In a recent review published in the journal Nature Reviews Neurology, a group of authors outlined the factors necessary for the widespread implementation and interpretation of Alzheimer’s disease (AD) blood-based biomarkers (BBMs) at the population level.
Study: Alzheimer disease blood biomarkers: considerations for population-level use. Image Credit: nobeastsofierce / Shutterstock
Background
Due to rising life expectancies, the global population aged 60 and older is increasing, currently comprising about 12% of the total population. As age is the most potent risk factor for AD and related dementias (ADRD), the number of diagnosed cases is projected to rise from 57.4 million in 2019 to over 152 million by 2050. High-income countries, already with long life expectancies, will see less dramatic increases in AD/ADRD compared to low- and middle-income countries experiencing rapid life expectancy growth. This global rise in AD/ADRD has intensified efforts for early detection, diagnosis, and identification of effective treatments to delay disease onset. Further research is needed to optimize the implementation and interpretation of ADBBM across diverse populations and healthcare settings.
Incorporating biomarkers into AD diagnosis
AD has traditionally been defined by clinical symptoms like amnestic memory impairment and confirmed at autopsy by amyloid plaques and neurofibrillary tau tangles. Clinical symptoms alone cannot indicate AD pathology, as memory impairment could result from various conditions, including other neurodegenerative diseases, brain injury, or reversible conditions like depression. Thus, diagnosing AD solely based on symptoms is challenging. This challenge extends to assessing anti-amyloid (Aβ) or anti-tau therapies, as some clinical trial participants may not have AD pathology.
The development and standardization of cerebrospinal fluid (CSF) biomarkers (low Aβ42:40 ratio and high p-tau levels) and Positron Emission Tomography (PET) biomarkers (elevated Aβ) have improved the accuracy of AD diagnoses. These biomarkers confirm AD pathology in patients with clinical symptoms and those enrolled in disease-modifying therapy (DMT) trials. The shortage of dementia specialists further complicates timely diagnosis and treatment, prompting calls for primary care providers (PCPs) to play a more prominent role in diagnosing and managing AD.
Overview of AD BBMs
Technological advances in the past five years have enabled the measurement of much lower concentrations of Aβ and p-tau in blood compared to CSF. BBMs are now available for clinical use and have been incorporated into clinical trials, offering a less invasive and potentially more accessible alternative to CSF and PET biomarkers. Despite their promise, questions remain about their implementation and utilization at the population level.
Aβ42:40 Ratio
Plasma Aβ42:40 ratios show less pronounced differences between individuals with and without elevated brain amyloid pathology than CSF ratios. However, the plasma Aβ42:40 ratio has demonstrated excellent diagnostic accuracy for detecting elevated brain amyloid across the AD cognitive spectrum.
Phosphorylated tau181 and tau217
Plasma p-tau181 and p-tau217 are specific to AD brain pathology and not elevated in other tauopathies. These biomarkers correlate with CSF and PET biomarkers and predict progression from mild cognitive impairment to AD. Studies suggest that p-tau217 may be a better indicator than p-tau181.
Neurofilament Light Chain (NfL)
NfL is a biomarker for the degeneration of large-caliber axons, elevated in many neurodegenerative diseases. Changes in blood NfL correlate strongly with cognitive symptoms and brain atrophy, making it a useful but nonspecific neurodegeneration biomarker.
Platforms and assays
Ultrasensitive immunoassays and mass spectrometry platforms measure BBMs in clinical settings. Immunoassays can measure Aβ42:40 ratios and p-tau181, p-tau217, and NfL levels. However, the accuracy of BBMs compared to amyloid PET varies across platforms. Automated immunoassays may offer advantages in scalability and throughput over mass spectrometry.
Exclusionary versus confirmatory test
The role of BBMs in diagnosis, whether as triage tools or confirmatory tests, is debated. Some BBMs match Food and Drug Administration (FDA)- approved CSF tests for classifying amyloid PET status, but conclusions are based on batch testing and non-representative study cohorts. Currently, BBMs are primarily considered triaging tools.
Effects of chronic conditions on AD BBMs
In the United States of America (USA), the average age at dementia diagnosis is 83, with most older adults with AD having multiple chronic conditions, which complicate the interpretation of BBM levels.
Chronic kidney disease (CKD)
CKD, low estimated glomerular filtration rate (eGFR), and high blood creatinine levels are associated with elevated blood levels of Aβ40, Aβ42, p-tau181, p-tau217, and NfL, which are attributed to reduced renal clearance. If CKD is not considered, this can result in false-positive or false-negative AD diagnoses.
Obesity
Due to increased blood volume, obesity lowers plasma levels of Aβ40, Aβ42, p-tau181, p-tau217, and NfL. Significant weight loss, such as from gastric bypass surgery, can normalize these levels, complicating interpretation in obese individuals.
Population use of AD BBMs
Interpreting BBM levels in the context of multiple chronic conditions is crucial for their use at the population level. Factors like incidental findings, indeterminate results, stigma, and discrimination must be addressed. Additionally, the real-world accuracy of BBMs in diverse populations and their implementation in primary care remain uncertain. Widespread education and new patient care models are essential for practical use.
Conclusions
To summarize, technological advancements in BBMs for AD pathology have created an unprecedented opportunity to improve the timeliness and accuracy of AD diagnosis at the population level, including in low-resource settings. However, extensive research is needed to determine optimal implementation in primary care. Many older adults with cognitive impairment have multiple chronic conditions that must be considered when interpreting BBM levels to avoid false positives or negatives. Additional issues include potential incidental findings, increased stigma, indeterminate results, implications for driving or insurance, and the inclusion of biomarker results in medical records.