Differences in protein expression in Alzheimer’s disease patients based on risk factors for amyloid‐related imaging abnormalities.

Background: The exact mechanism underlying amyloid‐related imaging abnormalities (ARIA) is unknown. Several factors explain ARIA risk, including the presence of microbleeds, APOE4 carriership, and very low Aβ42 levels. The cerebrospinal fluid (CSF) proteome reflects ongoing mechanisms and, thereby, provides an accessible fluid to refine risk of ARIA development.

Heritability of plasma biomarkers for Alzheimer’s Disease: A Nuclear Twin Family Design.

Background: Plasma biomarkers may be a non‐invasive and cost‐effective tool for diagnosing Alzheimer’s Disease. Promising markers include amyloid‐β‐42/40 ratio (Aβ‐42/40), glial fibrillary acidic protein (GFAP), and neurofilament‐light (NfL). Not much is known about what genetic and environmental factors influence and potentially confound these biomarker levels.

Exploring barriers and facilitators for the implementation of Alzheimer’s disease blood‐based biomarkers in primary care: The CANTATE‐Perspectives study.

Background: Adequately diagnosing Alzheimer’s disease (AD) in primary care can be challenging. Early symptoms often go unrecognized and other (neurodegenerative) diseases may be misdiagnosed as AD. AD blood‐based biomarkers could improve the diagnostic process for cognitive complaints in primary care.

Using a blood‐based biomarker panel for Alzheimer’s disease to determine eligibility for disease modifying treatment in a memory clinic setting: three scenarios.

Background: Blood‐based biomarkers (BBM) for Alzheimer’s disease (AD) may be able to identify individuals eligible for emerging anti‐amyloid treatments (DMT). We aimed to evaluate how to use BBM as (pre‐) selection tools for DMTs by simulating different triaging scenarios in a memory clinic setting.

Methods: We included 1199 participants from the Amsterdam Dementia Cohort with measured BBM (plasma pTau181, GFAP and NfL) and used a predefined Youden‐index based cut point for amyloid positivity (method: https://doi.

The impact of tau‐PET in a selected memory clinic cohort: design and rationale of the TAP‐TAU study.

Background: Tau‐PET is a diagnostic tool with high sensitivity and high specificity for discriminating Alzheimer Disease (AD) dementia from other neurodegenerative disorders in well‐controlled research environments. The role of tau‐PET in “real‐world” clinical practice, however, remains to be established. We hypothesize that tau‐PET will lead to some changes of the pre‐PET clinical diagnosis and will improve diagnostic certainty and patient management in patients with considerable diagnostic uncertainty.

Combination of CSF synaptic biomarkers and qEEG leads to a better prediction of disease progression in Alzheimer’s disease.

Background: Synaptic dysfunction plays an important role in Alzheimer’s disease (AD) and cognitive decline. We investigated the association between cerebrospinal fluid (CSF) synaptic protein levels and quantitative EEG (qEEG) measures, two modalities to measure synaptic dysfunction in AD pathology. We assessed combined and independent prognostic value of both modalities for cognitive decline along the AD continuum.

CSF ATN and α‐synuclein co‐pathology in AD, PD, and DLB.

Background: Co‐pathology between Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α‐synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity.

Method: As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers.

Clinical consequences of the Alzheimer’s blood‐based biomarker panel: a prospective evaluation in memory clinics ‐ the CANTATE project.

Background: Blood‐based biomarkers (BBM) are emerging as minimally invasive, scalable and relatively low‐cost options for discriminating different neurodegenerative diseases. Before implementation in clinical practice can take place, it is important to determine their real‐world clinical validity in patients presenting at a memory clinic. Therefore, we prospectively evaluated changes in diagnosis and diagnostic confidence resulting from the use of a BBM panel tailored to common differential diagnostic considerations (Verberk et al.

Longitudinal Trajectories of Blood‐based biomarkers for Alzheimer’s Disease in Subjective Cognitive Decline; the SCIENCe project.

Background: Blood‐based biomarkers are increasingly able to identify Alzheimer’s Disease pathology in the preclinical stages of the disease. These biomarkers hold promise to study development and progression of the disease. Our aim is to investigate the longitudinal trajectories of Aβ ratio, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in individuals with subjective cognitive decline (SCD).

Reduced plasma Aß42/40 in individuals with SCD predicts increasing plasma p‐Tau 181.

Background: In Alzheimer’s disease (AD), the decline of plasma Aß42/40 occurs before cognitive decline, presenting a potential early screening tool. However, the factors leading to the progression of the disease, specifically the increase in plasma p‐Tau 181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), remain unclear. This study investigates whether perceived cognitive impairment is associated with downstream biomarker changes in individuals with decreasing Aß42/40.

In‐vivo plasma biomarker concentrations correlate with postmortem AD‐neuropathology in the oldest old.

Background: There has been ongoing uncertainty to what extent plasma biomarkers are representative of neuropathological markers of AD pathology in the oldest old. A complicating factor is that with increasing age, Aβ‐ and Tau pathologies accumulate in the brains of cognitively healthy individuals to highly variable levels (Zhang & Ganz et al., 2022).

International Initiative for Harmonization of Plasma Neurofilament light chain NfL clinical reporting in neurodegenerative diseases.

Background: The quantification of neurofilament light chain (NfL) in blood and cerebrospinal fluid (CSF) has proved useful in many contexts, for the diagnosis and prognosis of various neurological disorders. There is, however, a diversity of practices between centers, essentially linked to the context of use (COU), analytical methods, consideration of comorbidities, determination of cut‐points or use of interpretation scales. Finally, for the same biochemical profile, the interpretation and reporting of results may differ from one center to another, raising the question of test commutability.

CSF biomarkers trajectories across the AD spectrum reveal the temporal dynamics of amyloid and tau.

Background: The Alzheimer’s disease (AD) research framework proposes a biological definition of the disease. Still, little is known about longitudinal dynamics of core AD biomarker trajectories and how they map to each stage on the clinical spectrum.

Methods: Participants with abnormal amyloid across the cognitive spectrum (i.

Changes in plasma biomarker levels are predictive of amyloid pathology and memory decline in cognitively unimpaired individuals.

Background: Plasma levels of amyloid‐β, and glial fibrillary acidic protein (GFAP) have demonstrated predictive potential for amyloid pathology in the early stages of Alzheimer’s disease (AD) development. Utilizing baseline and up to 6‐year follow‐up plasma, positron emission tomography (PET) and cognitive data from cognitively unimpaired individuals, we here aim to test whether early changes in plasma biomarker levels associate with change in amyloid status and cognitive decline.

Methods: From the EMIF‐AD PreclinAD study we selected individuals with normal cognition and longitudinal plasma, PET and cognitive data available (n=200, table 1).

Coronary artery calcium and Alzheimer’s Disease biomarkers in cognitively unimpaired adults.

Background: Atherosclerosis, the hardening of arterial walls resulting in atherosclerotic plaques, is linked to cognitive dysfunction and an increased risk of cognitive decline. Findings on the impact of high coronary artery calcium (CAC), a subclinical atherosclerosis biomarker, on cognition remain inconsistent. Additionally, its effect on Alzheimer’s Disease (AD) biomarkers has not been previously analysed.

Distinct CSF proteomic signatures are associated with cognitive decline in A+T+ and A+T‐ individuals with MCI due to Alzheimer’s Disease.

Background: Individuals with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) show variability in cognitive decline. Little is known about the underlying mechanisms, but these are likely to depend on tau levels. Using untargeted proteomics in cerebrospinal fluid (CSF), we studied which processes were associated with cognitive decline in A+T‐ and A+T+ MCI individuals.

Correlations between monoaminergic biomarkers, classical biomarkers and the BPSD‐DSII behavioral scale in Down individuals with and without Alzheimer's dementia.

Background: Down syndrome (DS, trisomy 21) is the most frequent genetic cause of intellectual disability (ID), prevalent in approximately 1 in 900 live births (Loane et al., 2013). People with DS are at high risk to develop Alzheimer’s disease dementia (AD) (Lott & Head, 2001).

Computerized decision support to optimally funnel patients through the diagnostic pathway.

Background: The increasing dementia prevalence and potential introduction of disease‐modifying therapies (DMTs) highlight the need for efficient diagnostic pathways. Clear recommendations to guide the choice of diagnostic tests are lacking and may vary depending on different clinical scenarios. We used a data‐driven approach to identify efficient and effective stepwise diagnostic testing for three clinical scenarios: 1) syndrome diagnosis, 2) etiological diagnosis, 3) potential eligibility for DMT.

Novel plasma pTau205 and BD‐tau prototype assays on LUMIPULSE G1200.

Background: Among the different phospho‐tau sites, phosphorylation at Threonine 205 (pTau205) in CSF has been shown to be closely associated with Tau‐PET (Lantero‐Rodriguez et al. 2024; Barthélemy et al. 2023).

Sabirnetug (ACU193) Lowers CSF Levels of Synaptic Biomarkers in INTERCEPT‐AD Phase 1 Study in Early AD.

Background: Sabirnetug (ACU193) is a humanized IgG2 antibody targeting soluble, synaptotoxic amyloid β oligomers (AβOs). AβOs accumulate in Alzheimer’s disease (AD) and induce pre‐ and post‐synaptic changes, resulting in dendritic spine loss, neuronal degeneration, and release of synaptic proteins into the CSF. Recently, we reported that three administrations of sabirnetug in an early AD population (INTERCEPT‐AD Phase 1 study, NCT04931459) significantly lowered CSF levels of the post‐synaptic protein neurogranin as well as pTau181.

Improved Precision and Sensitivity: Refinement of a Homebrew Simoa Assay for Detecting pTau181 in Plasma and Serum.

Background: Plasma tau phosphorylated at Threonine181 (pTau181) has been extensively studied as an accessible biomarker of amyloid pathology and is compared in various studies with other pTau epitopes. ADx has developed a Quanterix Homebrew Simoa assay using a highly pTau181 specific capture mAb (ADx252) and an N‐terminal tau detector ADx204 demonstrating high clinical performance (Janelidze ., 2023; Ashton .

Discovery of dementia type specific biomarkers with untargeted CSF proteomics.

Background: Different pathologies can cause dementia, including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia. Understanding the biological mechanisms underlying these diseases is important in order to develop therapies. Here we performed cerebrospinal fluid (CSF) proteomics in AD, DLB and FTD in order to study proteomic changes and identify novel potential biomarkers.

Evidence‐based Clinical Practice Guideline on the Use of Blood‐based Biomarkers in Alzheimer’s Disease: Presentation of Preliminary Evidence, and Opportunity for Public Comment.

Background: The rapid development of blood‐based biomarkers (BBMs) has improved Alzheimer’s disease (AD) diagnostics with some tests now potentially suitable for clinical use. This aligns with the clinical availability of anti‐Aβ immunotherapies for early symptomatic AD, where BBMs can help address the increasing need for more rapid and early diagnosis. Clinical practice guidelines (CPG) can help guide healthcare professionals in incorporating BBMs into their clinical practice.

TOP‐LINE CSF Biomarker Outcomes from the Phase 2 Clinical Trial SHINE in Alzheimer’s Patients.

Background: A Phase 2 randomized, double‐blind, placebo‐controlled 6‐month trial, SHINE (NCT03507790), was designed to include up to 144 participants with mild to moderate Alzheimer’s disease (AD) to study the effects of the sigma‐2 receptor (S2R) modulator CT1812 on cognition, safety, and biomarkers. CSF canonical and exploratory biomarkers were assessed to determine treatment effects with CT1812.

Method: Participants (n = 153) received a daily oral dose of either CT1812 (100 mg or 300 mg) or placebo during the treatment period of 6‐months.

Multi‐Marker Approach to Reducing the Intermediate Range of a High Accuracy 2‐Cutoff Plasma p‐Tau 217 Test for Amyloid Detection.

Background: p‐Tau 217 is considered the most accurate single plasma biomarker for detecting amyloid pathology. Recent draft Alzheimer’s Association criteria for diagnosing Alzheimer’s recommends that p‐Tau 217 tests be designed with two cut‐offs in recognition of signal overlap between diseased and non‐diseased subjects. Two cutoffs maximizes the accuracy of the test, but leaves a diagnostic intermediate zone with uncertainty of amyloid status.