Blood Test May Predict Future Cognitive Decline in Preclinical Alzheimer's Disease

Megan Brooks

February 07, 2023

Plasma phosphorylated (P)-tau217 can help identify amyloid-beta­–positive, cognitively unimpaired individuals with preclinical Alzheimer's disease (AD) who are most likely to deteriorate in the coming years, new research suggests.

The study specifically identified plasma P-tau217 among several candidates as the best predictor of progression during the earliest stages of AD.

"This is very important because it is this subgroup of individuals with preclinical AD that really needs effective disease modifying therapies in the future," study investigator Oskar Hansson, MD, PhD, professor of neurology, Lund University, Lund, Sweden, told Medscape Medical News.

The findings also highlight the potential of easily available blood tests to increase the power of clinical trials, the researchers note.

The study was published online February 6 in JAMA Neurology.

Clinical, Research Implications

The investigators examined associations between the plasma biomarkers P-tau217, P-tau181, P-tau231, glial fibrillary filament protein, and neurofilament light with longitudinal cognitive decline in 171 amyloid-beta–positive, cognitively unimpaired older adults from the Swedish BioFINDER-1 cohort and the Wisconsin Registry for Alzheimer's Prevention (WRAP). 

Brain amyloid-beta pathology was defined by cerebrospinal fluid (CSF) amyloid-beta 42/40 in the BioFINDER-1 cohort and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP cohort.

The primary outcome was longitudinal measures of cognition using the Mini-Mental State Examination (MMSE) and the modified Preclinical Alzheimer Cognitive Composite (mPACC) over 2-10 years (median time, 6 years).

In BioFINDER-1, plasma P-tau217 was the best biomarker to predict cognitive decline in both the mPACC (P < .001) and the MMSE (P < .001) — with correlation coefficients of .41 and .34, respectively, and was superior to the covariates-only models (P < .001 for both).

In addition, baseline plasma P-tau217 was associated with significant conversion to AD dementia compared with no conversion or conversion to non-AD dementia (hazard ratio, 2.03; 95% CI, 1.57-2.63; P < .001).

These results were validated in the WRAP cohort.

Moreover, in clinical trial simulations, the researchers showed that "substantial reductions" in sample size is possible when cohorts are enriched for amyloid-beta–positive cognitively unimpaired individuals who have elevated plasma P-tau217.

"This type of enrichment may increase the power of clinical trials in the earliest stages of AD, when cognitive decline is variable and the power to detect associations in unenriched populations of amyloid-beta–positive cognitively unimpaired individuals is low," the investigators write.

In addition, "the results have immediate implications for clinical trials evaluating novel interventions in preclinical AD populations, because the number of included participants can be substantially reduced if only including those with elevated plasma P-tau217 levels," Hansson said.

In the future, one could also envision using plasma P-tau217 in clinical practice when a disease-modifying therapy is approved for clinical use at this early disease stage, he added.  

'Highlights the Potential Value'

Commenting for Medscape Medical News, Eric Reiman, MD, executive director, Banner Alzheimer's Institute, Phoenix, Arizona, said, "This is a very nice paper from an outstanding group; and it adds to previous work from this group and others that plasma P-tau, an indicator of amyloid plaques and the diagnosis of AD, can help to inform cognitively unimpaired individuals' subsequent cognitive decline and later progression to dementia."

Reiman, who was not involved in the study, noted that it "supports the potential value of this blood-based biomarker in the design and analysis of secondary AD prevention trials of cognitively unimpaired persons with biomarker evidence of AD."

"It could support design and analysis of post-marketing data, once an AD prevention therapy is approved, to show the treatment's ability to reduce the prevalence of dementia," he said.

It also "highlights the potential value of emerging blood-based biomarkers in the screening of unimpaired older adults, particularly after future prevention therapies become available," Reiman added.

This study had no commercial funding. Hansson reported receiving grants from the Swedish Alzheimer Foundation and the Swedish Research Council, and nonfinancial support from Eli Lilly and Company during the conduct of the study. He also received personal fees from Biogen, Eli Lilly and Company, and Eisai outside the submitted work. Reiman is a cofounder and advisor of ALZpath, a start-up company interested in advancing the role of emerging blood-based biomarkers in research, treatment development, and clinical care. ALZpath has been developing a plasma P-tau217 assay that was not used in this study.

JAMA Neurol. Published online February 6, 2023. Full text.

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