br We approached the definition of AD with the distinction
We approached the definition of AD with the distinction between a syndrome and a disease in mind. Some will argue that a specific syndrome, that is, a multidomain amnestic dementia (after other potential etiologies have been excluded), should define AD in living people. Our position, however, is that dementia is not a “disease” but rather is a syndrome composed of signs and symptoms that can be caused by multiple diseases, one of which is AD. As we elaborate in the following paragraph, there are two major problems with using a syndrome to define AD; it is neither sensitive nor specific for the neuropathologic changes that define the disease, and it cannot identify individuals who have biological evidence of the disease but do not (yet) manifest signs or symptoms [48,49]. It is now well established that the prototypical multidomain amnestic dementia SB-222200 sale historically used to define probable AD  does not “rule in” AD pathologic change (which implies change from normal) at autopsy [50–52] and the absence of the syndrome does not “rule out” AD pathologic change. From 10% to 30% of individuals clinically diagnosed as AD dementia by experts do not display AD neuropathologic changes at autopsy , and a similar proportion has normal amyloid PET or CSF Aβ42 studies [53–62]. Thus, the multidomain amnestic dementia phenotype is not specific; it can be the product of other diseases as well as AD . Nonamnestic clinical presentations, that is, language, visuospatial, and executive disorders, may also be due to AD [63–66]. In addition, AD neuropathologic changes are often present without signs or symptoms, especially in older persons. Thirty to forty percent of cognitively unimpaired (CU) elderly persons have AD neuropathologic changes at autopsy [67–69], and a similar proportion has abnormal amyloid biomarkers [33,53–55,60,70–73]. The fact that an amnestic multidomain dementia is neither sensitive nor specific for AD neuropathologic change suggests that cognitive symptoms are not an ideal way to define AD. The traditional approach to incorporating biomarkers into models of AD began with patients' clinical symptoms, which appear relatively late in the disease, and worked backward to relate symptoms to biomarker findings. The committee recommends a different approach where the neuropathologic changes detected by biomarkers define the disease. Defining AD by biomarkers indicative of neuropathologic change independent from clinical symptoms represents a profound shift in thinking. For many years, AD was conceived as a clinical-pathological construct ; it was assumed that if an individual had typical amnestic multidomain symptoms, they would have AD neuropathologic changes at autopsy and if symptoms were absent, they would not have AD at autopsy. Symptoms/signs defined the presence of the disease in living persons, and therefore, the concepts of symptoms and disease became interchangeable. AD later became a clinical-biomarker construct with the International Work Group (IWG) [64,74,75] and 2011 NIA-AA guidelines where biomarkers were used to support a diagnosis of AD in symptomatic individuals, but the definition of AD was not divorced from clinical symptoms (with the exceptions of the 2011 NIA-AA recommendations on preclinical AD and IWG criteria in autosomal dominant mutation carriers, and NIA-AA neuropathologic guidelines).
AD biomarkers Various imaging and CSF biomarkers are widely used in AD and brain aging research, and an organized approach is needed for a generalizable research framework. The committee addressed this by following the recommendations from a recent position paper that outlined an unbiased descriptive classification scheme for biomarkers used in AD and brain aging research . The scheme [which is labeled AT(N)] recognizes three general groups of biomarkers based on the nature of the pathologic process that each measures (Table 1) . See section 9.4 for explanation of (N) notation. Biomarkers of Aβ plaques (labeled “A”) are cortical amyloid PET ligand binding [76,77] or low CSF Aβ42[78–80]. Biomarkers of fibrillar tau (labeled “T”) are elevated CSF phosphorylated tau (P-tau) and cortical tau PET ligand binding [79,81–83]. Biomarkers of neurodegeneration or neuronal injury [labeled “(N)”] are CSF T-tau , FDG PET hypometabolism, and atrophy on MRI [85–91].