.2023.5319. Epub ahead of print. PMID: 38252443.

²⁾

Yu H, Li M, Pan Q, Liu Y, Zhang Y, He T, Yang H, Xiao Y, Weng Y, Gao Y, Ke D, Chai G, Wang JZ. Integrated analyses of brain and platelet omics reveal their common altered and driven molecules in Alzheimer's disease. MedComm (2020). 2022 Oct 13;3(4):e180. doi: 10.1002/mco2.180. PMID: 36254251; PMCID: PMC9560744.

³⁾

Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER. Astrocyte Biomarkers in Alzheimer's Disease. Trends Mol Med. 2019 Feb;25(2):77-95. doi: 10.1016/j.molmed.2018.11.006. Epub 2019 Jan 2. PMID: 30611668.

⁴⁾

Hoshi K, Kanno M, Abe M, Murakami T, Ugawa Y, Goto A, Honda T, Saito T, Saido TC, Yamaguchi Y, Miyajima M, Furukawa K, Arai H, Hashimoto Y. High Correlation among Brain-Derived Major Protein Levels in Cerebrospinal Fluid: Implication for Amyloid-Beta and Tau Protein Changes in Alzheimer's Disease. Metabolites. 2022 Apr 15;12(4):355. doi: 10.3390/metabo12040355. PMID: 35448543.

⁵⁾

Benedet AL, Milà-Alomà M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, Hourregue C, Cognat E, Dumurgier J, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, Salvadó G, Shekari M, Operto G, Gispert JD, Minguillon C, Fauria K, Kollmorgen G, Suridjan I, Zimmer ER, Zetterberg H, Molinuevo JL, Paquet C, Rosa-Neto P, Blennow K, Suárez-Calvet M; Translational Biomarkers in Aging and Dementia (TRIAD) study, Alzheimer’s and Families (ALFA) study, and BioCogBank Paris Lariboisière cohort. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum. JAMA Neurol. 2021 Oct 18:e213671. doi: 10.1001/jamaneurol.2021.3671. Epub ahead of print. PMID: 34661615; PMCID: PMC8524356.

⁶⁾

Snyder PJ, Alber J, Alt C, Bain LJ, Bouma BE, Bouwman FH, DeBuc DC, Campbell MCW, Carrillo MC, Chew EY, Cordeiro MF, Dueñas MR, Fernández BM, Koronyo-Hamaoui M, La Morgia C, Carare RO, Sadda SR, van Wijngaarden P, Snyder HM. Retinal imaging in Alzheimer's and neurodegenerative diseases. Alzheimers Dement. 2020 Oct 8. doi: 10.1002/alz.12179. Epub ahead of print. PMID: 33090722.

⁷⁾

Dolatshahi M, Salehipour A, Saghazadeh A, Sanjeari Moghaddam H, Aghamollaii V, Fotouhi A, Tafakhori A. Thyroid hormone levels in Alzheimer disease: a systematic review and meta-analysis. Endocrine. 2022 Sep 27. doi: 10.1007/s12020-022-03190-w. Epub ahead of print. PMID: 36166162.