Jintao Sheng

All Publications

• Longitudinal trajectories of divergent cortical tau patterns in preclinical Alzheimer's disease. Brain : a journal of neurology Young, C. B., Sheng, J., Winer, J. R., Cody, K., Sai, I., Carlson, M. L., Younes, K., Insel, P. S., Schultz, A. P., Mormino, E. C. 2026

  Abstract

  Approximately 10% of clinically unimpaired individuals with abnormal amyloid (A+; preclinical Alzheimer's disease) have "divergent" cortical tau pathology (A+TCortical+), defined as greater than expected tau in cortical regions relative to medial temporal lobe and/or cortical asymmetry on tau PET in addition to or instead of traditional medial temporal lobe tau burden. Although these A+TCortical+ individuals have subtle cognitive deficits at baseline, the longitudinal imaging and clinical outcomes are unknown. We aimed to characterize longitudinal trajectories of A+TCortical+ individuals compared to other biomarker-defined clinically unimpaired groups given that identifying those at highest risk for decline is critical for informing prevention trials and understanding early disease mechanisms. In this longitudinal study, we examined tau PET, MRI, cognitive, and functional data from 395 clinically unimpaired participants, ages 65 to 85 years, enrolled in the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study. Participants had 2-5 flortaucipir scans over a mean (standard deviation) follow-up period of 4.7 (1.6) years. Change in regional and voxelwise tau patterns, atrophy, cognition, and functioning were examined. Longitudinal trajectories from A+TCortical+ (n=34) were compared to preclinical Alzheimer's disease with elevated tau PET signal in medial temporal lobe only (A+TMTL+, n=102), preclinical Alzheimer's disease without significant tau (A+TMTL-, n=210), and those without amyloid or tau (A-TMTL-, n=49). Cortical tau accumulation was fastest in A+TCortical+ (0.018-0.034 standardized uptake value ratios per year), whereas medial temporal lobe tau accumulation was comparable across A+TCortical+, A+TMTL+, and A+TMTL- groups (0.010-0.013 standardized uptake value ratios per year). Tau continued to accumulate in affected regions and contralateral homotopic regions in A+TCortical+ participants with asymmetrical tau at baseline such that asymmetrical patterns were maintained over time. Younger A+TCortical+ participants had an especially fast cortical accumulation rate. The A+TCortical+ group showed significantly greater neurodegeneration and faster clinical decline (Clinical Dementia Rating Scale Sum of Boxes = 0.610 points per year; Mini-Mental State Examination = -0.780 points per year) than all other biomarker-defined subgroups (Clinical Dementia Rating Scale Sum of Boxes = 0.048-0.182 points per year; Mini-Mental State Examination = -0.189-0.006 points per year). In summary, individuals with divergent cortical tau patterns continue to accumulate cortical tau at a faster rate, show greater neurodegeneration, and have faster cognitive and functional decline than other preclinical Alzheimer's disease subgroups. Clinical trials and research examining tau progression and clinical decline in preclinical Alzheimer's disease without subtyping may be disproportionately influenced by this small, high-risk subgroup.

  View details for DOI 10.1093/brain/awag113

  View details for PubMedID 41885175

• Alzheimer's Imaging Consortium. Alzheimer's & dementia : the journal of the Alzheimer's Association Trelle, A. N., Sheng, J., Tran, T. T., Wilson, T. N., Sai, I., Romero, A., Park, J., Guerra, L. M., Deutsch, G. K., Wagner, A. D., Mormino, E. C. 2025; 21 Suppl 8 (Suppl 8): e110143

  Abstract

  Episodic memory function in aging varies considerably both across individuals and within individuals over time. Identifying factors that explain variance in memory is important for improving prediction of risk for cognitive decline in older adults. Here we examine associations of structural, functional, and molecular factors with cross-sectional and longitudinal memory function in a normal aging cohort.Participants were enrolled in the Stanford Aging and Memory Study (SAMS; N = 212; mean age: 69.5 ± 5.8 years, 57% female) and cognitively unimpaired at baseline. As part of an ongoing longitudinal extension of SAMS, a subset of participants (N = 79) have returned for longitudinal cognitive assessment (mean follow-up: 7.08 ± 1.14 years). Memory was assessed using a composite score comprised of delayed recall subtests from Logical Memory, Hopkins Verbal Learning Test and the Brief Visual Memory Test. Baseline predictors of interest included Lumipulse CSF pTau181, hippocampus volume from manually segmented T2-structural MRI, and fMRI measures of neural selectivity and cortical reinstatement measured during associative memory encoding and retrieval, respectively. Linear models and linear mixed effects models examined cross-sectional and longitudinal associations, respectively, between predictors of interest and memory performance. All models included age, sex, and education as covariates.All baseline predictors exhibited significant associations with age (p < .005). Among baseline predictors, associations were observed between reinstatement and neural selectivity (β = 0.37, p < .001) and between reinstatement and CSF pTau181 (β = -0.20, p < .05). Cross-sectional effects with the memory composite were observed across both functional measures (neural selectivity: β = 0.20, p < .01; reinstatement: β = 0.20, p < .001). Associations with CSF pTau (p < .001) and hippocampus volume (p < .01) were observed when examining longitudinal change in memory over time. A trend level association between neural selectivity and longitudinal memory performance was also present (p = .07).Functional, structural, and molecular markers relevant for aging and Alzheimer's disease independently impact memory performance in human aging. Combining these measures may improve the prediction of clinically meaningful decline and elucidate factors that promote cognitive maintenance in older age.

  View details for DOI 10.1002/alz70862_110143

  View details for PubMedID 41434279

  View details for PubMedCentralID PMC12726113

• Alzheimer's Imaging Consortium. Alzheimer's & dementia : the journal of the Alzheimer's Association Sai, I., Trelle, A. N., Sheng, J., Young, C. B., Younes, K., Park, J., Guerra, L. M., Romero, A., Vossler, H., Wagner, A. D., Mormino, E. C. 2025; 21 Suppl 8 (Suppl 8): e109870

  Abstract

  Decline in episodic memory and proper name retrieval are common in aging and may be linked to early Alzheimer's pathology in medial and ventral temporal cortex. We investigated associations between regional tau PET, associative memory, and proper name retrieval in a normal aging cohort.Participants were 59 cognitively unimpaired older adults (mean age = 75.97 ± 6.04 years, 61% female) from the Stanford Aging and Memory Study (SAMS). Participants completed a word-picture (famous face or place) associative memory task concurrent with fMRI and a post-scan cued-recall test for word-image associations. Proper name recall for face and place stimuli from the memory test was assessed on a separate visit 3.6 ± 3.82 months following the associative memory paradigm. Regional Tau accumulation was measured using 18F-PI2620 PET, and standardized uptake value ratios (SUVRs) were extracted from the entorhinal cortex (ERC) and ventral temporal cortex (VTC; comprised of parahippocampal, inferior temporal, and fusiform gyrus). Linear and logistic mixed-effects models assessed the associations between name recall, associative memory and tau PET controlling for age, sex, education, category, and random intercepts for subject.Regional Tau in ERC (β = -0.52, p < .01) and VTC (β = -0.68, p < .01) was negatively associated with naming scores, with a stronger association for face stimuli (Tau x Category: p = 0.02; Figure 1). ERC Tau was negatively related to associative d' (in-scan category memory) (β = -1.52, p = 0.037; Figure 2). Within individuals, item-level analyses revealed a positive association between proper name recall and post-scan test word-image pair cued-recall, with a stronger association observed for face stimuli (β = 1.2, p < .01; Figure 3A). Across individuals, naming score was positively associated with both associative d' (β = 0.97, p = 0.028; Figure 3B) and word-image pair recall (β = 0.28, p < 0.01; Figure 3C).These findings suggest early tau burden is linked to impairments in episodic memory and proper name retrieval in aging. Furthermore, proper name retrieval is positively related to associative memory both within and across individuals, suggesting an influence of semantic knowledge on episodic memory.

  View details for DOI 10.1002/alz70862_109870

  View details for PubMedID 41433454

  View details for PubMedCentralID PMC12724792

• Continuum of Core 1 Biomarkers in Preclinical Alzheimer's Disease. medRxiv : the preprint server for health sciences Digma, L. A., Young, C. B., Winer, J. R., Cody, K. A., Younes, K., Sheng, J., Insel, P. S., Rissman, R. A., Sperling, R., Mormino, E. C. 2025

  Abstract

  Background and Objectives: Biological Staging for Alzheimer's disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma ptau-217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predicts progression of downstream biomarkers and cognition.Methods: We used baseline plasma ptau-217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between continuous baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether continuous p-tau217 and amyloid-PET burden within this group was associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage.Results: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, continuous baseline plasma p-tau217 and amyloid-PET burden were independently associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean follow-up time for both tau-PET and MRI: 4.2 years), as well as faster cognitive decline (mean follow-up time for PACC: 5.7 years) (all p<0.05). Plasma p-tau217 and amyloid-PET burden were independently associated with higher risk of progression to Biological Stage B+.Discussion: In CU individuals, early changing AD biomarkers during the initial stage of AD (Biological Stage A) provide prognostic information of downstream markers of disease. Evaluation of the utility of these continuous measures in a real-world setting is warranted.Clinical Trial Information: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2023. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.

  View details for DOI 10.1101/2025.09.17.25336007

  View details for PubMedID 41001450

• Synergistic effects of APOE ε4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults. bioRxiv : the preprint server for biology Trelle, A. N., Sheng, J., Wilson, E. N., Romero, A., Park, J., Deutsch, G. K., Sha, S. J., Greicius, M. D., Andreasson, K. I., Kerchner, G. A., Mormino, E. C., Wagner, A. D. 2025

  Abstract

  Amyloid-β (Aβ) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE ε4, a key genetic risk factor for Alzheimer's disease (AD). Although the presence of Aβ, tau, and APOE ε4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9±5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. Aβ was measured using CSF Aβ 42 /Aβ 40 or Florbetaben-PET imaging and tau was measured using CSF pTau 181 . Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE ε4 was independently associated with greater Aβ and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE ε4. Among APOE ε4 non-carriers, Aβ burden was linked to a pattern of hippocampal hyperactivity. Among APOE ε4 carriers, CSF pTau 181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE ε4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD.Hippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimer's disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by APOE ε4 in cognitively unimpaired older adults. Amyloid-β-related hyperactivity was observed in the hippocampus among APOE ε4 non-carriers, while CSF pTau 181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE ε4 carriers. Our findings highlight synergistic effects of APOE and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.

  View details for DOI 10.1101/2025.06.20.660774

  View details for PubMedID 40667041

  View details for PubMedCentralID PMC12262513

• Top-down attention and Alzheimer's pathology affect cortical selectivity during learning, influencing episodic memory in older adults. Science advances Sheng, J., Trelle, A. N., Romero, A., Park, J., Tran, T. T., Sha, S. J., Andreasson, K. I., Wilson, E. N., Mormino, E. C., Wagner, A. D. 2025; 11 (24): eads4206

  Abstract

  Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During learning, neural selectivity in place- and, to a lesser extent, face-selective regions was greater for subsequently remembered than forgotten events; positively scaled with variability in dorsal attention network activity, within and across individuals; and negatively related to AD pathology, evidenced by elevated plasma phosphorylated Tau181 (pTau181). Path analysis revealed that neural selectivity mediated the effects of age, attention, and pTau181 on memory. These data reveal multiple pathways that contribute to memory differences among older adults-AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.

  View details for DOI 10.1126/sciadv.ads4206

  View details for PubMedID 40512843

• Top-down attention and Alzheimer's pathology impact cortical selectivity during learning, influencing episodic memory in older adults. bioRxiv : the preprint server for biology Sheng, J., Trelle, A. N., Romero, A., Park, J., Tran, T. T., Sha, S. J., Andreasson, K. I., Wilson, E. N., Mormino, E. C., Wagner, A. D. 2024

  Abstract

  Human aging affects the ability to remember new experiences, in part, because of altered neural function during memory formation. One potential contributor to age-related memory decline is diminished neural selectivity -- i.e., a decline in the differential response of cortical regions to preferred vs. non-preferred stimuli during event perception -- yet the factors driving variability in neural selectivity with age remain unclear. We examined the impact of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity during memory encoding in 156 cognitively unimpaired older participants who underwent fMRI while performing a word-face and word-scene associative memory task. Neural selectivity in face- and place-selective cortical regions was greater during events that were later remembered compared to forgotten. Critically, neural selectivity during learning positively scaled with memory-related variability in top-down attention, whereas selectivity negatively related to early AD pathology, evidenced by elevated plasma pTau181. Path analysis revealed that neural selectivity at encoding mediated the effects of age, top-down attention, and pTau181 on associative memory. Collectively, these data reveal multiple pathways that contribute to memory differences among older adults -- AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.

  View details for DOI 10.1101/2024.12.04.626911

  View details for PubMedID 39713293

  View details for PubMedCentralID PMC11661099

• Intersubject similarity in neural representations underlies shared episodic memory content PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sheng, J., Wang, S., Zhang, L., Liu, C., Shi, L., Zhou, Y., Hu, H., Chen, C., Xue, G. 2023; 120 (35): e2308951120

  Abstract

  Individuals generally form their unique memories from shared experiences, yet the neural representational mechanisms underlying this subjectiveness of memory are poorly understood. The current study addressed this important question from the cross-subject neural representational perspective, leveraging a large functional magnetic resonance imaging dataset (n = 415) of a face-name associative memory task. We found that individuals' memory abilities were predicted by their synchronization to the group-averaged, canonical trial-by-trial activation level and, to a lesser degree, by their similarity to the group-averaged representational patterns during encoding. More importantly, the memory content shared between pairs of participants could be predicted by their shared local neural activation pattern, particularly in the angular gyrus and ventromedial prefrontal cortex, even after controlling for differences in memory abilities. These results uncover neural representational mechanisms for individualized memory and underscore the constructive nature of episodic memory.

  View details for DOI 10.1073/pnas.2308951120

  View details for Web of Science ID 001138989500001

  View details for PubMedID 37603733

  View details for PubMedCentralID PMC10466090

• Higher-dimensional neural representations predict better episodic memory SCIENCE ADVANCES Sheng, J., Zhang, L., Liu, C., Liu, J., Feng, J., Zhou, Y., Hu, H., Xue, G. 2022; 8 (16): eabm3829

  Abstract

  Episodic memory enables humans to encode and later vividly retrieve information about our rich experiences, yet the neural representations that support this mental capacity are poorly understood. Using a large fMRI dataset (n = 468) of face-name associative memory tasks and principal component analysis to examine neural representational dimensionality (RD), we found that the human brain maintained a high-dimensional representation of faces through hierarchical representation within and beyond the face-selective regions. Critically, greater RD was associated with better subsequent memory performance both within and across participants, and this association was specific to episodic memory but not general cognitive abilities. Furthermore, the frontoparietal activities could suppress the shared low-dimensional fluctuations and reduce the correlations of local neural responses, resulting in greater RD. RD was not associated with the degree of item-specific pattern similarity, and it made complementary contributions to episodic memory. These results provide a mechanistic understanding of the role of RD in supporting accurate episodic memory.

  View details for DOI 10.1126/sciadv.abm3829

  View details for Web of Science ID 000786214100024

  View details for PubMedID 35442734

  View details for PubMedCentralID PMC9020666