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.

Purpose In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). Methods Forty-nine participants were scanned with 18 F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. Results SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18 F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. Conclusion Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18 F-PI-2620 in patients along the AD trajectory. This work confirms that 18 F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

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.

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...

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