For decades, physicians have relied on diverse biological indicators to diagnose and monitor normal development, health, and diseases. Such indicators are important from the time we are born, when APGAR scores are recorded in the labor and delivery room, throughout our childhoods, when pediatricians monitor growth curves closely, and into adulthood, when our height, weight, and vital signs initiate virtually every medical appointment. For adults, these indicators, collectively known as biomarkers, have long since revolutionized fields like cardiology and oncology. Now, biomarkers are poised to transform how we approach the diagnosis, prognosis, and monitoring of treatment response and disease progression in older adults with cognitive impairment, particularly Alzheimer’s disease (AD).

Just what are biomarkers anyway?

The word “biomarker” is a portmanteau of “biology” and “marker.” Measurable substances or characteristics in the body that signal risk or presence of disease, biomarkers function like biological “red flags”: they are early warning signals for monitoring normal health or disease progression. Neurological biomarkers occur in genes, blood, cerebrospinal fluid (CSF), and brain scans. Frequently, biomarkers can signal the presence of underlying disease before symptoms even appear.

The National Institutes of Health Biomarkers Definitions Working Group defined biomarker in 1998 as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” Blood glucose levels have long been used to diagnose and monitor diabetes. Prostate-specific antigen (PSA) levels and BRCA genetic tests have been crucial in detecting prostate and breast cancers since the 1990s. The first AD biomarker, the APOE ε4 allele, was described more than 30 years ago.

Biomarkers in Alzheimer’s disease: historically expensive and hard to access

The APOE ε4 genetic polymorphism assesses AD risk but cannot be used for diagnosis. Since the early 2000s, analyzing CSF for levels of beta-amyloid and tau proteins has helped diagnose AD. However, obtaining CSF requires a lumbar puncture (LP), which is invasive, expensive, and often necessitates exposure to ionizing radiation. Techniques like MRI to evaluate brain structure are now nearly ubiquitous, albeit structural biomarkers specific to AD or other dementias are somewhat less accessible. Positron emission tomography (PET) scans to detect abnormal amyloid deposited into the infamous AD neuritic plaques have been available to researchers since 2012. PET imaging for abnormal tau protein in the equally infamous neurofibrillary tangles arrived on the research scene in 2020. Both PET types allow actual visualization of AD proteinopathy. Amyloid PET is now available clinically via registry enrollment, though commercial payer coverage is not yet widespread. At present, tau PET remains restricted to research. FDG-PET scans are less expensive than amyloid or tau PET. Still, in AD, FDG-PET offers only indirect metabolic markers rather than explicit visualization of the underlying amyloid and tau pathology.

Blood-based biomarkers: a game changer

One of the most exciting recent developments in dementia medicine is the advent of blood-based biomarkers for AD. Blood tests offer great advantages: they are less invasive, more easily accessible, and potentially more cost-effective than imaging or LP, making their widespread use more feasible and more attractive for patients, clinicians, and payers alike.

Key blood-based biomarkers include:

1. In AD, the plasma Aβ42/Aβ40 ratio assesses the burden of abnormal “Alzheimer-y” amyloid protein compared to its non-pathogenic forms. As abnormal amyloid deposits into neuritic plaques, its relative concentration in CSF and blood drops.

2. Also in AD, plasma levels of p-tau181 and p-tau217 correlate strongly with AD pathology in the brain. A 2024 study published in JAMA Neurology reported “high accuracy” in identifying amyloid and tau pathology, comparable to CSF biomarkers. Notably, longitudinally, p-tau217 values rose only in Aβ-positive individuals.

3. Neurofilament light chain (NfL) elevations occur in many neurodegenerative disorders, including AD, frontotemporal dementia, multiple sclerosis, and traumatic brain injury. Though non-specific, NfL levels mark the severity of neuronal damage and drop with effective treatment. The best use of NfL in AD lies in prognosis and monitoring of progression rather than diagnosis.

4. Glial fibrillary acidic protein (GFAP) can discriminate between AD and healthy controls, although other neurodegenerative diseases or injuries may alter its concentration. GFAP is unusual in AD because its utility as a biomarker is better in blood than CSF.

Why blood-based biomarkers matter in AD

These blood tests could revolutionize AD diagnosis, prognosis, and disease monitoring by enabling earlier detection of AD pathology years before symptom onset. Using blood-based biomarkers to determine eligibility for clinical trials of emerging AD drugs facilitates the recruitment of a population highly likely to have the target disease. Finally, combining blood-based biomarkers with comprehensive history, cognitive tests, and imaging will inaugurate unprecedented diagnostic precision.

Beyond Alzheimer’s disease: biomarkers for other dementias

Research is also progressing on biomarkers for non-AD forms of dementia. In frontotemporal dementia, NfL is particularly useful for prognostication: serum levels rise before disease manifestation and correlate inversely with survival time. In dementia with Lewy bodies, real-time quaking-induced conversion (RT-QuIC) assays offer novel ways to better the disappointing diagnostic performance of alpha-synuclein, the underlying proteinopathy. In vascular dementia, the only non-neurodegenerative form of dementia, the placental growth factor is being explored as a method for distinguishing vascular dementia from AD.

Final thoughts

The emergence of blood-based biomarkers represents notable progress in our ability to detect and understand AD and, increasingly, other dementias. There is much we do not yet know—diagnostic thresholds require additional research into reliability and reproducibility, few head-to-head comparisons exist, and how blood-based biomarkers work in non-white populations, just to name a few. These tools provide hope for earlier intervention, more precise diagnoses, and accelerated research into new treatments. As we continue to unlock the secrets hidden in our biology, we move closer to a future of profoundly advanced precision in dementia diagnosis, prognosis, and monitoring, one that will minimize the impact of this hateful condition on individuals and society alike.

Amy E. Sanders is a neurologist.