Blood based biomarkers - a game changer for Alzheimer's disease diagnosis and treatment?

Dementia is one of the leading causes of mortality and morbidity in the elderly. It results in cognitive and  behavioral impairments that significantly interfere with social and occupational functioning. Alzheimer’s  disease (AD) is the most common cause of dementia. Diagnosis usually involves two steps: first, to diagnose the  syndromes of dementia (major neurocognitive disorder) and mild cognitive impairment (mild neurocognitive  disorder) based on history, examination, and appropriate objective assessments, using recommended standard criteria ^1,2; second, to identify etiological subtypes of these syndromes to guide treatments.

In 1906, Dr. Alois Alzheimer first described the symptoms and the amyloid plaques and neurofibrillary tangles in the brain, which have come to be considered the hallmarks of AD. The recommended criteria  permit a probable clinical diagnosis of  AD that can be confirmed as definite only after the  person’s death if an autopsy is performed and the mentioned plaques and tangles are observed. Researchers  have shown that these criteria have low accuracy and that only 70% of diagnoses were correct, with the others being false positive or false negative cases.³

The International Working Group (IWG and IWG2), the National Institute on Aging and the Alzheimer’s Association (NIA-AA) agree that  AD should be considered as a continuum, ranging from normal cognition to severe dementia, including three phases: ^4,5

1. Preclinical  AD: asymptomatic at risk or presymptomatic  AD (abnormal pathophysiological biomarkers and no cognitive impairment)
2. Mild cognitive impairment (MCI) due to AD (NIA-AA) or prodromal AD (IWG) (abnormal pathophysiological biomarkers and mild cognitive impairment)
3. Dementia due to AD (abnormal pathophysiological biomarkers and dementia), which could be further categorized into mild, moderate, and severe levels.

Abnormal pathophysiological biomarkers are critical in confirming the presence of AD. Positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers are approved for AD diagnosis and are widely used in clinical research. However, the routine use of these modalities is limited due to the need for specialized neuroimaging infrastructure and expertise for PET-based measures, and the requirement for skilled operators to perform diagnostic lumbar punctures for CSF testing. These procedures are often perceived as invasive and risky by some patients ⁶. It has been reported that only 2% of individuals diagnosed with dementia in the UK have undergone PET scans or lumbar punctures ⁷.

Blood-based biomarkers (BBBMs) have great potential in AD management, as using a routine blood draw is much more accessible in primary care settings. 

In October 2023, the Alzheimer's Association (AA) workgroup proposed that the following tests are sufficient to diagnose AD: positive amyloid PET scans, specific CSF biomarkers (including Aβ42/40, p-tau 181/Aβ42, and t-tau/Aβ42), or "accurate" blood-based assays. "Accurate" here means blood-based assays matching the precision of approved CSF biomarkers in detecting abnormal amyloid PET scan results for the intended population. This new proposal means that "accurate" BBBMs could be accepted for the diagnosis of AD, even before symptoms appear ⁸.

In Sweden, a team studied how well a commercially available plasma assay called pTau217 (ALZpath pTau 217 assay) performed. Their findings indicated that this assay is as accurate as CSF biomarkers in detecting AD ⁹.

A team in Hong Kong developed a commercial blood test called the PlasmarkAD Blood Test, which can simultaneously measure the levels of 21 AD-related proteins. Using machine learning-based mathematical models, the team created an AD risk scoring system that generates a risk score for individuals based on the levels of these 21 proteins in their blood. In a study involving a Hong Kong Chinese Cohort, this AD risk score accurately distinguished patients with AD (AUC = 0.9667) and patients with MCI (AUC = 0.8718) from cognitively normal individuals ¹⁰.

The researchers also looked at how AD risk scores were distributed among patients with AD those with MCI and individuals with normal cognition. They categorized people with AD risk scores below 32 as having a low risk, those with scores between 32 to 72 as having moderate risk, and those with scores above 72 as having a high risk of AD ¹⁰.

Some dementia specialists with expertise in BBBMs have already integrated such assays into the care of selected patients. We anticipate a broader adoption of these assays among dementia specialists. Within primary care settings, BBBMs hold potential to serve as part of a stepwise neurodiagnostic approach for AD, facilitating the identification of individuals who may not require further costly and invasive investigation. This stratification could lead to a reduction in anxiety among patients and overall burden on the healthcare system.

Given the promise of BBBMs in early detection of AD, they potentially offer a more cost-effective and less invasive option for early intervention in AD. Recent clinical trials suggest that the use of disease-modifying drugs during the stages of MCI or mild dementia due to AD has the potential to slow cognitive and functional deterioration.^{11, 12, 13}

Medical reimbursement claims are likely to increase due to the increased clinical use of disease-modifying drugs (depending on policy coverage). If these drugs are able to significantly slow disease progression over the long term, insurers are likely to observe a delay and/or reduction in AD-related disability and death claims in the future .

On the other hand, widespread use of BBBMs in general clinical practice will likely increase the cases of  AD detected at early stages including presymptomatic, MCI and mild dementia due to AD. This could result in an increase in early Alzheimer's dementia claims, for Critical Illness (CI) policies that cover early-stage AD based on clinical diagnosis only. On the other hand, early treatment of these cases could delay and / or reduce disease progression, which would in turn lead to a reduction in CI claims for definitions that cover more advanced stages of the disease based on significant functional impairments.

Finally, the PlasmarkAD Blood Test has demonstrated its potential in stratifying people into different risk levels of AD, which may provide a potentially, reliable tool for underwriting risk of AD.

• Blood-Based Biomarkers (BBBMs) Revolutionize Early Detection of AD and Enables Early Intervention BBBMs offer a less invasive and more accessible alternative to conventional methods for early detection of AD even before clinical symptoms appear. This early detection facilitates timely intervention and management strategies.
• Potential Implications to Insurance – The introduction of BBBMs with supported disease-modifying treatments may help improve claim experiences in AD defined in CI policies by significant functional impairments and reduce or delay AD-related disability and death. Depending on policy coverage, medical reimbursement claims may increase due to increased disease-modifying drug prescriptions. The future introduction of BBBMs into general clinical practice could increase claims of early stage AD, based on clinical diagnosis only, depending on policy definitions.