Stage, Eddie C.Svaldi, DianaPhillips, MeredithCanela, Victor HugoDuran, TugceGoukasian, NairaRisacher, Shannon L.Saykin, Andrew J.Apostolova, Liana G.2021-04-232021-04-232020-08-05Stage, E. C., Svaldi, D., Phillips, M., Canela, V. H., Duran, T., Goukasian, N., Risacher, S. L., Saykin, A. J., Apostolova, L. G., & for the Alzheimer’s Disease Neuroimaging Initiative. (2020). Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis. Alzheimer’s Research & Therapy, 12(1), 93. https://doi.org/10.1186/s13195-020-00647-w1758-9193https://hdl.handle.net/1805/25724Background 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 pFWE < 0.05). A subset of these subjects also received 18F-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. EOnonADMCI showed no significant neurodegeneration, while EOnonADDEM showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonADMCI and LOnonADDEM 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 EOnonADDEM seems similar to the one observed in EOADMCI. Further investigation into the underlying etiology of EOnonAD is warranted.en-USAttribution 4.0 InternationalEarly onsetLate onsetAlzheimer’s diseaseADMRIPETTauNeurodegenerationHippocampal sclerosisLimbic-predominant age-related TDP-43 encephalopathyLATEArticle