Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

Why do we sometimes easily retrieve memories, but other times appear to forget them? We often look to our external environment for retrieval cues, but another way to optimize memory retrieval is to be in a mental state, or mode, that prioritizes access to our internal representation of the world. Such a 'retrieval mode' was proposed by Endel Tulving (1983), who considered it a neurocognitive state in which one keeps the goal of memory retrieval in mind. Building on Tulving's proposal, we review converging evidence from multiple lines of research that emphasize the importance of internal states in the instantiation of retrieval modes that optimize successful remembering. We identify three key factors that contribute to a retrieval mode by modulating either the likelihood or the content of retrieval: (1) an intention to remember or forget (either in the present or the future), (2) attentional selection of goalrelevant memories and suppression of distractors, and (3) fluctuating levels of acetylcholine in the hippocampus. We discuss empirical evidence that these internal states individually influence memory retrieval and propose how they may interact synergistically. Characterizing these dynamic internal factors is an important key for unlocking our understanding of the organization and accessibility of our memories.

Objective:To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer’s disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).Methods:CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied ‘target’ objects, novel ‘foil’ objects, and perceptually similar ‘lure’ objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.Results:Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.Conclusions:Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

Why do we sometimes easily retrieve memories, but other times appear to forget them? We often look to our external environment for retrieval cues, but another way to optimize memory retrieval is to be in a mental state, or mode, that prioritizes access to our internal representation of the world. Such a ‘retrieval mode’ was proposed by Endel Tulving (1983), who considered it a neurocognitive state in which one keeps the goal of memory retrieval in mind. Building on Tulving’s proposal, we review converging evidence from multiple lines of research that emphasize the importance of internal states in the instantiation of retrieval modes that optimize successful remembering. We identify three key factors that contribute to a retrieval mode by modulating either the likelihood or the content of retrieval: (1) an intention to remember or forget (either in the present or the future), (2) attentional selection of goal-relevant memories and suppression of distractors, and (3) fluctuating levels of acetylcholine in the hippocampus. We discuss empirical evidence that these internal states individually influence memory retrieval and propose how they may interact synergistically. Characterizing these dynamic internal factors is an important key for unlocking our understanding of the organization and accessibility of our memories.

Prior fMRI studies have reported relationships between memory-related activity in the hippocampus and in-scanner memory performance, but whether such activity is predictive of longitudinal memory change remains unclear. Here, we administered a neuropsychological test battery to a sample of cognitively healthy older adults on three occasions, the second and third sessions occurring one month and three years after the first session. Structural and functional MRI data were acquired between the first two sessions. The fMRI data were derived from an associative recognition procedure and allowed estimation of hippocampal effects associated with both successful associative encoding and successful associative recognition (recollection).Baseline memory performance and memory change were evaluated using memory component scores derived from a principal components analysis of the neuropsychological test scores.Across participants, right hippocampal encoding effects correlated significantly with baseline memory performance after controlling for chronological age. Additionally, both left and right hippocampal associative recognition effects correlated significantly with longitudinal memory change after controlling for age, and the relationship with the left hippocampal effect remained after also controlling for left hippocampal volume. Thus, in cognitively healthy older adults, the magnitude of hippocampal recollection effects appears to be a robust predictor of future memory change.

Event boundaries and temporal context shape the organization of episodic memories. We hypothesized that attentional fluctuations during encoding serve as “events” that shape temporal context representations and recall organization. Individuals encoded trial-unique objects during a modified sustained attention task. Memory was tested with free recall. Response time variability during the encoding tasks was used to characterize “in the zone” and "out of the zone" attentional states. We predicted that: 1) “in the zone”, vs. “out of the zone”, attentional states should be more conducive to maintaining temporal context representations that can cue temporally organized recall; and 2) temporally distant “in the zone” states may enable more recall “leaps” across intervening items. We replicated several important findings in the sustained attention and memory fields, including more online errors during “out of the zone” vs “in the zone” attentional states, and recall that was temporally structured. Yet, across four studies, we found no consistent evidence for either of our main hypotheses. Recall was robustly temporally organized, and there was no difference in recall organization for items encoded “in the zone” vs “out of the zone”. We conclude that temporal context serves as a strong scaffold for episodic memory, one that can support organized recall even for items encoded during relatively poor attentional states.

Blood labeling duration (LD) and postlabeling delay (PLD) design in the experiments T1 t2 t3 t4 t5 t6 t7 t8 t9 t10 t11 t12 LD (s) 1.

2Age-related episodic memory decline is characterized by striking heterogeneity across 36 individuals. Hippocampal pattern completion is a fundamental process supporting episodic 37 memory. Yet, the degree to which this mechanism is impaired with age, and contributes to 38 variability in episodic memory, remains unclear. We combine univariate and multivariate 39 analyses of fMRI data from a large cohort of cognitively normal older adults (N=100; 60-82 40 yrs) to measure hippocampal activity and cortical reinstatement during retrieval of trial-41 unique associations. Trial-wise analyses revealed that hippocampal activity predicted 42 cortical reinstatement strength, and these two metrics of pattern completion independently 43 predicted retrieval success. However, increased age weakened cortical reinstatement and 44 its relationship to memory behaviour. Critically, individual differences in the strength of 45 hippocampal activity and cortical reinstatement explained unique variance in performance 46 across multiple assays of episodic memory. These results indicate that fMRI indices of 47 hippocampal pattern completion explain within-and across-individual memory variability in 48 older adults. 49 50 51 52 53 54 55 56 57 3 Episodic memory -in particular the ability to form and retrieve associations between multiple 58 event elements that comprise past experiences -declines with age (1-3). Retrieval of an 59 episodic memory relies critically on hippocampal-dependent pattern completion, which 60 entails reactivation of a stored memory trace by the hippocampus in response to a partial 61 cue, leading to replay of cortical activity patterns that were present at the time of memory 62 encoding (4-7). Given observed links between in vivo measures of pattern completion and 63 episodic remembering (8-10), and evidence of altered hippocampal function with age (11-64 12), changes in hippocampal pattern completion may play an important role in explaining 65 age-related impairments in episodic memory. While a leading hypothesis, the degree to 66 which the integrity of pattern completion can explain (a) trial-to-trial differences in episodic 67 remembering within older adults and (b) differences in memory performance between older 68 individuals remain underspecified. 69Functional MRI (fMRI) studies in younger adults suggest that hippocampal pattern 70 completion is associated with at least two key neural markers: (a) an increase in 71 hippocampal univariate activity (13-15) and (b) cortical reinstatement of content-specific 72 activity patterns present during encoding (16-18). Multivariate pattern analyses --machine 73 learning classification (19) and pattern similarity (20) --reveal evidence for cortical 74 reinstatement of categorical event features (10, 21-22) and event-specific details (23-25) 75 during successful recollection. Moreover, hippocampal and cortical metrics of pattern 76 completion covary, such that trial-wise fluctuations in hippocampal univariate retrieval 77 activity predict the strength of cortical r...