Event boundaries and temporal context shape the organization of episodic memories. We hypothesized that attentional fluctuations during encoding serve as “events” that affect 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 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. We also highlight the numerous challenges in striking a balance between sustained attention tasks (long blocks of a repetitive task) and memory recall tasks (short lists of unique items) and describe strategies for researchers interested in uniting these two fields.

Objective To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF beta-amyloid (A beta)(42)/A beta(40) and phosopho-tau181 (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 years; 94 female) completed a lumbar puncture and memory assessments. CSF A beta(42), A beta(40), and 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 (wordpicture) 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 among memory performance, age, and CSF measures, controlling for sex and education. Results Age and lower A beta(42)/A beta(40) were independently associated with elevated p-tau181. Age, A beta 42/A beta 40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of A beta(42)/A beta(40) on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF A beta(42) 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 CU with preclinical AD pathology.

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.

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 negatively with longitudinal memory decline 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.

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.

Measurement of the spatial distribution of Tau pathology is critical for early diagnosis and disease monitoring. We sought to investigate a novel Tau PET ligand, 18F-PI2620, in aging and throughout the spectrum of Alzheimer's disease (AD). Seventeen participants within known Amyloid status (via CSF or Amyloid PET) underwent Tau PET scanning with 18F-PI2620 on a GE PET-MRI scanner: ten older clinically normal (CN) individuals (five Amyloid- CN, mean age=72.6±4.0; and five Amyloid+ CN, mean age=72.2±6.8), six clinically impaired patients on the AD trajectory (mean age=65.0±8.2; three Amyloid+ Mild Cognitive Impairment and three Amyloid+ AD dementia), as well as one Amyloid- patient with Dementia with Lewy Bodies (DLB). Standardized uptake value ratios were computed 60-90 minutes post-injection and normalized to the inferior cerebellum. We examined target regions known to show high Tau uptake in AD (entorhinal cortex, hippocampus, amygdala, inferior temporal cortex, precuneus, and lateral parietal cortex). Group differences (Amyloid- CN vs. Amyloid+ CN vs. Amyloid+ Impaired) in regional Tau were assessed with Wilcoxon signed-rank tests, whereas associations between continuous CSF measures (Aβ42 and pTau) with regional Tau within the CN group were assessed with Spearman's Rank correlation coefficients. Compared to Amyloid- CN, Amyloid+ CN showed greater PI2620 uptake in entorhinal cortex, hippocampus, and amygdala (p-values<0.032). The Amyloid+ Impaired group showed elevated Tau in all regions compared to Amyloid- CN (p-values<0.008), as well as elevated Tau in inferior temporal cortex (p= 0.016), precuneus (p<0.001), and lateral parietal cortex (p<0.001) compared to the Amyloid+ CN group (Figure 1). Within the CN group, continuous levels of CSF Aβ42 were negatively associated with elevated Tau PET in entorhinal cortext (p=0.026), hippocampus (p=0.004), and amygdala (p=0.007). CSF pTau was not related to any regional Tau PET value (Figure 2). The Amyloid- DLB case did not show evidence of uptake in any Tau PET region.

Memory decline is a key feature of cognitive aging, even among putatively healthy individuals who do not meet clinical criteria for cognitive impairment. However, the magnitude of this decline varies considerably across individuals. Emerging evidence suggests that two hallmark AD pathologies, including the aberrant accumulation of the beta-amyloid (AB) and tau proteins, are present decades before clinical diagnosis of dementia. The Stanford Aging and Memory Study (SAMS) examines the contribution of abnormal AD biomarkers, together with changes in brain structure and function, to individual differences in episodic memory among healthy older adults. Cognitively normal older adults aged 60-88 years (CDR=0) provided molecular (CSF phospho-tau, AB42) biomarkers of Alzheimer's disease (AD) and underwent ultra-high resolution 7T structural MRI and whole-brain high-resolution functional MRI (fMRI). The structural metrics obtained here include CA1-SRLM thickness, ERC thickness, whole hippocampal volume, and DG/CA3 subfield volume. During high-resolution fMRI, participants engaged in encoding and retrieval phases of an associative memory task, yielding univariate measures of regional BOLD activity and multivariate measures of cortical reinstatement during memory retrieval. Behavioural measures of item memory and associative recollection werealso obtained. Functional measures of (a) univariate BOLD activity in the hippocampus and (b) hippocampal-mediated cortical reinstatement in ventral temporal and parietal cortex during memory retrieval explained significant variance in associative memory performance across participants. CSF AB42 exhibited a marginally significant positive relationship with associative memory and neuropsychological tests of delayed recall, and a significant positive relationship with CA1-SRLM thickness, DG/CA3 volume, and total hippocampal volume; by contrast, p-tau showed a significant negative relationship with reduced CA1-SRLM thickness. These initial results suggest that the presence of abnormal AD biomarkers exert early effects on both hippocampal microstructure and individual differences in memory among cognitively normal older adults. The results also reveal that fMRI assays of hippocampal-mediated retrieval processes partially explain individual differences in memory performance. Ongoing analyses will further examine the relationships between age-related changes in the functional and structural integrity of the hippocampus and MTL cortex, continuous levels of CSF AB42 and p-tau, and their unique or combined contributions to individual differences in episodic memory in cognitively normal older adults.