br Comparison to IWG In addition
Comparison to IWG In addition to the NIA AA, the other group that has established diagnostic guidelines for AD that incorporate biomarkers is the IWG [64,74,75]. In the most recent formal IWG document, published in 2014 , the diagnosis of AD required the presence of cognitive symptoms plus an AD biomarker signature. This could be either an abnormal amyloid PET study or both abnormal CSF Aβ and tau. The NIA-AA research framework aligns with these criteria in recognizing that neither hypometabolism nor atrophy are specific for AD and thus cannot be used to support a diagnosis of AD. One difference though is that we regard CSF T-tau as a nonspecific marker of neuronal injury, while the IWG 2014 treats the combination of elevated T-tau and low Aβ42 as a biomarker signature that is specific for AD. In addition, tau PET was not available in 2014 and thus was not included in the 2014 IWG criteria. In addition to an AD biomarker signature, cognitive symptoms (specifically either a typical or a known atypical AD phenotype) were also required to diagnose AD in IWG 2014. Individuals with symptoms that fell short of dementia were labeled prodromal AD. CU individuals with an abnormal amyloid PET study or a CSF study demonstrating both abnormal Aβ and tau were labeled “asymptomatic at risk for AD”. The most significant difference between the 2014 IWG criteria and the NIA-AA research framework is that, with the exception of genetically determined AD, the 2014 IWG diagnosis of AD in living persons required both biomarker and clinical findings and therefore was not purely a biological construct. In an article on preclinical AD (published in 2016  that may be considered part of the IWG series), the diagnosis of AD was extended to include asymptomatic individuals with biomarker evidence of both Aβ and tau. In r78 to IWG 2014, symptoms were no longer required to reach a diagnosis of AD. Some differences with the NIA-AA research framework remain, however. Preclinical AD in IWG 2016  defines a CU individual with an abnormal Aβ biomarker and normal tau (A+T−) as “at risk for AD, asymptomatic A+” and one with A−T+ as “at risk for AD, asymptomatic T+”. We label the former Alzheimer's pathologic change and the latter suspected non-Alzheimer's pathologic change (in keeping with the NIA-AA pathologic definition of primary age-related tauopathy as not AD [105,106]). Importantly, the NIA-AA research framework uses “at risk” in a much different connotation, referring to asymptomatic individuals with biomarker evidence of AD as having AD but being “at risk” of subsequent cognitive decline (as opposed to “at risk” for AD). While differences remain, IWG 2016 and the NIA research framework are aligned on the key issue that the combination of an abnormal Aβ and tau biomarker constitutes AD regardless of cognitive symptoms, and thus AD is a biologically defined entity throughout its continuum. This is an important step toward harmonization.
Clinical research without biomarkers or with incomplete biomarker information While the main thesis of this research framework focuses on a biological definition of AD, we stress that for some types of studies, incorporation of biomarkers is not necessary. PET and CSF biomarkers can be difficult to acquire in some types of studies and in some geographic locations PET may not be possible. This is particularly true for large population- and community-based cohort studies. Such studies typically seek to identify risk factors for cognitive or other clinically determined outcomes. For these studies, high participant engagement is essential for internal validity and many rely on home visits to achieve both high participation and high follow-up rates. Such studies would have more limited participation and greater expense if PET or CSF biomarkers were required. Thus, research without biomarkers remains a significant enterprise and will continue to find risk factors for clinically defined syndromes or for resilience indices. The extent to which these risk factors are associated with AD will require complementary studies with imaging or biofluid biomarkers, or brain autopsy. While imaging/CSF biomarker data on subsets of individuals from well-designed community-based cohorts would provide additional research value, incorporating biomarkers on a large scale in many settings will require low-cost and minimally invasive biomarkers (e.g., blood or saliva) that are now emerging [202–205].