The medial temporal lobe (MTL) is the earliest site of tau accumulation. MTL dysfunction may underlie episodic memory decline in normal aging and early dementia. Postmortem data indicate that transentorhinal cortex and hippocampus (HC) tau pathology is common over 60 years-of-age, while spread to inferior temporal (IFT) regions and worsening cognition is associated with beta-amyloid (Aβ). We used PET to investigate how in vivo tau accumulation in temporal lobe regions, Aβ deposition, and MTL atrophy measures contribute to memory and memory decline in cognitively normal older adults. Seventy-five subjects (77±6yrs) underwent [18F]AV-1451 tau PET, [11C]PiB amyloid PET, T1-weighted structural MRI, and neuropsychological assessment (60 with ≥ 2 sessions). T1-images were segmented (FreeSurfer v5.3) to derive volume/thickness measures, a global cortical PiB DVR, and regional AV-1451 measures in native space (80–100min SUVR, cerebellar gray reference, partial volume corrected). Mean SUVRs were derived from MTL and IFT, and temporal lobe subregions (after automated division along the anterior-posterior axis). An episodic memory composite score was derived by averaging Z-transformed verbal and visual early recall, late recall and recognition performance. Changes in memory were estimated by linear-mixed effects models. Stepwise multiple regressions identified the best predictor(s) for memory or memory change, among demographic variables, MTL and IFT tau, global Aβ, HC volume, and entorhinal (EC) thickness. Interactive effects of MTL or IFT tau x Aβ on memory were tested by general linear models. Contributions of temporal lobe subregions were assessed by subsequent regressions. Stepwise regressions identified MTL tau as the best predictor of memory and memory decline (R2=.34 and .33, p<.001). Correlations between MTL tau and memory were seen in both PiB- and PiB+ individuals (Figure). GLMs did not reveal any significant interactive effect of MTL or IFT tau with Aβ on memory. Among temporal lobe subregions, posterior EC and parahippocampal cortex best predicted memory (R2=.32), whereas medial IFT and posterior EC best predicted memory decline (R2=.34). Consistent with neuropathological studies, our data suggest close links between MTL tau pathology (particularly in posterior EC) and age-related memory dysfunction, with stronger decline associated with involvement of IFT regions. Relationship between episodic memory at session closest to AV-1451 tau scan and tau tracer uptake in the posterior EC (PiB- subjects: rPearson=-.43; rSpearman=-.41; PiB+ subjects: rPearson=-.52; rSpearman=-.54; all p<.001). A similar relationship was seen between memory and whole MTL mean SUVR, which we defined as average across Freesurfer-defined EC, para-hippocampal gyrus, hippocampus and amygdala. Posterior EC was defined here as the part of EC/parahippocampal gyrus (Freesurfer nomenclature) that covers the same slices as the anterior half of the hippocampus.
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