Entorhinal Tau Pathology, Episodic Memory Decline, and Neurodegeneration in Aging

Abstract

The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with β-amyloid (Aβ). We used [¹⁸F]AV-1451 and [¹¹C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how in vivo tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults (n = 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aβ status. There was no interactive effect of MTL tau with Aβ on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aβ. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (n = 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aβ.SIGNIFICANCE STATEMENT Tau tangles and β-amyloid (Aβ) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aβ affects this relationship. Using tau-specific and Aβ-specific positron emission tomography tracers, we show that in vivo MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aβ. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.

Keywords: aging; episodic memory; positron emission tomography; tau; transentorhinal cortex; β-amyloid.

Figure 1.

Temporal lobe parcellation. To assess subregional tau patterns measured by AV-1451 tau-tracer uptake in the temporal lobe, slicing was performed at three landmarks (cut points 1–3) across the longitudinal axis: at start, middle, and end of HC. This led to four segments (ant, med, post, postHC; y-axis in A) of each gyrus (x-axis in A). Note that only the med and post segments are equal in size. A, The black outline highlights regions that compose the medial temporal lobe memory system. B, The parcellation scheme is shown for the MNI group template (mean of normalized T1 images) but was also performed at individual (subject) level. Note that images are anterior commissure–posterior commissure aligned and not perpendicular to the long axis of the HC. Amy, Amygdala.

Figure 2.

Relationships of tau, Aβ, age, and structural measures to episodic memory. Skipped Pearson correlation coefficients (r) and bootstrapped 95% CI were derived by robust correlations. Colors indicate Aβ status defined by PiB DVR (Aβ⁻ ≤1.065; Aβ⁺ >1.065). Bivariate outliers excluded from the correlation are colored black. Asterisks highlight significant correlations where the bootstrapped 95% CI of r does not include zero. Episodic memory was measured as a composite Z score of verbal and visual recall. A, Tau was assessed by AV-1451 uptake in composite regions that approximate Braak stages (after PVC). Global Aβ was measured as PiB DVR in cortical regions. B, Bilateral mean HC volume (cm³) and entorhinal thickness (cm²) were derived by FreeSurfer segmentation from the MRI closest to the tau PET scan. HC volumes are adjusted for ICV.

Figure 3.

Relationships of Aβ (A) and age (B) to regional tau measures. Skipped Pearson correlation coefficients (r) and bootstrapped 95% CI were derived by robust correlations. Colors indicate Aβ status defined by PiB DVR (Aβ⁻, ≤1.065; Aβ⁺, >1.065). Bivariate outliers excluded from the correlation are colored in black. Asterisks highlight significant correlations where the bootstrapped 95% CI of r does not include zero. Tau was assessed by AV-1451 uptake in composite regions that approximate Braak stages (after PVC).

Figure 4.

Relationships between memory and temporal lobe regional tau PET measures. A, Correlation matrix showing absolute skipped Pearson correlation coefficients for the association between bilateral AV-1451 mean SUVR in temporal lobe subregions and episodic memory (n = 83). Correlations were strongest with PhG, specifically PhG_med corresponding to the posterior EC. Parcellation was performed in subject space with PVC. B, Correlation plots for PhG/LiG subregions from anterior to posterior: PhG_ant (=EC_ant), PhG_med (=EC_post), PhG_post (=PHC), and LiG. R values denote skipped Pearson correlation coefficients after exclusion of outliers, which are colored black. Asterisks highlight significant correlations where the bootstrapped 95% CI of r does not include zero. C, Skipped Pearson correlations between bilateral SUVRs derived from individual space parcellation and verbal (left) versus visual (right) recall memory. Correlations were strongest in EC_post across modalities. The color bar in A also applies to C.

Figure 5.

Voxelwise regressions of episodic memory on tau-tracer uptake (whole brain) in MNI space. AV-1451 SUVR significantly predicted episodic memory in four regions: left EC/PHC (global maximum in left transentorhinal region at level of anterior HC head; blue cross), right EC/PHC, left posterior ITG and posterior MTG. Results are FWE-corrected at cluster level (p_cluster < 0.05, p_voxel < 0.001). No explicit mask was used.

Figure 6.

Relationship between entorhinal-thickness atrophy, tau, and Aβ PET measures, and episodic-memory decline. Longitudinal MRI data were available for 57 OAs and processed with the longitudinal FreeSurfer pipeline. The same subjects had longitudinal cognitive data. Bilateral mean entorhinal-thickness and episodic-memory changes were estimated by linear mixed-effects models. A, Skipped Pearson correlation coefficients (r) and bootstrapped 95% CI were derived by robust correlations. Colors indicate Aβ status defined by PiB DVR (Aβ⁻, ≤1.065; Aβ⁺, >1.065). Asterisks highlight significant correlations where the bootstrapped 95% CI of r does not include zero. B, Correlation matrix showing absolute skipped Pearson correlation coefficients for the association between bilateral AV-1451 mean SUVR in temporal lobe subregions and entorhinal-thickness change (left) and episodic-memory change (right).