Memory performance is related to amyloid and tau pathology in the hippocampus

Abstract

Objective: To determine the relation of amyloid and tau pathology in the hippocampal formation to decline in memory and other cognitive functions in Alzheimer's disease (AD). Methods: Regression models were used to relate semiquantitative measurements of amyloid plaques, neurofibrillary tangles (NFTs) and neuropil threads (NTs) at autopsy with antemortem performance in memory, abstract/visuospatial and language domains in two independent samples (n = 41, n = 66) that had repeated neuropsychological measurements before death. Results: In both groups, the number of NFTs in the entorhinal cortex, subiculum and CA1 region was inversely associated with memory performance at the last visit before death. However, the number of amyloid plaques and NTs in the entorhinal cortex was also inversely related to poor memory function. Moreover, as the number of plaques or NTs increased in any region of the hippocampal formation, there was a more rapid decline in memory performance over time; a similar decline was associated with increasing numbers of NFTs in the CA1 or subiculum. In contrast, there was no association between amyloid plaques, NFTs or NTs in the frontal or parietal lobe and performance in memory, nor was there an association between plaques, NFTs or NTs in the hippocampal formation and cognitive functions unrelated to memory. Discussion: This study implicates both amyloid deposition and tau pathology in the hippocampus as an early and late cause of decline in memory function over time in AD. Memory performance appears to be specifically related to the amount of amyloid plaques, NFTs and NTs in the entorhinal cortex and hippocampus.Alzheimer's disease (AD) is characterised by progressive cognitive deterioration leading to impairment in activities of daily living. Neuropathological key features in the brain are amyloid plaques, neurofibrillary tangles (NFTs) and neuropil threads (NTs). Amyloid plaques consist of fibrils formed from the amyloid-b (Ab) peptide accompanied by microgliosis, dystrophic neuritis and astrocytic processes. NFTs and NTs are intraneuronal protein aggregates arranged in paired helical filaments, formed by hyperphosphorylation of the microtubule associated protein tau.All three features occur in an increasing number during the progression of AD, 1 with prominence in the temporal neocortex, entorhinal cortex and hippocampus in the early phases.1 Degenerative changes in these structures play a major role in the memory dysfunction observed at early stages of AD.2 3 Which underlying abnormality drives the dysfunction remains unknown, and few data are available regarding the relation of NFT formation and amyloid deposition in these structures to specific cognitive functions.We characterised hippocampal tau and amyloid pathology in the brains of participants of two independent cohorts. Specifically, we quantified NFTs, NTs and amyloid plaques in the entorhinal cortex and hippocampus, explored the degree to which they relate to memory and other cognitive abilities assessed proximate to death...

Cognition and Amyloid Load in Alzheimer Disease Imaged With Florbetapir F 18(AV-45) Positron Emission Tomography

“…These results conceptually concur with recent reports that greater [ 11 C]-PIB uptake is associated with poorer episodic memory in individuals with MCI as well as cognitively normal controls (5, 6, 16–20)(21) and that hippocampal amyloid plaque number (quantitated in autopsy samples) is associated with memory impairment(22). In our cohort, one of two HC participants with cortical SUVRs well within the AD range had evidence of impairment in episodic recall and has been observed to develop memory complaints on followup, suggesting that that participant now meets criteria for amnestic MCI.…”

Cognition and Amyloid Load in Alzheimer Disease Imaged With Florbetapir F 18(AV-45) Positron Emission Tomography

“…These results conceptually concur with recent reports that greater [ 11 C]-PIB uptake is associated with poorer episodic memory in individuals with MCI as well as cognitively normal controls (5, 6, 16–20)(21) and that hippocampal amyloid plaque number (quantitated in autopsy samples) is associated with memory impairment(22). In our cohort, one of two HC participants with cortical SUVRs well within the AD range had evidence of impairment in episodic recall and has been observed to develop memory complaints on followup, suggesting that that participant now meets criteria for amnestic MCI.…”

Association of Subjective Memory Complaints with the Left Parahippocampal Amyloid Burden in Mild Cognitive Impairment

“…The present study reported an association between A␤ deposition and SMC in individuals with MCI. These observations are in line with neuropathology literature reporting the number of plaques and neurofibrillary tangles in the entorhinal cortex is inversely related to poor memory function [28]. These findings could also suggest a potential temporal sequence of two different AD pathologies in the parahippocampus related to self-perception of cognitive worsening; correlation of SMC with tauopathy in cognitively normal individuals and with A␤ deposition in individuals with MCI.…”

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

“…One potential explanation for this is that individuals with reduced PE do not optimally benefit from previous exposure to test material, suggesting worse consolidation and retention of recently learned information induced by deficits in the integrity of their learning and memory system. Impairments in learning and retention of new information have been determined to be the earliest and most robust manifestation of AD, which is in line with consistent observations that AD pathology typically manifests earliest in the MTL and specifically the hippocampal and perirhinal regions that play a crucial role in the learning and consolidation system (Reitz et al, 2009). Our finding that lower PE are associated with greater global amyloid burden and tau deposition in the entorhinal cortex contribute to previous work suggesting that we can potentially capture the first, subtle alterations in learning in preclinical AD by capitalizing on the phenomenon of PE (Samaroo et al, 2020).…”

Cognition and Amyloid Load in Alzheimer Disease Imaged With Florbetapir F 18(AV-45) Positron Emission Tomography

“…These results conceptually concur with recent reports that greater [ 11 C]-PIB uptake is associated with poorer episodic memory in individuals with MCI as well as cognitively normal controls (5, 6, 16–20)(21) and that hippocampal amyloid plaque number (quantitated in autopsy samples) is associated with memory impairment(22). In our cohort, one of two HC participants with cortical SUVRs well within the AD range had evidence of impairment in episodic recall and has been observed to develop memory complaints on followup, suggesting that that participant now meets criteria for amnestic MCI.…”

Association of Subjective Memory Complaints with the Left Parahippocampal Amyloid Burden in Mild Cognitive Impairment

“…The present study reported an association between A␤ deposition and SMC in individuals with MCI. These observations are in line with neuropathology literature reporting the number of plaques and neurofibrillary tangles in the entorhinal cortex is inversely related to poor memory function [28]. These findings could also suggest a potential temporal sequence of two different AD pathologies in the parahippocampus related to self-perception of cognitive worsening; correlation of SMC with tauopathy in cognitively normal individuals and with A␤ deposition in individuals with MCI.…”

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

“…One potential explanation for this is that individuals with reduced PE do not optimally benefit from previous exposure to test material, suggesting worse consolidation and retention of recently learned information induced by deficits in the integrity of their learning and memory system. Impairments in learning and retention of new information have been determined to be the earliest and most robust manifestation of AD, which is in line with consistent observations that AD pathology typically manifests earliest in the MTL and specifically the hippocampal and perirhinal regions that play a crucial role in the learning and consolidation system (Reitz et al, 2009). Our finding that lower PE are associated with greater global amyloid burden and tau deposition in the entorhinal cortex contribute to previous work suggesting that we can potentially capture the first, subtle alterations in learning in preclinical AD by capitalizing on the phenomenon of PE (Samaroo et al, 2020).…”

Cognition and Amyloid Load in Alzheimer Disease Imaged With Florbetapir F 18(AV-45) Positron Emission Tomography

“…These results conceptually concur with recent reports that greater [ 11 C]-PIB uptake is associated with poorer episodic memory in individuals with MCI as well as cognitively normal controls (5, 6, 16–20)(21) and that hippocampal amyloid plaque number (quantitated in autopsy samples) is associated with memory impairment(22). In our cohort, one of two HC participants with cortical SUVRs well within the AD range had evidence of impairment in episodic recall and has been observed to develop memory complaints on followup, suggesting that that participant now meets criteria for amnestic MCI.…”

Association of Subjective Memory Complaints with the Left Parahippocampal Amyloid Burden in Mild Cognitive Impairment

“…The present study reported an association between A␤ deposition and SMC in individuals with MCI. These observations are in line with neuropathology literature reporting the number of plaques and neurofibrillary tangles in the entorhinal cortex is inversely related to poor memory function [28]. These findings could also suggest a potential temporal sequence of two different AD pathologies in the parahippocampus related to self-perception of cognitive worsening; correlation of SMC with tauopathy in cognitively normal individuals and with A␤ deposition in individuals with MCI.…”

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

“…One potential explanation for this is that individuals with reduced PE do not optimally benefit from previous exposure to test material, suggesting worse consolidation and retention of recently learned information induced by deficits in the integrity of their learning and memory system. Impairments in learning and retention of new information have been determined to be the earliest and most robust manifestation of AD, which is in line with consistent observations that AD pathology typically manifests earliest in the MTL and specifically the hippocampal and perirhinal regions that play a crucial role in the learning and consolidation system (Reitz et al, 2009). Our finding that lower PE are associated with greater global amyloid burden and tau deposition in the entorhinal cortex contribute to previous work suggesting that we can potentially capture the first, subtle alterations in learning in preclinical AD by capitalizing on the phenomenon of PE (Samaroo et al, 2020).…”