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 [F]AV-1451 and [C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults ( = 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 ( = 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. 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 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.

Data‐driven approaches for tau‐PET imaging biomarkers in Alzheimer's disease

“…This finding supports previous literature highlighting relationships between medial temporal lobe tau pathology and decline in episodic memory (Maass et al, 2018 (Stern, 2012), and suggests that more highly educated subjects may experience preserved cognition in the face of tau pathology (Hoenig et al, 2017). In our study, ROIs representing the earliest stages of tau pathology, especially the FIGURE 7 Assessing reproducibility of clusters across cohorts.…”

Association of deposition of tau and amyloid‐β proteins with structural connectivity changes in cognitively normal older adults and Alzheimer’s disease spectrum patients

“…Meanwhile, the amyloid‐positive AD‐spectrum group showed decreased connectivity, which is consistent with previous studies that MCI/AD in general has often been associated with decreased structural connectivity (Mielke et al, ; Nowrangi et al, ; Wisse et al, ) and atrophy (Das et al, ; Maass et al, ; Xia et al, ). Aβ is hypothesized to increase tau deposition and to accelerate the spread of hyperphosphorylated tau beyond the collateral sulcus into the neocortex, via transsynaptic spread across neural networks.…”

The impact of amyloid‐beta and tau on prospective cognitive decline in older individuals

“…Our findings may also be relevant to the question as to whether tau, in the setting of low Aβ, might underlie age-related decline in episodic memory, given the nearly ubiquitous presence of tau pathology in the EC (Braak stage 1-2) by age 80, 18 and the recent interest in "primary age-related tauopathy" (PART), 35 defined as early neocortical tau accumulation with absent or low Aβ pathology (Thal phase <3 corresponding approximately to PET Aβ -) in very elderly individuals (average ages, 88-90). 13,14 Our overall results are consistent with the Berkeley group findings; however, we did not find supporting evidence for tau-associated cognitive decline among Aβin any region or in any cognitive domain. 36 There have also been two reports of memory decline, using primarily retrospective cognitive trajectories, associated with Linear mixed models were repeated with Aβ treated as a dichotomous variable, and the effect of tau on memory change (Regional tau × Time) was estimated in Aβand Aβ + groups from these models for entorhinal cortex (EC), hippocampus (Hip), and inferior temporal (IT) cortex.…”