Tau pathology in cognitively normal older adults: Associations with brain atrophy and cognitive decline

Introduction: Tau pathology, a hallmark of Alzheimer9s disease, is observed in the brains of virtually all individuals over 70. Tau PET imaging enables the in vivo characterization of tau distribution and its effects on changes in brain volume and cognitive performance in cognitively normal older individuals. Methods: Using 18 F-AV-1451 ( 18 F-flortaucipir) PET, we evaluated tau pathology in 54 cognitively normal participants (mean age 77.5, SD 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between PET signal and age, sex, race, and amyloid positivity using voxel-wise linear regression. We further investigated associations between regional PET signal and retrospective longitudinal rates of change in regional volumes and domain-specific cognitive function using linear mixed effects models adjusting for age, sex, and amyloid status. Results: Greater age, male sex, black race, and amyloid positivity were associated with higher 18 F-AV-1451 retention in distinct brain regions. Areas of likely tauopathy based on the intersection of associations with age and amyloid positivity were also identified. Adjusting for age, sex, and amyloid status, tracer retention in the entorhinal cortex was related to lower entorhinal volume (β = -1.124, SE = 0.485, p = 0.025) and trend to steeper declines in hippocampal volume (β = -0.061, SE = 0.032, p = 0.061). Entorhinal 18 F-AV-1451 retention was also associated with steeper decline in memory performance (β = -0.086, SE = 0.039, p = 0.029), and signal in Braak III/IV regions was associated with steeper decline in verbal long-delay free recall (β = -0.163, SE = 0.073, p = 0.026). Discussion: Entorhinal tau pathology is associated with declines in memory and medial temporal lobe volume even in cognitively normal individuals with low overall tau burden. The ability to assess medial temporal tau pathology will provide critical insights into early structural brain changes associated with later cognitive impairment and Alzheimer9s disease.