A blood test that may eventually be done in a doctor’s office can swiftly reveal if a patient with memory issues has Alzheimer‘s disease or mild cognitive impairment and can also distinguish both conditions from frontotemporal dementia.
If approved, the blood test could lead to a jump in the number of Alzheimer’s patients enrolling in clinical trials and be used to monitor response to those investigational treatments.
In a study led by UC San Francisco, researchers measured blood levels of phosphorylated tau 181 (pTau181), a brain protein that aggregates in tangles in patients with Alzheimer’s.
They found that pTau181 was 3.5-times higher in people with the disease compared to their healthy peers.
In contrast, in patients with frontotemporal dementia, a condition that is often misdiagnosed as Alzheimer’s, pTau181 was found to be within the same range as the control group.
The study publishes in Nature Medicine on March 2, 2020.
“This test could eventually be deployed in a primary care setting for people with memory concerns to identify who should be referred to specialized centers to participate in clinical trials or to be treated with new Alzheimer’s therapies, once they are approved,” said senior author Adam Boxer, MD, Ph.D., of the UCSF Memory and Aging Center.
Being able to easily diagnose Alzheimer’s disease at early stages may be especially beneficial to patients with mild cognitive impairment, some of whom may have early Alzheimer’s disease.
Individuals with early Alzheimer’s are more likely to respond to many of the new treatments that are being developed.”
Current Alzheimer’s Testing Expensive, Invasive
Existing methods for diagnosing Alzheimer’s include measurement of the deposits of amyloid, another protein implicated in dementia, from a PET scan; or using lumbar puncture to quantify amyloid and tau in cerebrospinal fluid.
PET scans are expensive, only available in specialized centers and currently not covered by insurance, and lumbar punctures are invasive, labor intensive and not easy to perform in large populations, the authors noted.
There are 132 drugs in clinical trials for Alzheimer’s, according to a 2019 study, including 28 that are being tested in 42 phase-3 trials – the final part of a study before approval is sought from the federal Food and Drug Administration.
Among those phase-3 drugs is aducanumab, which some experts believe may be the first drug approved to slow the progression of Alzheimer’s.
In the study, participants underwent testing to measure pTau181 from plasma, the liquid part of blood. They were aged from 58 to 70 and included 56 who had been diagnosed with Alzheimer’s, 47 with mild cognitive impairment and 69 of their healthy peers.
Additionally, participants included 190 people with different types of frontotemporal dementia, a group of brain disorders caused by degeneration of the frontal and temporal lobes, areas of the brain associated with decision-making, behavioral control, emotion and language. Among adults under 65, frontotemporal dementia is as common as Alzheimer’s.
Blood Test Measures Up to Established Tool
The researchers found that blood measures of pTau181 were 2.4 pg/ml among healthy controls, 3.7 pg/ml among those with mild cognitive impairment and 8.4 pg/ml for those with Alzheimer’s.
In people with variants of frontotemporal dementia, levels ranged from 1.9 to 2.8 pg/ml. These results gave similar information to the more established diagnostic tools of PET scan measures of amyloid or tau protein, Boxer said.
The study follows research by other investigators published last year that found high levels of plasma amyloid were a predictor of Alzheimer’s.
However, amyloid accumulates in the brain many years before symptoms emerge, if they emerge, said Boxer, who is affiliated with the UCSF Weill Institute for Neurosciences.
“In contrast, the amount of tau that accumulates in the brain is very strongly linked to the onset, the severity and characteristic symptoms of the disease,” he said.
A companion study by Oskar Hansson, MD, Ph.D., of Lund University, Sweden, published in the same issue of Nature Medicine corroborated the results of the UCSF-led study. It concluded that pTau181 was a stronger predictor of developing Alzheimer’s in healthy elders than amyloid.
The researchers said they hope to see the blood test available in doctor’s offices within five years.
The neuropathologic hallmarks of Alzheimer disease (AD) are the presence of neuritic amyloid plaques, primarily of the amyloid-β peptide, and the intraneuronal accumulation of neurofibrillary tangles (NFTs) and neuropil threads composed of hyperphosphorylated, aggregated tau protein.1,2
Our understanding of AD has evolved substantially over the past 2 decades, with neuroimaging and fluid biomarkers allowing for early detection of AD-related pathologic abnormalities.3–5
In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1, presenilin 2, or amyloid precursor protein genes. Dominantly inherited AD (DIAD) is considered clinically similar to sporadic AD except for a younger age at onset (AAO).6 Mutation carriers (MCs) have a somewhat predictable age at AD symptom onset.7
Biomarker studies6,8 have contributed to hypothesized trajectories of fluid and imaging biomarker changes that occur over the course of the disease, from the preclinical phase to the end stages characterized by advanced dementia.
However, models of biomarker change in AD have been based mostly on cross-sectional data.6,9,10 More recently, many models have classified biomarkers according to their proposed association with the biological underpinnings of the disease; the recent amyloid/tau/neurodegeneration (A/T/N) framework11 was developed to provide a more biological rationale to the classification of the disease.
Phosphorylated tau 181 (pTau181) in the cerebrospinal fluid (CSF) has been suggested to represent NFT pathologic abnormalities, whereas total tau (tTau) in the CSF is thought to be a marker of neurodegeneration that is passively released with cell death or injury.8,12
Given these putative mechanisms, it might be expected that levels of both tTau and pTau181 would continue to become more abnormal with disease progression, as NFT pathologic abnormalities increase and neurodegeneration accelerates.
However, recent longitudinal studies13–17 from the Dominantly Inherited Alzheimer Network (DIAN) and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts have challenged the linear model from previous cross-sectional studies,3,9,18 which have consistently found higher CSF levels of tTau and pTau181 as the disease progresses.
These findings highlight a need for accurate determination of the evolution of longitudinal changes in CSF levels of tTau and pTau181 and their association with disease progression.
In the present study, we assessed the longitudinal pattern of changes in CSF levels of tTau and pTau181 and their association with brain atrophy as measured by magnetic resonance imaging (MRI).
We hypothesized that if CSF tTau and pTau181 were passively released with neurodegeneration, they should be associated with MRI measures of neurodegeneration (eg, rate of atrophy). To evaluate this hypothesis, we used a well-characterized cohort with DIAD from the DIAN study.19
We analyzed data from 465 participants, including 283 MCs (183 [65%] without symptoms and 100 with symptoms) and 182 NCs (Table 1). The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women.
Of the MCs, 213 (75.3%) had presenilin 1 mutations, 22 (7.8%) had presenilin 2 mutations, and 48 (16.9%) had amyloid precursor protein mutations. There were no differences between MCs and NCs in terms of age (mean [SD] age, 37.8 [10.8] vs 37.9 [11.7] years), sex (55.1% vs 58.2% female), educational level (mean [SD] years, 14.3 [3.0] vs 14.8 [2.9]), or the presence of at least 1 apolipoprotein ε4 allele (29.7% vs 30.8%).
The EYO for the entire cohort ranged from 38.2 years before the parental AAO to 22.6 years after the parental AAO; however, to reduce the risk of identifying individual participants at the extremes of the EYO range, we show only the EYO interval of −25 to 10 years.
The NCs had no or very little evidence of AD pathologic abnormalities and almost all (171 [94.0%]) had normal cognition. At baseline, 183 MCs (64.7%) did not have symptoms (CDR score, 0). The CDR scores of the MCs with symptoms ranged from 0.5 (very mild) to 3 (severe) (Table 1). Two or more longitudinal CSF and MRI assessments were available for 160 and 247 participants, respectively (Table 1 and eTable 1 in the Supplement) with a mean (SD) follow-up of 2.7 (1.5) years.Longitudinal Change in CSF tTau and pTau181 Levels
Previous analyses14,17 of this cohort have found that CSF tTau and pTau181 levels were increased in MCs 15 years before expected symptom onset (EYO = −15). We also examined the longitudinal change in CSF tTau and pTau181 levels in terms of annual rate of change across the EYO (Figure 1 and Table 2).
Rates of change for NCs were not significantly different from 0. For MCs, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 near EYO −10 (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and EYO −15 (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively (Table 2).
Importantly, the longitudinal rates of change of CSF tTau and pTau181 levels depended on where the participant fell with respect to their EYO, and the pattern of change over the AD course was different for tTau and pTau181. Specifically, the positive rate of change of tTau gradually increased until EYO −10 and then remained constant after symptom onset (mean [SE] rate of change, 5.6 [2.3] for EYO 0, 5.6 [3.2] for EYO 5, and 5.7 [4.4] for EYO 10).
In contrast, the positive rate of change of pTau181 increased in those at early stages of the disease, starting at EYO −15 until EYO −5 (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE] 0.1 [0.3]) and then negative rates of change at EYO 5 (mean [SE], −0.3 [0.4]) and EYO 10 (mean [SE], −0.6 [0.6]) (Table 2), resulting in overall lower levels of pTau181 at later stages of disease.Longitudinal Change in Brain Volumes
The A/T/N framework uses CSF tTau levels and/or structural MRI measurements as a marker of neurodegeneration, so we sought to determine whether CSF tTau could be used as a suitable biomarker to track MRI atrophy rate. For MRI measurements in MCs, the individual annual rate of change in precuneus thickness started to show a difference from 0 approximately 20 years before expected symptom onset (mean [SE] rate of change, −0.008 [0.003]), followed by rate of change in hippocampal volume (mean [SE] rate of change, −53.5 [17.9]), entorhinal thickness (mean [SE] rate of change, −0.015 [0.007]), and superior-frontal thickness (mean [SE] rate of change, −0.010 [0.004]) around EYO −15. The longitudinal rate of change for all measured brain ROI increased 5 years before symptoms appeared (EYO −5) and followed a similar trend through the disease (Table 2 and Figure 1). For all ROIs included in the analysis, the rate of change followed similar trends.
To visually compare the differences in the trajectories of the rates of change of CSF tTau and pTau181 levels and structural MRI measures, locally estimated scatterplot smoothing curves were constructed for the standardized rate of change as a function of baseline EYO (Figure 2). Notably, after EYO 0, the rate of change became more negative (structures atrophied more quickly), compared with CSF tTau levels, which continued to have a stable positive rate of change.Association Between CSF and MRI Measures of Neurodegeneration
We found differences in nearly all posterior and limbic or paralimibic regions for associations in rates of change with tTau and pTau181 according to stage of disease when comparing MCs without symptoms vs those with symptoms (eTable 2 and eTable 3 in the Supplement).
Figure 3 shows patterns of correlation coefficients between the rates of change of CSF tTau and pTau181 and brain structure stratified by the absence or presence of symptoms (CDR score of 0 vs CDR score >0) and by posterior (early atrophy) and anterior (later atrophy) cortical or subcortical regions.
In individuals without symptoms (CDR score of 0), the rates of change of CSF tTau and pTau181 were inversely correlated with most brain structure measures, where higher CSF tTau levels were associated with smaller cortical thickness. Generally, there were higher correlation coefficients for CSF tTau in the asymptomatic phase and mostly for the posterior neocortical and allocortical (limbic) regions. However, after symptom onset, the correlation between CSF tTau and pTau181 and brain structures changed.
The intensity of neuronal damage as measured by brain atrophy continued at an increasing rate, whereas the rate of change of CSF tTau levels remained at a somewhat constant rate and the rate of change of CSF pTau181 actually switched from positive to negative. These results suggest that CSF tTau and structural brain measures have distinct patterns later in the disease course.Discussion
The use of biomarkers has become an essential component of AD research11,37 and therapeutic trials. The new framework from the National Institute on Aging and Alzheimer Association11 capitalizes on the use of biomarkers for early identification of AD, which has substantial implications for early treatment and trial enrollment. However, little work has been done regarding comparisons of longitudinal biomarker trajectories that are currently proposed to represent similar aspects of disease (eg, CSF tTau and MRI are both proposed as markers of neurodegeneration).38
In this study, on the basis of longitudinal data from the DIAN study,20 we evaluated the trajectories of CSF tTau and pTau181 over the course of AD. Notably, we included a bigger sample and used newer CSF tTau and pTau181 values generated with a fully automated, high-performance electroluminescence immunoassay.
We compared the trajectories of CSF tTau and pTau181 with the atrophy of brain structures as measured by MRI. First, consistent with previous reports,14,39 our study found mean concentrations of CSF tTau and pTau181 to be higher in MCs from the early stage of AD, supporting the use of CSF tau as a marker of AD risk and progression
. Second, we found that the positive rate of change of CSF tTau remained constant after EYO −10, whereas CSF pTau181 had a positive rate of change early in the disease course, which then reversed and became negative later in the disease.
This indicates that our previous results13,14 were not likely to be an artifact of the measurement used because we used a different method for this study. Third, the associations identified between the rates of change of CSF tTau and pTau181 with brain atrophy do not support the assumption that CSF tTau changes follow a pattern similar to that of structural brain changes.
Our findings indicate that neither CSF tTau nor pTau181 has the same pattern of change as brain measures and should be considered as associated but distinct biomarkers in AD. In addition, these findings indicate that, within the current biomarker classification, tTau is an important marker of AD but may not be the ideal marker of neurodegeneration.
Recent studies40,41 have suggested that in the presence of amyloid pathologic abnormalities, more CSF tTau and pTau181 is released. Moreover, increased tau in CSF seems to be dependent of amyloid deposition and occurs in the absence of tau brain pathologic abnormalities.42
Early disease stages may also be characterized by higher cellular stress43,44 and inflammation, with higher levels of tTau and pTau181 in CSF representing a response.45 However, if CSF tTau directly reflected neurodegeneration, it would be expected that the rate of change of CSF tTau would increase in concert with brain atrophy during the period of maximal rate of atrophy (EYO >0).
It is possible that during disease progression and neurodegeneration, the loss of neuronal cells results in less neuronal substrate to produce tau. Although this might account for some of the slowing in longitudinal changes in CSF tTau that we observed, it is unlikely that the degree of neurodegeneration is sufficient to fully explain our findings.
Early elevations may also be associated with acute neuronal membrane damage, whereas apparent later reductions reflect the death of a smaller number of neurons that remain. Acute neuronal injury may be associated with a stronger inflammatory response at early stages of the disease.46
The present findings challenge some previous assumptions about AD progression and its association with both pTau181 and tTau. Contrary to the idea that tTau and pTau181 levels continue to increase with greater neurodegeneration and the spread of NFT,47 we found evidence of a decrease in the rate of change, arguing against the use of these measures as a reflection of a passive release from neuronal death and NFT.
These data support the relevance of CSF tTau and pTau181 as markers of amyloid deposition and accompanying changes (eg, inflammation and neuronal membrane damage)11; however, the complex rates of change identified here and in our previous work suggest that using them as measures of therapeutic response requires further investigation, because levels vary as a function of where an individual is in the neuropathological cascade.
The apparent disconnect between CSF tTau and MRI measures may reflect the fact that they are measuring different stages of the neurodegenerative process, with CSF tTau accounting for the active phase of neuron injury and damage, and MRI measuring the subsequent structural sequelae of the active death process.
Our findings are consistent with previous studies15,38,48–50 of sporadic late-onset AD. Seppälä et al,48 in a longitudinal study in Finland, described higher levels of pTau181 level in mild cognitive impairment stages when compared with AD dementia, whereas levels of pTau181 decreased over a period of about 3 years.
Similarly, Toledo et al38 reported a decrease in tTau in those at the dementia stage from the ADNI cohort. More recently, in a similar analysis of ADNI participants with longitudinal follow-up and using similar methods to determine CSF tTau and pTau181 levels (ie, automated electroluminescence immunoassay), Sutphen et al15 reported that tTau and pTau181 showed consistent increases in the amyloid-positive participants with normal cognition and those with mild cognitive impairment, whereas pTau181 decreased substantially in those with AD dementia.
This study has potential implications for AD trials using tau-based therapies and other putative disease-modifying therapies. First, during trial design, the active group and the placebo group will have to be randomized by disease stage (according to disease severity measured using biomarkers and the severity of cognitive impairment), because minor differences in the neurodegeneration cascade stage might translate into major differences in biomarker trajectories, and as a result, might be misinterpreted as a treatment effect.
Second, one must consider how to interpret changes in biomarkers during clinical trials readout; in other words, one must consider how a successful treatment would be expected to affect CSF tau levels or rate of change. This study, along with recent work assessing neurofilament light chains,51,52 suggests that neurofilament light chains may be an advantageous marker of neurodegeneration in therapeutic trials of AD.52,53
More information: Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration, Nature Medicine (2020). DOI: 10.1038/s41591-020-0762-2 , https://nature.com/articles/s41591-020-0762-2