Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis
Eddie Stage, Diana Otero Svaldi, Meredith Phillips, Victor Hugo Canela, Tuğçe Duran, Naira Goukasian, Shannon L. Risacher, Andrew J. Saykin, Liana G. Apostolova, for the Alzheimer’s Disease Neuroimaging Initiative
Abstract
Abstract Background A substantial number of patients clinically diagnosed with Alzheimer’s disease do not harbor amyloid pathology. We analyzed the presence and extent of tau deposition and neurodegeneration in amyloid-positive (AD) and amyloid-negative (nonAD) ADNI subjects while also taking into account age of onset (< or > 65 years) as we expected that the emerging patterns could vary by age and presence or absence of brain amyloidosis. Methods One hundred and ten early-onset AD (EOAD), 121 EOnonAD, 364 late-onset AD (LOAD), and 175 LOnonAD mild cognitive impairment (MCI) and dementia (DEM) subjects were compared to 291 ADNI amyloid-negative control subjects using voxel-wise regression in SPM12 with cluster-level family-wise error correction at p FWE < 0.05). A subset of these subjects also received 18 F-flortaucipir scans and allowed for analysis of global tau burden. Results As expected, relative to LOAD, EOAD subjects showed more extensive neurodegeneration and tau deposition in AD-relevant regions. EOnonAD MCI showed no significant neurodegeneration, while EOnonAD DEM showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonAD MCI and LOnonAD DEM showed diffuse brain atrophy and a fronto-temporo-parietal hypometabolic pattern. LOnonAD and EOnonAD subjects failed to show significant tau binding. Conclusions LOnonAD subjects show a fronto-temporal neurodegenerative pattern in the absence of tau binding, which may represent underlying hippocampal sclerosis with TDP-43, also known as limbic-predominant age-related TDP-43 encephalopathy (LATE). The hypometabolic pattern observed in EOnonAD DEM seems similar to the one observed in EOAD MCI . Further investigation into the underlying etiology of EOnonAD is warranted.