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March 18, 2022

AD/PD 2022: plasma p-tau shows promise as a blood biomarker for Alzheimer’s

Presentations during a plenary session at AD/PD have explored the use of p-tau as a prognostic biomarker for Alzheimer’s disease.

By GlobalData Healthcare

A key theme at the AD/PD 2022 International Conference on Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) is the development of novel biomarkers for AD. On 16 March, expert physicians, researchers and industry representatives participated in a forum discussing how blood-based biomarkers compare to fluid biomarkers and imaging, and how they can be used in diagnosis and treatment. According to these experts, a key unmet need remains for simple, inexpensive, non-invasive biomarkers that can be used to diagnose AD earlier, as well as aid in clinical trial recruitment for the development of disease-modifying therapies (DMTs).

Current clinical biomarkers are hampered by limitations as they require either expensive positron emission tomography (PET) neuroimaging scans or a highly invasive lumbar puncture to collect a cerebrospinal fluid (CSF) sample for testing. One biomarker highlighted in the expert forum, as well as in numerous other presentations at the AD/PD 2022 conference, is plasma phosphorylated-tau (p-tau).

Tau protein is a hallmark pathology of AD and in the disease state, tau proteins become hyperphosphorylated and structurally compromised, often bending in shape or ‘tangling’. Misshapen tau proteins lose their functionality, leading to microtubule deficiency and, ultimately, neuronal death. It has also been postulated that elevated tau concentrations intensify the toxicity of amyloid beta, another hallmark pathology of AD.

While tau protein is a brain-specific protein, it can leak into plasma from brain interstitial fluid; elevated levels of p-tau in the plasma of AD patients make it a promising biomarker for AD. There are several varieties of p-tau dependent on where the tau protein is phosphorylated: plasma tau phosphorylated at threonine 217 (p-tau217), plasma tau phosphorylated at threonine 231 (p-tau231), and plasma tau phosphorylated at threonine 181 (p-tau181).

With many of the DMTs in development for AD targeting patients with early AD and mild cognitive impairment (MCI), it is important for a blood biomarker to be able to detect the disease very early in its progression, potentially even before any clinical symptoms manifest. Several presentations during a plenary session on fluid biomarkers on 16 March explored the use of p-tau as a prognostic biomarker for AD.

For example, data presented from the Mayo Clinic Study on Ageing demonstrated that in cognitively unimpaired participants, plasma p-tau181 and p-tau217 levels were both able to inform on the risk of incident MCI within two years, independent of the amyloid PET status of the participant. Another abstract presented in the same session further highlighted the potential of plasma p-tau as a prognostic biomarker. Data showed that in patients with amnestic MCI, plasma p-tau217, in combination with a brief cognitive composite score, was strongly linked to a greater risk of progression to AD dementia.

In addition to identifying patients with early AD/MCI, evidence is growing to support the use of plasma p-tau as a biomarker for disease worsening in clinical trials. For example, p-tau181 was a biomarker included in Biogen’s Aduhelm (aducanumab) clinical studies, with results from the ENGAGE (NCT02477800) and EMERGE (NCT02484547) Phase III trials demonstrating that a reduction in plasma p-tau181 correlated with reduced clinical decline. Experts from the AD/PD 2022 forum discussing blood biomarkers highlighted the promise of AD biomarkers being able to capture real clinical effect. They noted that further validation of such biomarkers, plasma p-tau181 as one possibility, would enhance their prospects as biomarkers for AD, and the experts could eventually see them being used as an outcome measure in clinical trials.

While there is currently a large amount of momentum behind the development of blood biomarkers for AD, experts participating in the 16 March forum stressed that there are many years of data behind the current, more invasive clinical biomarkers of AD. As such, it is likely to be some time before blood biomarkers are routinely used in the early diagnosis of AD, as they will require robust testing and validation.

This is particularly important for any prognostic biomarkers because false test results could be particularly damaging for patients, with false positives causing undue stress and potential unnecessary treatment, and false negatives resulting in patients missing out on initiation of any future DMTs that could prevent progression of the disease. Experts also highlighted that it is unlikely any such biomarkers would completely replace current diagnostic procedures; rather, they should be integrated into current practices to help streamline diagnosis, aid with patient stratification, and support clinical drug development.

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