Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis

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.