Striatal tau burden is increased in APOE-e4+ mild cognitive impairment

Background The presence of β-amyloid (Aβ) extracellular plaques and hyper-phosphorylated tau neurofibrillary tangles characterize the pathology of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Individuals carrying the apolipoprotein E-ε4 (APOE-ε4) allele are at increased risk of cognitive decline and developing AD pathology. The 18F-AV1451 radioligand allows for assessment of tau burden in vivo . However, this radioligand also binds with iron and this off-target binding can occlude tau deposition in iron rich gray matter structures such as the putamen and caudate nucleus. Methods We employ a MRI measure sensitive to iron, quantitative susceptibility mapping, to control for off-target binding effects of the 18F-AV1451 radioligand and examine tau burden in the striatum. 20 APOE-ε4 negative MCI, 20 APOE-ε4 positive MCI, and 29 APOE-ε4 negative control participants from ADNI were used in this analysis. Results Increased tau pathology (18F-AV1451 PET uptake), after controlling for tissue susceptibility, was found in the putamen and caudate nucleus of APOE-ε4+ MCI participants as compared to APOE-ε4 negative MCI and control participants. Tau burden in the caudate nucleus of the APOE-ε4+ MCI group was correlated with Montreal Cognitive Assessment (MOCA) score with higher caudate tau burden associated with greater cognitive impairment. Conclusions Controlling for iron allows for the assessment of tau burden in iron rich deep gray matter structures. Our findings suggest that APOE-ε4 allele increases the risk of developing AD pathology in the striatum. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data from the ADNI database I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data supporting these analyses are available through the Alzheimer's Disease Neuroimaging Initiative (ADNI).