Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, Garcia G, Villegas A, Sepulveda-Falla D, Villada M, Arboleda-Velasquez JF, Guzmán-Vélez E, Vila-Castelar C, Gordon BA, Schultz SA, Protas HD, Ghisays V, Giraldo M, Tirado V, Baena A, Munoz C, Rios-Romenets S, Tariot PN, Blennow K, Lopera F. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020 Jun;19(6):513-521. Epub 2020 May 26 PubMed.

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  1. This is a very clearly and thoughtfully described study of plasma NfL in the Colombian family with the presenilin-1 E280A mutation. Given the large age range (8 to 75) of this cohort and large number (>2,000) of enrolled mutation carriers (impaired and unimpaired) and age-matched noncarriers of the mutation, and inclusion of more than 400 sets of individual-subject longitudinal data, the study permitted a robust analysis of cross-sectional and longitudinal plasma NfL data with key findings. They are:

    1. plasma NfL increases with age in mutation carriers and noncarriers;
    2. well-defined statistical analyses show that higher NfL plasma concentrations begin to differentiate mutation carriers from non-mutation carriers at about age 22 years, which is 22 years prior to the estimated median age of 44 for the onset of MCI in mutation carriers;
    3. the authors emphatically point out that the sensitivity for detection of Alzheimer’s disease is rather low, estimated to be <60 percent and only reaching clinically meaningful values within about three years from the onset of MCI.

    Interpretation at the older ages is clouded by the overall increases with age of NfL plasma concentrations. Thus at a group level, the increased plasma concentrations of NfL in mutation carriers relative to noncarriers supports the hypothesis that this biomarker shows increased neurodegeneration over time. However, the authors point out it is not a robust test for disease presence or absence in the individual patient.

    This study data contributes in a number of ways to the study data provided by the DIAN study, including the above group-level increases over time in mutation carriers that are higher than in noncarriers and provides additional data by extending the timeline of changes in this genetically defined AD population to that provided by DIAN (Preische et al., 2019) and other ADAD studies, such as that of Weston et al. (2019). 

    Among the added values of this study is its clear and strong support for, and interest in, describing the need for further studies involving NfL in this and other study populations that will include combinations of biofluid and imaging biomarkers in order to assess what are the most useful combinations of biomarkers for disease detection over the continuum of Alzheimer’s disease. That will help to improve detection of disease stage and risk for decline in individual patients.

    The overall wide range of NfL plasma concentrations observed at various times across the wide study timeline can reflect influences of co-pathologic processes such as Lewy body pathology, known to be highly prevalent in ADAD and in sporadic AD. It could also reflect vascular changes such as cerebral amyloid angiography, also known to be prevalent in genetic and sporadic forms of the disease (Toledo et al., 2013; Cairns et al., 2015; Ringman et al., 2016). Other possibilities include the presence or absence of genetic markers such as APOE ε4, and other factors including pre-analytic steps as well as analytical methodology.

    NfL is described in this and other studies as a biomarker of neurodegeneration. This process is not specific for this disease, but is potentially highly valuable in defining this aspect of disease pathology. When combined with a measure of amyloid and of tau pathology, NfL can improve upon assessment of disease stage and predictive performance for future cognitive decline. Future studies are ongoing and needed to define how well plasma NfL reflects neurodegeneration and adds value in prediction of disease state and cognitive decline in the individual patient.  

    References:

    Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Gräber S, Kuder-Buletta E, LaFougere C, Laske C, Vöglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S, Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TL, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M, Dominantly Inherited Alzheimer Network. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019 Feb;25(2):277-283. Epub 2019 Jan 21 PubMed.

    Weston PS, Poole T, O'Connor A, Heslegrave A, Ryan NS, Liang Y, Druyeh R, Mead S, Blennow K, Schott JM, Frost C, Zetterberg H, Fox NC. Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease. Alzheimers Res Ther. 2019 Feb 20;11(1):19. PubMed.

    Toledo JB, Cairns NJ, Da X, Chen K, Carter D, Fleisher A, Householder E, Ayutyanont N, Roontiva A, Bauer RJ, Eisen P, Shaw LM, Davatzikos C, Weiner MW, Reiman EM, Morris JC, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative (ADNI). Clinical and multimodal biomarker correlates of ADNI neuropathological findings. Acta Neuropathol Commun. 2013 Oct 9;1(1):65. PubMed.

    Cairns NJ, Perrin RJ, Franklin EE, Carter D, Vincent B, Xie M, Bateman RJ, Benzinger T, Friedrichsen K, Brooks WS, Halliday GM, McLean C, Ghetti B, Morris JC, Alzheimer Disease Neuroimaging Initiative, Dominantly Inherited Alzheimer Network. Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). Neuropathology. 2015 Aug;35(4):390-400. Epub 2015 May 12 PubMed.

    Ringman JM, Monsell S, Ng DW, Zhou Y, Nguyen A, Coppola G, Van Berlo V, Mendez MF, Tung S, Weintraub S, Mesulam MM, Bigio EH, Gitelman DR, Fisher-Hubbard AO, Albin RL, Vinters HV. Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol. 2016 Mar;75(3):284-90. Epub 2016 Feb 17 PubMed.

    View all comments by Leslie Shaw

  2. This paper shows that, in a very large number of presenilin-1 E280A mutation carriers (Columbian kindred) and age-matched controls, plasma NfL is higher. Statistically, cross-sectional values begin to diverge ~22 years before expected age of onset but assessing these values does not differentiate mutations carriers vs. noncarriers reliably until ~ three years prior to expected age of onset.

    These data are very similar to those reported from the dominantly inherited Alzheimer’s network - DIAN (Preische et al., 2019).  The main differences between the 2 studies were:

    1. The DIAN study assessed people with many different mutations in APP/PSEN1/PSEN2 whereas the Colombian kindred individuals all have the same mutation in PSEN1;
    2. Larger numbers of people were studied in the Columbian kindred than the DIAN study. In the DIAN study, serum NfL rates of change were significantly elevated in mutation carriers relative to noncarriers, and increases became significant at ~16.2 years. It seems likely that the cross-sectional measures in plasma NfL being detected earlier in the Colombian kindred relate to the larger sample size assessed as well as the homogeneity of this sample, all of whom have the same PSEN1 mutation. 

    In general, this and other data in studies of neurodegenerative diseases suggest that serum/plasma NfL is a marker of neurodegeneration that will be useful in prognosis as well as in assessing response to disease modifying therapies.

    References:

    Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Gräber S, Kuder-Buletta E, LaFougere C, Laske C, Vöglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S, Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TL, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M, Dominantly Inherited Alzheimer Network. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019 Feb;25(2):277-283. Epub 2019 Jan 21 PubMed.

    View all comments by David Holtzman

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News

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Mutations

  1. PSEN1 E280A (Paisa)