. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer's disease: a longitudinal cohort study. Mol Psychiatry. 2020 Jul 14; PubMed.

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  1. In this study of P-tau181 and NfL in plasma of familial Alzheimer’s disease, O’Connor et al. leverage an in-house-developed P-tau181 assay and commercial Quanterix NF-Light assay. This NfL assay is widely used. The P-tau181 assay, although new, is gaining more widespread interest.

    There are small differences, less than twofold, between noncarriers and presymptomatic carriers indicating the changes occur prior to the development of obvious clinical symptoms. The levels are even higher in symptomatic carriers, but here age differences may account for some of the NfL difference. The P-tau181 difference in symptomatic carriers vs noncarriers is 2.44-fold and NfL-3.25 fold. 

    The study is small, but the differences in NfL are comparable to what has been shown in serum NfL measurements. The longitudinal data in P-tau181 is confounded by large within-person changes. Additional work will need to evaluate the factors that affect the levels of P-tau181 in plasma. Overall, the study by O’Connor et al. supports additional research of P-tau181 and NfL in preclinical AD.

  2. The paper describes changes in plasma concentrations of P-tau181 in familial Alzheimer’s disease. The authors found that similar to plasma NfL, the P-tau181 concentrations started to increase around 15 years prior to symptom onset. The unadjusted concentrations of P-tau181 were increased 1.7 times in 24 presymptomatic individuals and 2.4 times in 19 symptomatic cases when compared to seven noncarriers. The corresponding values for plasma NfL were 1.5 and 3.3, respectively.

    The study provides evidence that plasma P-tau181 might be a marker that can detect early changes in tau metabolism in familial Alzheimer’s and that it might be used in longitudinal clinical trials evaluating the effects of new treatments on tau pathology. However, as the authors note, the intra-individual variability of plasma P-tau181 concentrations over time needs to be better understood. Further, other tau species, such as P-tau217 and P-tau231, should be studied in this context.

  3. This paper provides further evidence that plasma ptau181 may be an excellent blood-based biomarker for Alzheimer disease brain pathology and symptomatic status.

    Interestingly, the investigators found very high intra-individual variation in p-tau181 levels. This is concerning, as it means that an individual could conceivably have a “positive” test one day and a “negative” test shortly thereafter. Further development of plasma ptau181 as an AD biomarker will require understanding and controlling for this variability.

    The authors also examined plasma NfL levels in the same samples, and it appeared that NfL performed well in distinguishing the three groups. It would be interesting to directly compare the performance of ptau181 and NfL in distinguishing these groups, and whether combining these measures improves prediction of EYO and/or symptomatic status. 

  4. This study involved persons with dominantly inherited Alzheimer disease mutations who donated plasma samples. The key finding was that ptau181 levels were elevated in both symptomatic and asymptomatic individuals and, in particular, modeling indicated that ptau181 levels began to rise in asymptomatic individuals as long as 16 years prior to estimated onset.

    It’s remarkable that these increases were present in plasma. Detecting a prodromal biochemical change in plasma is one step toward assigning risk for future symptomatic cognitive impairment using a minimally invasive and inexpensive technique. 

    From a conceptual perspective, these observations are another example of the very long prodromal biochemical phase of Alzheimer disease. To the extent that accumulation of brain neurofibrillary tangle pathology outside the medial temporal lobe is generally an event close in time to the onset of symptomatic disease, the fact that there are changes in tau protein trafficking sufficient to leak out into plasma more than a decade before symptom onset suggests that dysfunction in the tau pathway percolates for a long time prior to symptom onset.

    Whether these same phenomena occur in sporadic late-onset Alzheimer disease remains to be demonstrated, but is an important area to be investigated.

  5. Though we have made substantial progress in characterizing the behavior of biochemical and imaging biomarkers in presymptomatic and manifest Alzheimer’s disease, we still need an inexpensive and noninvasive index for the presence of AD pathology and its change over time. Measurements of Aβ species, total tau protein, tau phosphorylated at specific residues, and other molecules in the cerebrospinal fluid (CSF) have been shown to reflect cerebral AD pathology fairly reliably.

    Plasma, though more easily accessible, is a much more complicated milieu. In addition to being further removed from the central nervous system, it is composed of many more metabolites and proteins in higher concentrations than CSF, with those from brain represented at lower concentrations. Interactions with these other molecules, as well as metabolism in the liver and elimination by the kidneys, all potentially influence the levels of a given substance in plasma.

    Nonetheless, a sensitive plasma assay for tau phosphorylated at threonine 181, which specifically identifies p-tau181 derived from brain, was recently shown to reflect developing AD pathology across the spectrum of disease as well as distinguish it from non-AD pathology with AUCs of greater than 81 percent (Karikari et al., 2020). 

    In this article, O’Connor applied this assay in both cross-sectionally (n = 70 participants) and longitudinally (n = 38 participants) collected plasma samples obtained from persons with or at risk for inheriting pathogenic autosomal dominant Alzheimer’s disease (ADAD) mutations. Studying biomarker changes in this population enables the sensitive identification of AD pathology in presymptomatic persons in whom the future development of AD can be reliably predicted. They found differences between presymptomatic ADAD mutation carriers (mean age of seven years prior to estimated age of symptom onset) and noncarriers with an AUC of 86 percent and between symptomatic ADAD mutation carriers and noncarriers with an AUC of 93 percent, with the level being highest among symptomatic persons. The difference between mutation carriers and noncarriers emerged approximately 16 years before the estimated age of symptom onset, though the authors admit that this estimated age of onset is an imperfect measure. This was roughly the same time point at which measurements of neurofilament light change (NfL) in plasma, a less-specific marker of neuronal damage, differentiated the groups.

    When the investigators looked at the correlation between plasma p-tau181 levels and clinical and cognitive measures, they found correlations with the CDR-SOB scores, a global measure of clinical status among symptomatic persons and with a measure of memory function among asymptomatic persons. In additional analyses, no differences were found between carriers of APP and PSEN mutations, though differences were found among symptomatic carriers of PSEN1 mutations with persons with mutations beyond codon 200 having the highest levels, consistent with prior studies showing more severe neuropathology in this group. These are important observations, as it is important to begin to differentiate the behavior of biomarkers among different subtypes of AD.

    In this study, there was great intra-individual variability in p-tau181 levels in persons providing longitudinal samples, with one subject being excluded in light of having a value 10 times that controls. Factors such as time of day and hydration status of participants were not controlled for, indicating that further studies of non-CNS factors affecting plasma p-tau181 levels are necessary prior to its implementation as a diagnostic measures or as an outcome in clinical trials or other longitudinal studies.

    In conclusion, in this study the investigators verified that changes in plasma p-tau181 are indeed identifiable in the preclinical stage of AD in a young population with what can be described as a “pure” form of AD not confounded by the other pathology of aging. As such, it extends the findings of Karikari et al. to another subtype of what can be considered the Alzheimer's diseases. However, given the overlap in values between groups and the observed intra-subject variability, further work is needed to understand additional factors determining the levels of p-tau181 in plasma and to establish if the simultaneous measurement of other substances (e.g., Aβ species) is necessary for optimal diagnostic and prognostic precision.

    References:

    . Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020 May;19(5):422-433. PubMed.

  6. This excellent study by O’Connor et al. shows the timing of changes of the main Alzheimer’s disease blood biomarkers, namely p-tau181 and neurofilament light. The authors investigate individuals carrying a familiar Alzheimer’s disease (FAD) mutation and their noncarrier relatives. Studying FAD provides a unique opportunity to study Alzheimer’s disease in its preclinical stages and to determine the trajectories of markers during the natural course of the disease. In my view, the main result of the study is that plasma p-tau181 and neurofilament light start to increase in FAD 16 and 17 years before symptom onset, respectively. These results are similar to those of CSF p-tau181 and CSF neurofilament light, highlighting the readability of these blood biomarkers. Moreover, plasma p-tau181 very accurately discriminates between symptomatic carriers and noncarriers and, importantly, between presymptomatic carriers seven years before the estimated symptom onset and noncarriers.

    This study is very timely since the development of blood biomarkers has become a priority in the field and several recent exciting developments have occurred in the last months. Plasma p-tau181 is probably the most promising blood biomarker for AD and can discriminate symptomatic AD from other neurological diseases and healthy controls (Janelidze et al., 2020; Karikari et al., 2020; Thijssen et al., 2020). These studies included some individuals with preclinical sporadic Alzheimer’s and showed a significant increase in plasma p-tau181, but not as high as that observed in symptomatic cases. In this work, O’Connor et al. clearly show that there is a significant increase of plasma p-tau181 in presymptomatic FAD. If these exciting results are confirmed in larger cohorts of asymptomatic sporadic Alzheimer, plasma p-tau181 may be used in the very near future as a biomarker for detecting preclinical Alzheimer’s in primary care, selecting individuals to test therapeutic interventions or, eventually, triaging for preclinical Alzheimer’s at the population level.

    Congrats to the UCL and University of Gothenburg teams!

    References:

    . Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med. 2020 Mar;26(3):379-386. Epub 2020 Mar 2 PubMed.

    . Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020 May;19(5):422-433. PubMed.

    . Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med. 2020 Mar;26(3):387-397. Epub 2020 Mar 2 PubMed.

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