The impact of young controls in the detection of tau load in cognitively impaired and asymptomatic elderly

Abstract Background Neuropathological observations report incipient tau accumulation in the human brain starting in the third decade of life, with the proportion of individuals with some degree of tau deposition increasing with age. Given the high prevalence of tau positive cases among cognitively unimpaired (CU) older adults, one may question whether these individuals constitute an ideal reference group when assessing tau load in symptomatic population. Here, we compare tau biomarker levels of participants with Alzheimer’s disease (AD) and CU of different ages. Method We evaluated 35 CU young individuals (aged <26 years) and 124 amyloid‐beta (Aβ)‐ elderly, considered the two control groups. We also assessed 42 Aβ+ CU and 122 Aβ+ cognitively impaired (CI) individuals, diagnosed with either mild cognitive impairment or AD dementia. Participants were assessed with 18F‐MK6240 positron emission tomography (PET) and CSF and plasma pTau181, 217, 231 and 235. We used linear regression to perform voxel‐wise comparisons of tau‐PET signal between groups. We compared the standardized uptake value ratio (SUVR) in medial‐temporal and Braak‐like regions‐of‐interest (ROI) and fluid biomarkers levels using the Wilcoxon rank sum test. Result In the voxel‐wise comparisons (Figure 1A‐E), CI participants presented more widespread cortical signal than control groups. Less signal in the parietal cortex was observed in the comparison with CU young. Higher t‐values were observed in Aβ+ CU individuals in the medial temporal region, compared to both control groups, and adjacent neocortex, especially compared to CU young. Temporal and Braak V‐VI SUVR were higher in CI but not in Aβ+ CU individuals compared to controls. Moreover, Braak I‐II and III‐IV SUVR and the fluid biomarkers levels were higher in both Aβ+ groups compared to controls (Figures 2A‐D; 3A‐G). Importantly, Braak I‐II SUVR and the CSF biomarkers levels were higher in CU old Aβ‐ versus young. Conclusion Here, we provide in vivo evidence that tau‐load in age‐matched Aβ‐ controls constitutes a bias for identifying tau pathology, particularly in individuals at early stages of AD pathophysiology. Age‐related tau load should be considered when selecting control groups to assess tau in symptomatic populations, especially those with early AD, and when defining criteria for tau abnormality.

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