Elevated tau‐PET signal predicts near‐term conversion to mild cognitive impairment in cognitively unimpaired older adults

Abstract Background National Institute on Aging‐Alzheimer’s Association workgroups have proposed biological research criteria to identify individuals with preclinical Alzheimer’s disease (AD). It remains unclear whether cognitively unimpaired individuals with abnormality in both amyloid (A) and tau (T) biomarkers will go on to develop a clinical AD syndrome. In two independent cohorts, we investigated whether elevated tau‐PET signal in persons with elevated amyloid‐PET predicts near‐term conversion to mild cognitive impairment (MCI). We also tested whether neurodegeneration (N), a non‐specific marker typical of later‐stage AD, improved such prediction. Method We studied 128 cognitively unimpaired participants from the parental history‐positive PREVENT‐AD cohort and 153 individuals from the Harvard Aging Brain Study. Participants had >1 year of clinical evaluation following tau‐PET scanning (PREVENT‐AD median follow‐up time = 3.21 years [1.51‐4.50]; HABS median=1.94 years [1.13‐5.42]). At the time of PET, participants were stratified as abnormal (+) or normal (‐) on global amyloid‐PET (A), a temporal tau‐PET meta‐ROI (T), and hippocampal volume (N). Tau‐PET scans were also visually inspected for significant neocortical binding. Result Within the A+T+ groups, 61.5% (8/13; PREVENT‐AD) and 45.5% (5/11; HABS) of participants converted to MCI during follow‐up, compared with <13% of participants in all other PET‐biomarker groups (Figures 1 & 2). In Cox regression models, hazard ratios for conversion to MCI in the A+T+ group vs. the other biomarker groups were all >5 (Figure 3). Importantly, the majority of the A+T+ “non‐converters” still showed longitudinal cognitive decline (80% in PREVENT‐AD and 50% in HABS), suggesting likely future clinical progression (Figures 4 and 5). By contrast, cognitive trajectories in the A+T‐, A‐T+, and A‐T‐ groups remained predominantly stable. Evidence of neurodegeneration increased MCI conversion rates in the A+T+ group to 75%, though ∼33% of A+T+N‐ individuals also progressed (Figure 6). Conclusion Among two cohorts of cognitively unimpaired older individuals, abnormality in both amyloid‐ and tau‐PET biomarkers was associated a dramatic increase in MCI progression within a short period of time as compared against individuals having only amyloid pathology or no pathology. These findings support the clinical prognostic relevance of a biological definition of AD in individuals without cognitive impairment.

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