Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity

Abstract

Objective: To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.Methods: Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n 5 207). Twelve subjects with Alzheimer disease dementia were included for comparison.Results: Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline. Conclusions:The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both "amyloid-first" and "neurodegeneration-first" biomarker profile pathways to preclinical AD exist. Amyloid positivity is associated with higher rates of brain atrophy in cognitively normal (CN) subjects and subjects with mild cognitive impairment (MCI).1,2 CN subjects 3-5 and subjects with MCI 6,7 who are amyloid-positive experience greater cognitive decline than amyloid-negative individuals. Amyloid positivity must therefore be recognized as a pathologic state.Like any quantitative biomarker, amyloid PET values exist on a continuous scale. However, defining incident amyloid positivity requires that a precise normal/abnormal threshold be adopted. Categorizing individual subjects as amyloid-positive or -negative is required to implement new diagnostic criteria for preclinical Alzheimer disease (AD) and to integrate amyloid biomarkers into the new diagnostic criteria for MCI and AD dementia. 8,9 A precise normal/abnormal threshold is also required to define eligibility for some antiamyloid therapeutic trials. 10A popular model of the temporal evolution of AD biomarkers 11,12 proposes that amyloid biomarkers are the first to become abnormal in the pathophysiologic cascade and do so while subjects are still considered CN via neuropsychological and clinical criteria. Thus, characterization of incident amyloid PET positivity should focus on subjects who are CN at baseline. The state of amyloid positivity is clinically important as this defines preclinical AD.9 Ther...

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

“…Twenty-nine percent of the MCI cases from the Mayo Clinic Aging Study and 17% from the Alzheimer's Disease Neuroimaging Initiative had neurodegeneration (by MRI or [ 18 F]-fluorodeoxyglucose-PET) without amyloid deposition, 31 and 42% of the Mayo Clinic Aging Study subjects who became amyloid-positive at follow-up had evidence of neurodegeneration before showing amyloid positivity. 32 WMLs, as markers of small vessel disease, are independent predictors of dementia. 15 Some studies found that WMLs were better predictors of dementia than hippocampal volume, 16 and others showed that WMLs were associated with increased Ab deposition in subjects with AD.…”

Spatially distinct atrophy is linked to β-amyloid and tau in preclinical Alzheimer disease

“…[2][3][4] However, the pathophysiologic correlates of Ab-independent atrophy remain unclear. Our work shows that AD-like neurodegeneration (i.e., AD signature cortical thinning) has a direct relationship with abnormal biomarker of tau pathology.…”

“…1 However, recent work has observed that some cognitively normal (CN) individuals have neurodegeneration (e.g., AD-like brain atrophy on structural MRI) independent of amyloidosis. [2][3][4] These observations motivate the investigation of tau-related neurodegenerative process in preclinical AD. In addition, discrepant data exist regarding the relationships between amyloidosis or neurodegeneration and cognitive decline in preclinical AD.…”

Neuropathology of Dementia Disorders

“…Demonstration that SDS-soluble Aβ measured by immunoassay was better than post mortem PiB binding has important implications for imaging-based biomarkers [66]. In some PiB-negative cases, a combination of pre-existent non-AD pathology and tau-mediated neurodegeneration may be present prior to Aβ pathology [67].…”

“…Demonstration that SDS-soluble Aβ measured by immunoassay was better than post mortem PiB binding has important implications for imaging-based biomarkers [66]. In some PiB-negative cases, a combination of pre-existent non-AD pathology and tau-mediated neurodegeneration may be present prior to Aβ pathology [67].Hippocampal atrophy in the elderly, demonstrated by modern imaging methods and confirmed by postmortem diagnosis of AD [44,68], has been shown to be an important and under-appreciated brain lesion of aging [69].A review of 2,861 neurodegenerative disease cases of the National Alzheimer's Coordinating Center Registry (NACCR) showed high diagnostic accuracy for AD (85% sensitivity, 51.1% specificity) and low sensitivity for DLB (32% for pure AD and 12% for AD+DLB) with a specificity over 58% [70]. Evaluation of the accuracy of current clinical diagnostic methods for AD in 919 autopsy cases from the database of the NACC (2005-2010) revealed a sensitivity from 70.9 to 87.3% and a specificity of 44.3 to 70.8%.…”