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    • Another possible scenario is that

    2022-10-25

    Another possible scenario is that the same pathologic process has different effects in different people. It might be that the pathway outlined in Fig. 6A is operative in some individuals, but other individuals have a factor Q (which could be genetic or environmental) that blocks the effect of A on T. In these individuals, A could accumulate harmlessly without leading to downstream events. If Q were discovered, then its effect on T, (N), and (C) given A could be tested empirically with the framework. However, this issue needs to be approached thoughtfully. The fact that individuals die with A without developing T, (N), or (C) in their lifetimes does not prove the existence of factor Q. Because of increasing death rates with age and the long preclinical period of AD [227], it cannot be known if that person would have developed T, (N), or (C) had they lived longer. For conceptual completeness, we have outlined what undoubtedly seems like a complex system, but it is important to note that the design of this framework poses many questions that are readily testable using subsets of the population. Many research questions may use only a few of the ML 154 in Table 4, and thus large research cohorts are not necessary to evaluate many aspects of this framework. For example, are rates of cognitive decline different for different manifestations of transitional cognitive decline (subjective report, subtle decline on testing, or neurobehavioral symptoms)? How do cognitive outcomes differ among various biomarker profiles? What is the influence of age on these relationships? Is the prevalence of cerebrovascular disease different among the three suspected non-AD pathologic change biomarker profiles [A−T+(N)−, A−T−(N)+, and A−T+(N)+]?
    Future directions The NIA-AA research framework defines AD biologically, by neuropathologic change or biomarkers, and treats cognitive impairment as a symptom/sign of the disease rather than the definition of the disease. This approach should enhance efforts to understand both the biology of AD and the multifactorial etiology of dementia, which has been obscured to some extent in the past by equating amnestic multidomain dementia with the presence of AD neuropathologic changes, and by equating the absence of the prototypical dementia syndrome with the absence of AD neuropathologic changes. The notion of providing a common language with which researchers can communicate is important. If one research group defines AD as Aβ plaques and pathologic tau (either by biomarkers or neuropathology) and a different group defines AD as the presence of amnestic dementia (see Fig. 5), then the findings from the two groups point to different entities, and the conclusions are not directly comparable. We recognize that current biomarkers used in AD research are either expensive or invasive. The current generation of biomarkers is invaluable for research; however, widespread, use will be facilitated by the development of less-expensive and less-invasive biomarkers. For example, new ultrasensitive immunoassay techniques may enable measurement of minute amounts of brain-specific proteins in blood samples [228]. Candidate blood biomarkers such as neurofilament light protein [204] and plasma tau [205] show promise as non–disease-specific tools to identify neurodegeneration. Plasma Aβ measures now show promise [202,203]. In the future, less-invasive/less-expensive blood-based biomarker tests along with genetics, clinical, and demographic information will likely play an important screening role in selecting individuals for more-expensive/more-invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease (see, e.g., the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults) [229]. This unifying research framework is a natural descendant of the 2011 NIA-AA preclinical AD recommendations that were based on the concept that AD, identified by biomarkers, can exist in the absence of symptoms [4]. The present research framework extends this concept throughout the entire Alzheimer's continuum (Text box 4); however, it will also need to be updated at some point in the future when a modified or different conceptual approach to AD is needed to accommodate scientific advances.