CYBERSPACE – Data presented at the virtual 2020 Alzheimer's Association International Conference (AAIC) and reported in the July 28, 2020, online issue of the Journal of the American Medical Association (JAMA) demonstrated that blood levels of phosphorylated tau-217 (Ptau-217) did as well as cerebrospinal (CSF)- and PET-based biomarkers, and significantly better than other blood-based biomarkers, at discriminating individuals with Alzheimer’s disease (AD) from those with other neurodegenerative disorders.

The test will not be available for widespread clinical use for several more years. And if the current absence of disease-modifying treatments persists at that time, such a test would not immediately affect how AD patients are treated.

But a good blood-based biomarker test could be a boon for clinical trials for the development of disease-modifying treatments in the first place.

Rat neurons growing in a culture dish. Purple: cell nuclei; red: phosphorylated tau (Ptau). Credit: Jack Reifert, UCSB

In their study, the researchers compared the ability of blood levels of P-tau217, which is a major component of tau tangles, to those of several other blood, CSF, and imaging biomarkers, including Ptau-181, which is tau protein that is phosphorylated at a different amino acid.

They looked at the test’s performance in roughly 1,400 individuals in three separate well-characterized research cohorts in the U.S., Sweden and Colombia. The U.S. and Swedish cohorts included individuals with AD dementia, mild cognitive impairment (MCI), and other neurodegenerative disorders, as well as cognitively normal individuals. The Colombia cohort consisted of individuals with a presenilin-1 mutation that leads to early-onset familial AD, and cognitively normal individuals.

The study showed that “plasma P-tau217 differentiated clinically diagnosed AD dementia from other neurodegenerative disorders …, and distinguished participants with neuropathologically defined AD from participants without diagnostic levels of AD histopathology,” the authors wrote in their paper. “Further, plasma P-tau217 had significantly higher diagnostic accuracy for clinical AD compared with plasma P-tau181, plasma NfL” – neurofilament light chain – “and MRI measures and did not perform significantly differently compared with [cerebrospinal fluid] P-tau181, CSF P-tau217, and tau-PET.”

In the Colombian study participants, “plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately age 25 years and older, which is 20 years prior to the estimated onset of MCI among mutation carriers.”

The work now presented at AAIC could help address several vexing issues in AD drug development.

In 2018, the National Institute on Aging and the Alzheimer's Association announced a biomarker-based definition of AD for research purposes to reflect the fact that before the onset of clinical symptoms, AD has a prodromal phase that can last years or even decades, but where neurodegeneration is quietly proceeding.

There is a widespread assumption that the abject failure of AD clinical trials to date is at least partly due to the fact that with clinical diagnoses, such treatments – mostly in the form of amyloid-b targeting drugs – come too late to affect the disease trajectory.

Another issue is that multiple neurodegenerative diseases have overlapping symptoms. In the absence of ways to specifically select individuals with prodromal AD, rather than another neurodegenerative disorder or no impending neurodegenerative disorder at all, clinical trials balloon to prohibitive lengths and sizes.

Current diagnostic biomarkers, though, have their own problems. At comparable levels of accuracy, they cost a lot more than clinical diagnoses, and the amyloid plaques they often measure are themselves an imperfect predictor of eventual clinical AD, particularly in populations that are already frequently being failed by the health care system – racial and ethnic minorities, rural populations and the oldest old.

Eli Lilly and Co. and its wholly owned subsidiary Avid Radiopharmaceuticals Inc. are developing Ptau-217 as a biomarker for clinical use. They plan to present further data at the Clinical Trials on Alzheimer’s Disease meeting later this year.