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    • Another issue is that the vast majority of data from

    2023-09-12

    Another issue is that the vast majority of data from PET and CSF are from selected participants recruited through tertiary care dementia centers [176]. It is widely recognized that clinic-based participants differ from community-based studies, for example, the amount, type, and distribution of neuropathologic changes differ by the source of a participant [206,207]. There are limited data on CSF and PET AD biomarkers from population-based studies. Therefore, incorporating biomarkers into these studies is highly warranted to increase our understanding of the biology of AD, but only when such inclusion does not compromise the overarching scientific goals of the parent project. Importantly, there are less data from diverse populations. As with population-based studies, we encourage the inclusion of AD biomarkers in studies of diverse populations that use this research framework [208], but it mps1 is clearly premature to recommend that all such studies incorporate biomarkers. The issues of clinical research without biomarkers and defining AD as amnestic dementia are often conflated, but it is important to recognize the distinction. Clinical research without biomarkers provides valuable information about the societal burden of cognitive disability and risk factors for cognitive impairment. However, amnestic multidomain dementia and other classic syndromal variants are not synonymous with the presence of Aβ deposition and neurofibrillary degeneration. In addition, the absence of amnestic dementia is clearly not synonymous with the absence of these hallmark lesions of AD. AD neuropathologic change is documented in approximately 80% of cases with a traditional clinical diagnosis of “AD dementia” (see Fig. 5 for an example of clinical misdiagnosis of “AD dementia”) [50–52,162,185,209–211]. However, preclinical AD cannot be ascertained without biomarkers. Up to 60% of CU individuals over age 80 years have AD neuropathologic changes at autopsy or by biomarkers [60,152,212–214]. Thus, using a clinical diagnosis of “AD” to ascertain absence of disease is associated with an error rate exceeding 50% in the elderly. Valuable clinical research will continue in contexts that do not use biomarkers where the outcome that is ascertained is a multi-(or single-) domain amnestic syndrome or a classic syndromal variant. Historically though such individuals have been labeled “probable or possible AD” [1,2] and in practice this is more often than not shortened to simply “AD” and this is problematic. Labeling individuals “AD” who do not have biomarker evidence of AD undermines the major theme of this framework. But, we also recognize the deeply engrained historic use of the term “Alzheimer” to denote particular syndromes. Thus, we strongly recommend that a clinically ascertained syndrome consistent with what has historically been labeled “probable or possible AD” be referred to as Alzheimer's clinical syndrome, but not as AD or some modified form of AD (e.g., “possible or probable AD”). This terminology applies to both mildly impaired and demented individuals and is consistent with our position that a syndrome is not a disease, while at the same time recognizing the deeply engrained use of the term Alzheimer. This terminology is also consistent with the frontotemporal lobar degeneration field where corticobasal syndrome refers to the syndrome and corticobasal degeneration refers to a specific disease. Studies without biomarkers that infer biological associations with “AD” can cause confusion. For example, in studies without biomarkers, diabetes has been claimed to be a risk factor for probable AD, when AD was defined as an amnestic dementia [215]. In contrast, in clinical-autopsy studies, diabetes was associated with cognitive impairment (and the clinical diagnosis of probable AD); however, the pathologic basis for this association was vascular brain injury and not Aβ plaques and neurofibrillary degeneration [50,216]. Population-based studies using biomarkers also show that mid-life risk factors (obesity, smoking, diabetes, hypertension, and cardiac disease) commonly found to be associated with cognitive decline and clinically ascertained impairment that is labeled “AD” dementia are associated with neurodegeneration but not amyloid pathology [183]. Certain genome-wide association studies provide another example of this phenomenon. When loci that were associated with clinically defined AD are examined against autopsy-defined AD, many of these loci have no association with neuritic plaques and neurofibrillary degeneration but rather with other pathologic findings such as cerebrovascular disease [217]. Apparently, conflicting conclusions like these in the literature create confusion in the medical field and in the general public, which highlights the need to investigate the relationship of risk factors to AD biomarkers or neuropathologic change to understand the biologic basis of such associations. Thus, non–biomarker studies can establish robust and valid associations between risk factors and Alzheimer's clinical syndrome, but the biologically based studies are needed to determine if these associations are with AD.