Blood Biomarkers: Revolutionizing Alzheimer's Diagnosis

In a recent analysis published in the journal Nature Reviews Neurology, a group of writers identified the elements required for widespread application and interpretation of Alzheimer’s disease (AD) blood-based biomarkers (BBMs at the population level).

Background

Because of expanding life expectancies, the global population of 60 and over is growing, accounting for around 12% of the total population. Because age is the most powerful risk factor for AD and related dementias (ADRD), the number of diagnosed cases is expected to increase from 57.4 million in 2019 to more than 152 million by 2050. High-income countries, which already have lengthy life expectancies, will witness less severe rises in AD/ADRD than low- and middle-income countries with rapid life expectancy growth. The global growth in AD/ADRD has fueled efforts to improve early detection, diagnosis, and development of viable treatments to delay disease onset. More study is needed to improve ADBBM application and interpretation across varied populations and healthcare settings.

Incorporating biomarkers into Alzheimer’s disease diagnosis

Alzheimer’s disease has traditionally been diagnosed by clinical symptoms such as amnestic memory impairment, which are verified at autopsy by amyloid plaques and neurofibrillary tau tangles. Clinical symptoms alone do not imply AD pathology, as memory impairment can be caused by a variety of disorders, including other neurodegenerative diseases, brain damage, or reversible conditions such as depression. Thus, identifying AD merely only on symptoms is difficult. This problem also applies to evaluating anti-amyloid (Aβ) or anti-tau medications, as some clinical trial participants may not exhibit AD pathology.

Standardization of cerebrospinal fluid (CSF) biomarkers (low Aβ42:40 ratio and high p-tau levels) and Positron Emission Tomography (PET) biomarkers (elevated Aβ) has increased AD diagnosis accuracy. These biomarkers confirm Alzheimer’s disease pathology in both clinically symptomatic patients and those involved in disease-modifying treatment trials. The dearth of dementia experts hinders early diagnosis and treatment, leading requests for primary care practitioners (PCPs) to have a larger role in AD diagnosis and management.

Overview of Alzheimer’s disease BBMs

Over the last five years, technological advancements have made it possible to assess lower quantities of Aβ and p-tau in blood than in CSF. BBMs are currently available for clinical usage and have been included in clinical trials, providing a less intrusive and maybe more accessible alternative to CSF and PET biomarkers. Despite their promise, there are still doubts about their deployment and use at the population level.

Aβ_42:40Ratio

Plasma Aβ42:40 ratios varied less significantly between persons with and without increased brain amyloid disease than CSF ratios. The plasma Aβ42:40 ratio is highly accurate in detecting elevated brain amyloid across the AD cognitive spectrum.

Phosphorylated tau181 and tau217

Plasma p-tau181 and p-tau217 are exclusive to Alzheimer’s disease brain pathology and are not enhanced in other tauopathies. These indicators correlate with CSF and PET biomarkers, predicting the progression from moderate cognitive impairment to Alzheimer’s disease. According to studies, p-tau217 may be a more reliable indicator than p-tau181.

Neurofilament Light Chain (NfL)

NfL is a biomarker for large-caliber axon degeneration that is raised in a variety of neurodegenerative disorders. Changes in blood NfL are closely associated with cognitive deficits and brain atrophy, making it an effective yet generic neurodegenerative biomarker.

Platforms and assays

In clinical settings, BBMs are measured using ultrasensitive immunoassays and mass spectrometry systems. Immunoassays can evaluate Aβ42:40 ratios, p-tau181, p-tau217, and NfL levels. However, the accuracy of BBMs compared to amyloid PET differs by platform. Automated immunoassays may be more scalable and efficient than mass spectrometry.

Exclusionary versus confirmatory test

The use of BBMs in diagnosis, whether as triage tools or confirmatory tests, is debatable. Some BBMs match FDA-approved CSF tests for determining amyloid PET status, but the findings are based on batch testing and non-representative study groups. Currently, BBMs are largely used as triage tools.

Effects of chronic conditions on AD BBMs

In the United States of America (USA), the average age of dementia diagnosis is 83, with the majority of older persons with Alzheimer’s disease having numerous chronic diseases that complicate BBM level assessment.

Chronic kidney disease (CKD)

Elevated blood levels of Aβ40, Aβ42, p-tau181, p-tau217, and NfL are linked to CKD, low eGFR, and high creatinine levels, indicating decreased renal clearance. If CKD is overlooked, it can lead to false-positive or false-negative AD diagnoses.

Obesity

Obese individuals have decreased plasma levels of Aβ40, Aβ42, p-tau181, p-tau217, and NfL due to increased blood volume. Significant weight loss, such as via gastric bypass surgery, can restore these levels, confounding interpretation in obese people.

Population use of AD BBMs

Interpreting BBM levels in the context of several chronic diseases is critical for their application at the population level. Incidental findings, unclear results, stigma, and discrimination all need to be addressed. Furthermore, the real-world accuracy of BBMs in varied populations and their use in primary care remain unknown. Broader education and new patient care models are required for practical application.

Conclusion

To summarize, technology advances in BBMs for AD pathology have created an unprecedented possibility to improve the timeliness and accuracy of AD diagnosis at the population level, even in low-resource settings. However, more research is required to determine the best application in primary care. Many older persons with cognitive impairment have various chronic diseases, which must be taken into account when analyzing BBM levels to avoid false positives or negatives. Other concerns include probable incidental findings, increased stigma, unclear results, implications for driving or insurance, and the inclusion of biomarker results in medical records.

For more information: Mielke, M.M., Fowler, N.R. Alzheimer disease blood biomarkers: considerations for population-level use. Nat Rev Neurol (2024), DOI – 10.1038/s41582-024-00989-1