Clinical translation of fluid, imaging, and digital biomarkers for Alzheimer's disease.

BackgroundAt the beginning of the century, Alzheimer disease (AD) biomarkers were only used in research studies and included hippocampal volume and cerebrospinal fluid (CSF) concentrations of Aβ42, total tau, and tau phosphorylated at position 181 (p‐tau181). Twenty‐five years later, imaging and fluid biomarkers have become critical tools in AD clinical trials and are increasingly being used in clinical care.MethodsThe development of imaging and fluid AD biomarkers will be reviewed. The evolving roles of different modalities of biomarkers in research, clinical trials, and clinical care will be described.ResultsIn 2004, the first radiotracer that bound amyloid plaques was reported, which enabled visualization of the amount and regional distribution of amyloid plaques in the brains of living individuals via positron emission tomography (PET). Radiotracers binding to insoluble tau aggregates were described in 2013 and 2014. The use of amyloid and tau PET as a reference standard, as well as improvements in fluid biomarker assay technology, led to the first of many accurate AD blood tests in 2017 and 2018. These imaging and fluid biomarkers of AD have undergone waves of development, validation, and regulatory approval. AD research studies now use biomarkers extensively to study the biology of disease. Clinical trials use biomarkers to confirm that participants have AD pathology and to monitor the effects of treatment. AD biomarkers are increasingly being used in the clinical diagnosis of AD. The high acceptability and accessibility of AD blood tests may enable AD biomarker testing to become the standard of care in patients with cognitive impairment. In the future, if trials of preventative treatments are positive, AD biomarker testing of cognitively unimpaired older individuals may become routine.ConclusionsAdvances in imaging and fluid biomarkers over the past quarter century have enabled greater understanding of AD biology and led to the successful development, approval, and clinical use of disease‐modifying AD treatments that target amyloid pathology. The clinical availability of AD‐specific treatments and high‐accuracy AD blood tests is currently transforming the clinical diagnosis and care of patients with AD.

BackgroundBiomarkers are critically important for Alzheimer's Disease (AD) drug development. They have a role in patient diagnosis and trial eligibility, pharmacodynamic changes, safety, monitoring, disease modification, and target engagement. In AD clinical trials, biomarkers are vital in determining the treatment efficacy, reliability, and safety.MethodWe created the Biomarker Observatory (BMO) to provide curated information on AD biomarkers for drug developers and clinical trialists. From the BMO, our aim is to explore and present the biomarkers that are currently being used in active AD intervention trials. We extract information from clinicaltrials.gov and annotate the eligibility, primary, secondary, and other biomarkers from each trial. Together with information from the Clinical Trial Observatory, we explore the imaging, fluid, and digital biomarkers being measured in active AD clinical trials, the trial characteristics, and influence of biomarkers on trials.ResultFor active trials in the year 2024 (January 1 to December 30, 2024), we found that 57% of the clinical trials used a biomarker as an eligibility criterion for patient participation. Imaging was the most common type of marker, with magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) most used as eligibility and primary outcome biomarkers. Fluid biomarkers (CSF, blood, plasma, or serum) were used in 28% of AD clinical trials as eligibility biomarkers and in 12% of trials as a primary outcome measure. Seventeen AD clinical trials measured amyloid beta protein (Aβ) in fluid samples as a criterion for eligibility and 17 evaluated hyperphosphorylated tau (p‐tau). As a primary outcome measure, 2 trials measured Aβ in fluid samples and 7 investigated p‐tau levels. Total tau and neurofilament light chain (NfL) were included as primary outcome measures in 2 and 3 trials, respectively.ConclusionOur data demonstrate how imaging, fluid, and digital biomarkers are used in current AD clinical trials and the impact they have on trial design and outcomes. We provide current biomarker information to advance AD drug development, aiming to increase trial success rates and reducing the time it takes for new AD therapeutics to reach patients.

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.

Tracking the potential involvement of metabolic disease in Alzheimer's disease—Biomarkers and beyond

PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients.

Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aβ1-42, total tau and phosphorylated tau181, and plasma Aβ measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aβ1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aβ1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aβ1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aβ1-42 or Aβ1-40. This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.

The diagnostic guidelines of Alzheimer’s disease (AD) have recently been updated to include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid β (Aβ42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.

To give perspectives on current limitations and recent developments in the field of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD). Three CSF biomarkers for the neuropathological hallmarks of Alzheimer's disease, namely total tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of amyloid β (Aβ42), reflecting neurodegeneration, neurofibrillary tangles and amyloid/senile plaques, respectively, have been developed, validated and incorporated into new diagnostic criteria for the disease. Thanks to global collaborative research efforts, these have been to a large extent a success story but there are a number of limitations that warrant further research and discussion. First, bias and random variation in biomarker measurements both within and between laboratories remain an issue. Second, current markers only reflect part of the pathology underlying Alzheimer's disease; new markers of synaptic dysfunction, microglial activation and protein aggregates that are frequently seen alongside plaque and tangle pathology are needed. Third, fluid markers do not represent the anatomic location of any pathological change; CSF markers may be complemented with high resolution molecular imaging techniques. There has been considerable progress in the validation and standardization of assays for CSF T-tau, P-tau and Aβ42. Novel biomarkers for synaptic function, microglial activation and protein accumulations other than tau and Aβ are in development. Future fluid biomarker research should be conducted in close collaboration with molecular imaging specialists.

It is estimated that Alzheimer’s disease (AD) is striking 1 in 20 over age 65, which yielded to 23–35 million people worldwide in 2015. The number of AD victims is expected to almost double every 20 years, thus placing the national healthcare systems under dramatically increasing pressure. This clearly underlines the need to find early biomarkers and efficient medical treatments for AD, both implying a better understanding of the mechanism from the origin of the disease to the death of the neurons. Oxidative damages on neuronal lipids and proteins, in particular, are an important feature of AD and a link with oxidative stress [1]. The latter can have different origins, but the overproduction of reactive oxygen species (ROS) is considered as a major contribution. Loosely bound metal ions (copper and iron), present in the brain and at high concentration in senile plaques of AD patients, may bind to the amyloid beta peptide (Aβ) thus catalyzing very efficiently the production of ROS (in particular, the oligomeric forms of Aβ, known as being the most toxic). This represents one of the source for ROS production in brain, a second one being mitochondria dysfunction.

An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known hallmarks of Alzheimer's disease include amyloid-β plaques and neurofibrillary tau tangles. It is now clear that an imbalance between production and clearance of the amyloid beta protein and related Aβ peptides, especially Aβ42, is a very early, initiating factor in Alzheimer's disease (AD) pathogenesis, leading to aggregates of hyperphosphorylation and misfolded tau protein, inflammation, and neurodegeneration. In this article, we review how the AD diagnostic process has been transformed in recent decades by our ability to measure these various elements of the pathological cascade through the use of imaging and fluid biomarkers. The more recently developed plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have utility for screening and diagnosis of the earliest stages of AD. These biomarkers can also be used to measure target engagement by disease-modifying therapies and the response to treatment.

Principal components from untargeted cerebrospinal fluid metabolomics associated with Alzheimer's disease biomarkers

Battle against Alzheimer's Disease: The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers

Introduction: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, behavioral changes, and functional impairment. Reliable biomarkers are essential for early diagnosis, disease monitoring, and the development of effective therapeutic strategies. Method: This review, conducted in line with PRISMA 2020 guidelines, systematically analyzed recent studies on imaging, Cerebrospinal Fluid (CSF), blood-based, and digital biomarkers. Relevant literature was identified through database searches and screened for clinical applicability, advantages, and limitations. Results: Imaging biomarkers, such as amyloid-PET and tau-PET, provide direct visualization of AD pathology, while CSF biomarkers, including amyloid-β and tau proteins, demonstrate strong diagnostic and prognostic value. Blood-based biomarkers have emerged as minimally invasive alternatives suitable for large-scale screening and longitudinal follow-up. In addition, digital biomarkers derived from wearable devices and cognitive assessments offer innovative approaches for real-time monitoring of cognitive and functional decline. Discussion: Advances across these biomarker modalities indicate a shift toward earlier detection and personalized disease management. However, challenges remain, including population variability, lack of standardization, cost, and integration into clinical workflows. Addressing these issues is essential to ensure broader adoption in clinical practice. Conclusion: Recent progress in biomarker research offers great promise for transforming AD diagnosis and treatment. The combined application of imaging, fluid, and digital biomarkers may enable comprehensive, individualized management and support the development of more effective therapeutic interventions.

Declines in instrumental activities of daily living like driving are hallmarks sequelae of Alzheimer's disease (AD). Although driving has been shown to be associated with traditional imaging and cerebrospinal fluid (CSF) biomarkers, it is possible that some biomarkers have stronger associations with specific aspects of driving behavior. Furthermore, associations between newer plasma biomarkers and driving behaviors are unknown. This study assessed the extent to which individual plasma, imaging, and CSF biomarkers are related to specific driving behaviors and cognitive functions among cognitively normal older adults. We analyzed naturalistic driving behavior from cognitively healthy older drivers (N = 167, 47% female, mean age = 73.3 years). All participants had driving, clinical, and demographic data and completed biomarker testing, including imaging, CSF, and/or plasma, within two years of study commencement. AD biomarkers were associated with different characteristics of driving and cognitive functioning within the same individuals. Elevated levels of plasma Aβ40 were associated with more speeding incidents, higher levels of CSF tau were related to shorter duration of trips, and higher CSF neurofilament light chain values were associated with traveling shorter distances, smaller radius of gyration, and fewer trips at night. We demonstrated that plasma, like CSF and imaging biomarkers, were helpful in predicting everyday driving behaviors. These findings suggest that different biomarkers offer complementary information with respect to driving behaviors. These distinct relationships may help in understanding how different biological changes that occur during the preclinical stage of AD can impact various sensorimotor and cognitive processes.

Comparing MRI and CSF biomarkers in Alzheimer's disease: Intergroup discrimination and predicting clinical change