. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology. 2018 Oct 2;91(14):e1295-e1306. Epub 2018 Sep 14 PubMed.

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  1. Yet another major contribution from DIAN. The investigators conducted a comprehensive longitudinal biomarker study in volunteers around the world who do or do not have autosomal dominant mutations that cause onset of Alzheimer’s symptoms at a generally early age, providing the best picture yet of the temporal sequence of pathological brain changes in autosomal dominant AD (ADAD). Annual rates of Aβ deposition measured by PET distinguished carriers from noncarriers nearly 25 years before the onset of AD symptoms. These were followed by changes in regional glucose metabolic rates, measured by PET, about 10 years later, and, even later, greater regional atrophy measured by MRI, followed by eventual cognitive decline. These findings generally map onto cross-sectional data reported previously by DIAN as well as by the Alzheimer’s Prevention Initiative (API) Colombia collaborative. However, the longitudinal data indicate that changes in measures of tau appear to occur closer to the time of clinical onset than suggested by cross-sectional data, an inconsistency that underscores the need for further studies.

    The report overall provides the most detailed and compelling information yet about the progression of AD pathology in ADAD and supports the notion, also suggested by cross-sectional data, that measurable amyloid dysregulation precedes and possibly initiates neurodegeneration and cognitive decline in ADAD, not unlike the sequence reported in persons at elevated risk for late onset AD. These findings will undoubtedly impact the design of future preclinical trials in this population, in particular providing strong clues that, in future DIAN and API trials, we may need to intervene even earlier than we have thus far in the preclinical stage of illness. To this point, API reported at the 2018 AAIC that, in its preclinical trial in Colombia, a substantial proportion of ADAD mutation carriers lacked measurable Aβ deposition at baseline, a predefined goal in view of our collective uncertainty as to the predictive utility of this biomarker measure. That subgroup may ultimately prove to be especially informative.   

    View all comments by Pierre Tariot
  2. This study provides unique and important results in that it combines both cross-sectional and longitudinal biomarker data to map the pathogenesis of autosomal dominant AD. It also shows that the advantage of using longitudinal measures differs depending on biomarker type.

    The longitudinal CSF p-tau finding is a bit counterintuitive and should be interpreted with caution. Here, the p-tau rates are overall negative (and become even more negative with time), but still the p-tau levels increase with time cross-sectionally. This estimated rate of change in CSF p-tau needs to be replicated to make sure that it is not caused by statistical or preanalytical issues. It also highlights the possible limitation of using longitudinal CSF p-tau as outcome in clinical trials. Future studies tracking CSF biomarker changes over longer time periods with at least three lumbar punctures are probably needed to obtain even more reliable longitudinal data.

    When it comes to amyloid PET, FDG-PET, CSF Aβ42, and atrophy measures, the study nicely shows that longitudinal measures can increase the biomarker sensitivity to detect earlier pathological starting points that cannot be identified cross-sectionally because of large interindividual variability within the normal biomarker range.

    View all comments by Sebastian Palmqvist

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  1. In DIAN, Serial and Cross-Sectional Biomarker Trajectories Diverge