By Richard S. Isaacson, MD
Associate Professor of Neurology (Education), Weill Cornell Medical College
SYNOPSIS: Serum phospho-tau217, a biomarker of tau protein that can be detected in the blood, is increased in preclinical Alzheimer’s disease and may have clinical utility for the early detection of brain pathology.
SOURCE: Janelidze S, Berron D, Smith R, et al. Associations of plasma phospho-tau217 levels with tau positron emission tomography in early Alzheimer disease. JAMA Neurol 2021;78:149-156.
For the past decade, the National Institute on Aging/Alzheimer’s Association diagnostic criteria have described a broad spectrum of Alzheimer’s disease (AD). AD begins at least 20-30 years before the first symptoms occur, and these criteria divide AD into three distinct stages: Stage 1 refers to AD pathology starting in the brain without symptoms (pre-clinical AD); stage 2 refers to mild memory loss, but the person still can perform all of their usual daily activities (mild cognitive impairment [MCI] because of AD); and stage 3 refers to dementia caused by AD. Eventually, effective treatments will be best positioned to have a positive effect if initiated at a preclinical or prodromal stage to offer the most clinically meaningful neuroprotection. As such, it is of pressing need to have cost-effective and minimally invasive biomarker tests to help diagnose the earliest stages of AD. Beginning in 2017-2018, multiple research groups first reported reductions in the serum Aβ42:Aβ40 ratio in patients with brain amyloid. In 2020, plasma phospho-tau181 (P-tau181) was found to predict future progression to dementia caused by AD with high accuracy in patients without dementia. A new study by Janelidze and colleagues aimed to determine whether another serum tau marker (P-tau217) also may be a potential early biomarker of AD.
In this study, 490 subjects with a mean age of 65.9 years (standard deviation, 13.1 years) were included from the Swedish BioFINDER-2 study. Plasma P-tau217 was measured in 314 cognitively normal subjects and 176 subjects with MCI caused by AD. All subjects also underwent cerebrospinal fluid (CSF) amyloid and tau biomarker studies, and amyloid and tau positron emission tomography (PET) brain imaging.
The study found that plasma P-tau217 levels were increased in cognitively normal subjects with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (ERC). This was an important finding, since prior research has found that increases in biofluid P-tau217 precede changes in tau-PET in the ERC, which is an early region of neurofibrillary tangle formation. In this group, most patients who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET, which is consistent with the sequence of pathological progression. Event-based modeling predicted that in cognitively unimpaired subjects, and in those with MCI caused by AD, both plasma and CSF P-tau217 would change before the tau-PET signal in the ERC, followed by more widespread cortical tau-PET changes.
COMMENTARY
These results suggest that plasma P-tau217 becomes abnormal before tau-PET and that plasma P-tau217, thus, may be considered as an early biomarker for AD. The findings also add supportive evidence that fluid biomarkers can detect Aβ-triggered changes in tau phosphorylation and secretion. These types of changes likely precede the aggregation of hyperphosphorylated tau into paired helical filaments (that form the characteristic neurofibrillary tau tangles) and also bind PET tracer ligands.
For decades, clinicians have used serum lipid biomarkers (e.g., low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides) to evaluate cardiovascular (CV) risk and measure the effect of pharmacological and lifestyle-based treatments. CV serum tests also have evolved to detect even earlier preclinical stages of atherosclerotic disease (e.g., non-HDL-cholesterol [non-HDL-C] and apolipoprotein B [Apo B]). The future of AD soon will hinge on a parallel path. For example, a recent study reported that increased non-HDL-C in adolescence (ages 12-18 years) had the strongest association with atherosclerotic CV disease in midlife, and it seems only a matter of time for AD to be recognized in a similar way. From a practical clinical perspective, in the coming years serum biomarker tests, such as P-tau217, serum Aβ42:Aβ40 ratio, and others (neurofilament light), will emerge as tools more commonly available in both research and clinical settings. Although current lab specimen processing practices make it difficult for rapid adoption in the clinic setting (e.g., the need for rapid centrifugation, freezing of samples, or immediate need to mail on dry ice), experts in the field remain optimistic that a multi-biomarker panel to risk stratify and follow the longitudinal trajectory of patients in the earliest AD stages is within reach. Similar to CV disease, using these biomarkers not only for early diagnosis but also to evaluate therapeutic response to targeted interventions is a natural step forward for adoption in clinical practice.
