. Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers. JAMA Neurol. 2022 Aug 1;79(8):797-807. PubMed.

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  1. Plasma p-tau217 is currently considered the most promising blood-based biomarker of brain tau pathology. The paper by Janelidze et al. demonstrates that this is also the case with DS-related AD (DSAD) while also providing yet another example of how DSAD is similar to autosomal-dominant AD and late-onset AD. The results are part of a collaboration between the ABC-DS and Oskar Hansson’s laboratory. They show that a composite measure of p-tau217 and age showed excellent accuracy (AUC > 0.95) for distinguishing participants with DS having abnormal tau-PET scans from those with normal tau-PET scans. Moreover, increasing levels of plasma p-tau217 were found to be associated with lower cognitive performance as measured by the DS-MSE and CRT.

    We first reported a correlation between cognitive decline and tau pathology as measured by PET imaging in a small cohort of adults with DS (Rafii et al., 2017). This relationship between tau pathology on PET imaging and cognitive decline has recently been confirmed using the larger cohort in ABC-DS (Hartley et al., 2022). The prospect of being able to accurately stage individuals with DS within the A/T/N framework using plasma p-tau217 is a major advance in the field and sets the stage for more efficient clinical trials.

    References:

    . PET Imaging of Tau Pathology and Relationship to Amyloid, Longitudinal MRI, and Cognitive Change in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI). J Alzheimers Dis. 2017;60(2):439-450. PubMed.

    . Role of tau deposition in early cognitive decline in Down syndrome. Alzheimers Dement (Amst). 2022;14(1):e12256. Epub 2022 Apr 1 PubMed.

    View all comments by Michael Rafii
  2. The new aspect of Janelidze et al. is that plasma p-tau217 is as accurate a marker of Aβ and tau PET-detected pathology in DS as it is in late-onset AD. As in all studies, a plasma measure is much more accessible and less expensive and invasive than PET. While true in LOAD also, the even more important point in DS is that prospective trial participants or, ultimately, patients with DS, are often less willing or able to tolerate PET and MRI scans. Thus, accurate plasma biomarkers of AD are even more important in DS than in LOAD.

    This paper fits together with the other three to paint the picture that, while there may be some differences between AD pathology in LOAD and DS that can be detected at autopsy (although this was a small study of 11 subjects), biomarker findings are similar in DS and LOAD. That is, Aβ can be detected very early and is related to the progression of tau deposition, which is related to cognitive decline, and plasma p-tau-217 is a good proxy for more difficult and less-accessible PET biomarkers—the latter being more important in DS than LOAD.

    View all comments by William Klunk
  3. Individuals with Down’s syndrome are predisposed to Alzheimer's disease, and greater than 90 percent of these individuals will develop AD pathological changes. Despite these statistics, the progression of AD in individuals with Down’s syndrome remains severely understudied, and we as researchers have a moral obligation to help this population. The Alzheimer's Biomarker Consortium-Down’s Syndrome (ABC-DS), the world’s largest Down’s syndrome research cohort aimed at studying preclinical AD progression, has set out to evaluate the early stages of AD progression through a combination of neuroimaging, neuropsychological analysis, and analysis of fluid-based AD biomarkers. The findings from the ABC-DS study will greatly help inform the recruitment of individuals with Down’s syndrome into AD clinical trials.

    The study of Hartley et al. identifies that neurofibrillary tau is the driving factor of cognitive decline in individuals with Down’s syndrome based on neuroimaging and neuropsychological data. This is important because tau-based neuronal degeneration is speculated as the primary source of cognitive decline during AD in the general population. Due to the similarities, we can infer that novel AD treatments aimed at tau clearance would benefit both the general population and individuals with Down’s syndrome.

    Ichimata et al. focus on case studies from postmortem individuals with Down’s syndrome. While the sample size was small, they find that AD pathology was consistent in all cases. There were some cases in which other non-AD pathologies were noted, and these pathologies would be of interest to study during the lifetime of these individuals.

    My study (Zammit et al., 2021) is strictly a neuroimaging-based look at the progression of amyloid and tau in Down’s syndrome. For a time, it was speculated that there was a moderate latency period between amyloid and tau deposition during AD progression. However, through advancement in PET image quantification techniques, we found that tau begins to spread during the early stages of amyloid progression. Because of this, individuals with Down’s syndrome would greatly benefit from early intervention treatments targeting both amyloid and tau in the hope of hindering or preventing the onset of AD dementia.

    The most recent study of Janelidze et al. is the first to evaluate the novel blood-based biomarker, plasma p-tau217, in the Down’s syndrome population. Plasma p-tau217 is a very accurate and sensitive measure of neurofibrillary tau, and the collection of p-tau217 is much less invasive compared to obtaining CSF measures of tau. P-tau217 is speculated as a very early indicator of AD progression and can simplify the AD screening process for clinical trials. Because the Down’s syndrome population would greatly benefit from early intervention studies, as noted in the above studies, collection of p-tau217 would greatly facilitate their recruitment.

    References:

    . Role of tau deposition in early cognitive decline in Down syndrome. Alzheimers Dement (Amst). 2022;14(1):e12256. Epub 2022 Apr 1 PubMed.

    . Patterns of Mixed Pathologies in Down Syndrome. J Alzheimers Dis. 2022;87(2):595-607. PubMed.

    . Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome. Neuroimage Clin. 2021;31:102740. Epub 2021 Jun 24 PubMed.

    View all comments by Matthew Zammit
  4. The characterization of blood-based biomarkers not only is important for clinical practice and in preventive clinical trials as outcome measures, but they also shed light on possible underlying mechanisms of disease. The paper by Janelidze et al. describes a cross-sectional study in a reasonably sized cohort of people with Down’s syndrome (DS). It identifies p-tau217 (allowing for age) as a promising plasma biomarker of brain tauopathy as measured by PET, and shows a good correspondence to amyloid (A+/-) and tau (T+/-) staging.

    The study shows that some other popular candidate biomarkers including NfL appear to be less sensitive. Biomarkers can obviate the need for PET, keeping costs low.

    The paper also shows that GFAP, which is a marker of astroglial injury and which has been shown to associate well with the degree of brain injury post-trauma, is another correlate of pathology in the DS cohort. Astrocytes are likely to be playing an important role in disease progression, not just because of the overexpression of S100B (located on the triplicated chromosome-21 of DS), but also because of the likely immune activation.

    Future longitudinal studies will indicate the degree of closeness with specific pathology. The study also provides further evidence of the heterogeneity amongst the “genetic forms of AD” (familial autosomal-dominant AD, and the DS group) and late-onset or sporadic AD. Although in the late-onset forms of AD age-dependent confounds and co-occurring pathologies occur more frequently, neuropathology case studies of DS increasingly recognize some degrees of variations of the regional distribution of tau or amyloid and pathologies such as Lewy bodies and TDP-43 (Ichimata et al., 2022Davidson et al., 2018). 

     

    References:

    . Patterns of Mixed Pathologies in Down Syndrome. J Alzheimers Dis. 2022;87(2):595-607. PubMed.

    . The age of onset and evolution of Braak tangle stage and Thal amyloid pathology of Alzheimer's disease in individuals with Down syndrome. Acta Neuropathol Commun. 2018 Jul 4;6(1):56. PubMed.

    View all comments by Shahid Zaman

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  1. Trisomy 21