Objective: To examine the clinical and biomarker characteristics of patients with amyloid-negative Alzheimer disease (AD) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective cohort study.
Methods:We first investigated the reliability of florbetapir2 PET in patients with AD and patients with MCI using CSF-Ab 1-42 as a comparison amyloid measurement. We then compared florbetapir2 vs florbetapir1 patients with respect to several AD-specific biomarkers, baseline and longitudinal cognitive measurements, and demographic and clinician report data.Results: Florbetapir and CSF-Ab 1-42 1/2 status agreed for 98% of ADs (89% of MCIs), indicating that most florbetapir2 scans were a reliable representation of amyloid status. Florbetapir2 AD (n 5 27/177; 15%) and MCI (n 5 74/217, 34%) were more likely to be APOE4-negative (MCI 83%, AD 96%) than their florbetapir1 counterparts (MCI 30%, AD 24%). Florbetapir2 patients also had less AD-specific hypometabolism, lower CSF p-tau and t-tau, and better longitudinal cognitive performance, and were more likely to be taking medication for depression. In MCI only, florbetapir2 participants had less hippocampal atrophy and hypometabolism and lower functional activity questionnaire scores compared to florbetapir1 participants.
Conclusions:Overall, image analysis problems do not appear to be a primary explanation of amyloid negativity. Florbetapir2 ADNI patients have a variety of clinical and biomarker features that differ from their florbetapir1 counterparts, suggesting that one or more non-AD etiologies (which may include vascular disease and depression) account for their AD-like phenotype. Alzheimer's Disease Neuroimaging Initiative; AGD 5 argyrophilic grain disease; MCI 5 mild cognitive impairment; metaROI 5 previously validated region of interest; MMSE 5 Mini-Mental State Examination; MPRAGE 5 magnetization-prepared rapid gradient echo; RAVLT 5 Rey Auditory Verbal Learning Test; SUVR 5 standardized uptake value ratio; TBM-SyN 5 tensorbased morphometry-symmetric diffeomorphic image normalization method; VBM 5 voxel-based morphometry; WM 5 white matter.The rate of b-amyloid (Ab) negativity in clinically diagnosed Alzheimer disease (AD) varies across a variety of study populations and as a function of APOE genotype status.1-6 Previous studies of patients with clinically diagnosed AD have shown that 12% were negative on amyloid PET in a recent meta-analysis, 7 and 10%-25% of APOE4-negative patients with AD did not meet the neuropathologic criteria for AD at autopsy. 8,9 Older adults with an amnestic profile that is suggestive of AD comprise a diverse group with heterogeneous pathology. Hippocampal sclerosis, argyrophilic grain disease, vascular dementia, Lewy body disease, and frontotemporal dementia have been observed at autopsy in addition to AD pathology 10 and in Ab2 cases with an antemortem AD diagnosis.