Quiroz YT, Sperling RA, Norton DJ, Baena A, Arboleda-Velasquez JF, Cosio D, Schultz A, Lapoint M, Guzman-Velez E, Miller JB, Kim LA, Chen K, Tariot PN, Lopera F, Reiman EM, Johnson KA. Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease. JAMA Neurol. 2018 May 1;75(5):548-556. PubMed.

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  1. This is a unique study examining ADAD individuals with a single-gene (PSEN1) mutation. The well-characterized age of onset for mild cognitive impairment (MCI) and Alzheimer’s disease in the participants allowed for a crucial temporal assessment of Aβ and tau. Findings suggested elevated levels of neocortical Aβ occur over a decade prior to clinical symptoms (similar to reports in late-onset AD) and tau deposition occurs approximately six years prior to MCI onset. This study adds to a growing appreciation for the utility of biomarkers in identifying preclinical AD. The strong association between tau pathology and cognitive measures is of particular interest: Tau may add staging information indicative of the magnitude of change on clinical endpoints.

    View all comments by Samantha Burnham

  2. There are two big reasons I like this paper and think it will shape research to come, not only in ADAD but also in LOAD.

    First, it was very interesting to see how multimodal amyloid and tau PET biomarkers were associated with each other, with cognitive testing data, and with age/estimated year of onset in the Colombian (PSEN1 E280A) AD kindred. Quiroz and colleagues have nicely shown, using in vivo imaging, that in PSEN1 mutation carriers, amyloid pathology likely precedes tau pathology in the neocortex, and that after tau appears in the cortex that both measures continue to increase with respect to each other and to reduced cognitive performance. This helps us to better understand the preclinical trajectory of this early onset, autosomal-dominant disease, which is tightly linked to amyloid overproduction as its driving force.

    However, what I find most interesting about this article is how it sets the stage for understanding how the older adult brain is besieged by multiple co-occurring disease processes—not just amyloid pathology—in late life. With advancing age, people present more often with not just amyloid and tau pathology but also vascular disease and other proteinopathies. While there are differences between ADAD and LOAD, results like those presented here (e.g., Figs. 1 and 2) help demonstrate the background of amyloid-driven, tau-mediated neurodegeneration that may be present in patients with LOAD but may interact with other injurious processes to negatively impact cognition and function. This enables us to better investigate, for example, how elevated vascular risk factors may contribute to tau pathology in late life above and beyond the contributions of amyloid pathology.

    What I would be excited to see in terms of next steps are (1) a simultaneous examination of these ADAD carriers against LOAD patients with similar disease stage (e.g. CDR = 0.5) to directly compare PET patterns and other biomarkers, and (2) the associations between amyloid, tau, cognition, and MRI measures of neurodegeneration in this cohort.

    View all comments by Samuel Lockhart

  3. The authors are right to caution readers about the limitation of extrapolating this autosomal-dominant AD (ADAD) data to late-onset AD (LOAD). It is also a relatively small study of just 12 Presenilin 1 E280A mutation carriers and 12 noncarriers. Nevertheless, the findings are strikingly consistent with prospective and retrospective studies of LOAD and other studies of ADAD. Namely, the finding that Aβ pathology is apparent approximately 15 years prior to symptom onset, and tau pathologies are apparent approximately six years prior to symptom onset, is consistent with other studies in LOAD. The importance of this consistency is to support our hope that future findings in ADAD might translate to LOAD and vice versa.

    Clearly there is more variability in the age of onset in LOAD than in ADAD, but some variability still exists in ADAD. This suggests that the correlation between years to symptom onset and pathology would be even stronger than the correlation between age and pathology. We might see this borne out in future studies with longitudinal data in this cohort and others. And ongoing efforts to improve the estimation of years to symptom onset, e.g. “latent disease time,” might facilitate more useful comparisons of LOAD and ADAD (Li et al., 2017).

    References:

    Li D, Iddi S, Thompson WK, Donohue MC, Alzheimer’s Disease Neuroimaging Initiative. Bayesian latent time joint mixed effect models for multicohort longitudinal data. Stat Methods Med Res. 2017 Jan 1;:962280217737566. PubMed.

    View all comments by Michael C. Donohue

  4. To me, one of the most interesting results of this exciting study is the clear initial appearance of tau in the medial temporal lobe without notable neocortical tau. Although the medial temporal lobe has long been recognized as the initial site of tau pathology in sporadic AD (Braak and Braak, 1991), this does not necessarily have to translate to genetically determined forms of the disease. While there is accumulating evidence that genetically determined and sporadic forms of AD follow similar pathogenetic trajectories when observed on global biomarker levels (i.e., amyloid then tau then neurodegeneration), there may be important regional differences in the onset and evolution of the different types of pathology. For example, studies analyzing amyloid-PET data on a regional level have reported a very early striatal amyloid deposition in autosomal-dominant AD that appears before the occurrence of neocortical amyloid (Klunk et al., 2007). This is in striking contrast to the late-stage striatal involvement in established amyloid-staging schemes for sporadic AD (Thal et al., 2002), which we could recently reproduce using a PET-based in-vivo staging approach (Grothe et al., 2017). 

    Moreover, recent data from the DIAN study indicates that neurodegeneration as measured by structural MRI, which tends to follow the regional pattern of tau accumulation with some temporal delay, may manifest first in the precuneus in this cohort (Gordon et al., 2018). Yet the present data by Quiroz et al. suggest that the analyzed PSEN1 mutation carriers show a very similar regional spread of tau pathology, from an initially affected medial temporal lobe to inferior temporal and posterior parietal neocortical areas, as would be expected from sporadic AD. The observation of frequent medial temporal tau deposits in elderly individuals without any evidence of amyloid pathology, a phenomenon termed primary age-related tauopathy, has raised questions as to the general relation between medial temporal tau accumulation and AD pathology (Jellinger et al., 2015; Duyckaerts et al., 2015). 

    In this context it has been proposed that it is the additional amyloid pathology in AD that drives tau out of the medial temporal lobe and into neocortical areas. The PSEN1 mutation that characterizes the analyzed cohort of the present study is causally linked to an aberrant cellular metabolism of Aβ, and thus any tau deposits observed in these mutation carriers at this young age can be reasonably assumed to be a direct downstream consequence of the primary amyloid pathology. This underlines the high potential of cerebral amyloidosis to facilitate the accumulation of medial temporal tau pathology, even in the absence of initial age-related tau changes to act upon. Given the strikingly low levels of amyloid deposits in the medial temporal lobe in both autosomal-dominant and sporadic forms of AD, this effect is likely to be mediated by remote mechanisms that remain to be elucidated.

    References:

    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.

    Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.

    Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.

    Grothe MJ, Barthel H, Sepulcre J, Dyrba M, Sabri O, Teipel SJ, Alzheimer's Disease Neuroimaging Initiative. In vivo staging of regional amyloid deposition. Neurology. 2017 Nov 14;89(20):2031-2038. Epub 2017 Oct 18 PubMed.

    Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, Christensen J, McDade E, Wang G, Xiong C, Cairns NJ, Hassenstab J, Marcus DS, Fagan AM, Jack CR Jr, Hornbeck RC, Paumier KL, Ances BM, Berman SB, Brickman AM, Cash DM, Chhatwal JP, Correia S, Förster S, Fox NC, Graff-Radford NR, la Fougère C, Levin J, Masters CL, Rossor MN, Salloway S, Saykin AJ, Schofield PR, Thompson PM, Weiner MM, Holtzman DM, Raichle ME, Morris JC, Bateman RJ, Benzinger TL. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study. Lancet Neurol. 2018 Mar;17(3):241-250. Epub 2018 Feb 1 PubMed.

    Jellinger KA, Alafuzoff I, Attems J, Beach TG, Cairns NJ, Crary JF, Dickson DW, Hof PR, Hyman BT, Jack CR Jr, Jicha GA, Knopman DS, Kovacs GG, Mackenzie IR, Masliah E, Montine TJ, Nelson PT, Schmitt F, Schneider JA, Serrano-Pozo A, Thal DR, Toledo JB, Trojanowski JQ, Troncoso JC, Vonsattel JP, Wisniewski T. PART, a distinct tauopathy, different from classical sporadic Alzheimer disease. Acta Neuropathol. 2015 May;129(5):757-62. Epub 2015 Mar 17 PubMed.

    Jellinger KA, Alafuzoff I, Attems J, Beach TG, Cairns NJ, Crary JF, Dickson DW, Hof PR, Hyman BT, Jack CR Jr, Jicha GA, Knopman DS, Kovacs GG, Mackenzie IR, Masliah E, Montine TJ, Nelson PT, Schmitt F, Schneider JA, Serrano-Pozo A, Thal DR, Toledo JB, Trojanowski JQ, Troncoso JC, Vonsattel JP, Wisniewski T. PART, a distinct tauopathy, different from classical sporadic Alzheimer disease. Acta Neuropathol. 2015 May;129(5):757-62. Epub 2015 Mar 17 PubMed.

    View all comments by Michel Grothe

  5. Quiroz and colleagues provide the first report of AV1451 tau-PET in a cohort of at risk for autosomal-dominant Alzheimer's disease (ADAD) related to the PSEN1 E280A mutation. By studying mutation carriers at various stages of the disease cascade (amyloid-negative, amyloid-positive/asymptomatic, symptomatic) they provide one of the first comprehensive views of the pattern of AV1451 binding in ADAD. Importantly, this work supports many of the studies in sporadic AD by indicating that AV1451 binding is absent in those without fibrillar Aβ plaques, and that once symptoms begin, AV1451 binding increases in limbic/paralimbic cortices and then spreads to heteromodal cortices with increased symptoms. Besides being able to track AV1451 pathology across the AD spectrum with a small number of participants (24), this work clearly highlights the complexity of tau-related pathology and biology in AD. Specifically, previous work in this same population has suggested that CSF tau and p-tau increase up to 15 years before anticipated symptoms (Fleisher et al., 2015), but AV1451 only six years before. This work highlights the importance of considering the different measures of tau pathology as related, but distinct.

    One limitation of this study was the restriction of regional AV1451 (F18 FTP) to the inferior temporal regions when examining the association with cortical PiB-PET and neuropsychological measures. The voxel-wise comparison of AV1451 between mutation carriers and noncarriers (as well as symptomatic and asymptomatic mutation carriers) indicated important differences in AV1451 binding in areas outside of the inferior temporal lobes as well. Therefore, it is possible additional findings between regional AV1451 and cognition or fibrillar amyloid may have been identified, or had stronger correlations with regions like the posterior-cingulate and precuneus. This is particularly important to consider, as preliminary data from the DIAN study indicates the precuneus as a region with early and robust AV1451 binding (Benzinger et al., 2016). With increased numbers of participants from this cohort and in the DIAN study, the differences and similarities between ADAD and sporadic AD as it relates to neurofibrillary tau pathology will become clearer.

    References:

    Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W, Ayutyanont N, Lopez L, Moreno S, Muñoz C, Tirado V, Acosta-Baena N, Fagan AM, Giraldo M, Garcia G, Huentelman MJ, Tariot PN, Lopera F, Reiman EM. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015 Mar;72(3):316-24. PubMed.

    View all comments by Eric McDade

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This paper appears in the following:

News

  1. In Familial Alzheimer’s, Tau Creeps into Cortex as Symptoms Show
  2. Aβ, Then Metabolism, Then Atrophy: In Familial AD, Cascade is Definitive

Mutations

  1. PSEN1 E280A (Paisa)