Cognitive decline in community-dwelling older persons with primary age-related tauopathy: role of anatomical location of tangles and other co-existing brain pathologies.

Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-existing pathologies on cognitive decline are underappreciated. We used three harmonized community-based clinicopathologic studies to investigate the association of regional distributions of tangles and co-existing pathologies with cognitive decline. At autopsy, PART was defined by a Braak NFT stage of I-IV in the absence or with limited amyloid-β (Thal ≤ 2). Tau tangle density from the hippocampus and inferior temporal cortex were evaluated by AT8-immunohistochemistry. Other brain pathologies (LATE-NC, Lewy bodies (LBs), and vascular pathologies) were also evaluated. Linear mixed effect models were employed to examine the associations between regional tau tangles and other brain pathologies with decline in global cognition and 5 cognitive domains. Among 1,859 participants, 527 (28%) had neuropathologically confirmed PART: 385 had possible PART and 142 had definite PART, with an average age at death of 88 ± 6.9 years and 63% being female. Nearly all PART participants (N = 524) had hippocampal tangles and 449 also exhibited tangles in the inferior temporal neocortex. After controlling demographics and other brain pathologies, hippocampal and inferior temporal neocortical tangle burden were each associated with decline in global cognition and episodic memory; however, the effect of inferior temporal neocortical tangles on decline was 3.2 times stronger than that of hippocampal tangles. In further analyses, when included together in the same model, only the association of inferior temporal neocortical tangle burden persisted. However, using Braak staging alone, we did not find a clinical-pathological relationship between tangles and cognitive decline. Additionally, LATE-NC, LBs, atherosclerosis, and cerebral infarcts were each independently associated with cognitive decline. Our data also indicated that LATE-NC may have stronger impact on cognitive decline in PART than tau tangles. Overall, this study provides evidence that both extension of tangles to the nearby neocortex, specifically the inferior temporal, along with other co-pathologies, particularly LATE-NC, play a key role in cognitive decline in PART.