Introduction

Episodic memory is one of the first cognitive functions that declines with aging1 and Alzheimer’s disease (AD)2. Co-activation of medial temporal lobe (MTL) and posteromedial cortex (PMC) regions, which can be measured using functional magnetic resonance imaging (fMRI) and functional connectivity (FC) analysis, plays a critical role in supporting episodic memory encoding and retrieval3,4,5. In cognitively unimpaired older adults, cross-sectional studies reported connectivity alterations in this episodic memory network of MTL and PMC regions during resting-state (task-free) fMRI, particularly lower connectivity with aging6,7 and both higher an lower connectivity with early AD pathology8,9,10. However, most findings are based on resting-state fMRI, as only a few studies have examined FC of the episodic memory network in older adults during memory encoding or retrieval, or across multiple fMRI paradigms that combine rest and task states11,12,13. Moreover, it is unclear which network changes are dysfunctional and related to detrimental processes, i.e. production and spread of AD pathology, and which network changes could be beneficial or compensatory for memory performance14,15.

Accumulation of AD pathology, consisting of tau tangles starting within the MTL and amyloid-beta (Aβ) plaques occurring early within the PMC16,17, begins while older adults are still cognitively unimpaired18,19. The vulnerability of the MTL and the PMC to AD pathology on the one hand, and the importance of these regions for episodic memory on the other hand, highlights the need to better understand how changes in the functional dynamics of MTL and PMC relates to AD risk factors and pathology in cognitively unimpaired older adults[20](https://www.nature.com/articles/s41598-025-21596-0#ref-CR20 “Vogel, J. W. et al. Connectome-based modelling of neurodegenerative diseases: Towards precision medicine and mechanistic insight. Nat. Rev. Neurosci. https://doi.org/10.1038/s41583-023-00731-8

(2023).“). AD pathology can be measured via positron emission tomography (PET), and is associated with higher neural activity in cognitively unimpaired older adults15,21,22. Further, findings from predominantly resting-state FC (rsFC) studies suggest complex dynamics between connectivity, AD pathology, and episodic memory performance in older individuals. Increasing rsFC strength, or “hyperconnectivity”, within the MTL and between the MTL and the PMC could drive tau spread across the brain and thus represent an important factor in disease progression23,24,25. On the other hand, decreasing rsFC strength, or “hypoconnectivity”, and hypometabolism within the PMC have been linked to the accumulation of Aβ pathology and could represent a disconnection within the PMC26,27,28. Hypoconnectivity within the PMC at rest has been further related to cognitive decline in previous studies27,29,30,31, while hyperconnectivity between the MTL and the PMC at rest has been suggested to be detrimental for cognition25,[32](https://www.nature.com/articles/s41598-025-21596-0#ref-CR32 “Jiang, Y. et al. Alzheimer’s biomarkers are correlated with brain connectivity in older adults differentially during resting and task states. Front. Aging. Neurosci. https://doi.org/10.3389/fnagi.2016.00015

(2016).“). However, other studies also found a positive association9,33,34 or no relationship35 between MTL-PMC rsFC strength and cognitive performance in older adults.

The APOE4 genotype is the strongest genetic risk factor for sporadic AD and is correlated with Aβ accumulation36,37. Differences or longitudinal changes in rsFC strength involving the MTL and the PMC have also been reported in cognitively unimpaired older APOE4 carriers relative to non-carriers38,39. For instance, Salami and colleagues reported that longitudinal plasma p-tau181 increases were paralleled by elevated local hippocampal rsFC strength and subsequent reduction of hippocampus encoding-related activity in APOE4 carriers39. Further findings suggest that lower rsFC strength between episodic memory regions in APOE4 carriers is beneficial with regard to cognition30,38.

Age- and AD-related longitudinal changes in FC strength in cognitively unimpaired older adults have been investigated primarily using rsFC40,41. Only a few studies have investigated FC in parallel during rest and during the performance of cognitive tasks, such as mnemonic discrimination and delayed match-to-sample paradigms11,[32](https://www.nature.com/articles/s41598-025-21596-0#ref-CR32 “Jiang, Y. et al. Alzheimer’s biomarkers are correlated with brain connectivity in older adults differentially during resting and task states. Front. Aging. Neurosci. https://doi.org/10.3389/fnagi.2016.00015

(2016).“). These cross-sectional studies found differential associations of FC during rest and task states with AD pathology. It is, however, still unclear whether longitudinal network dynamics across rest, encoding, and retrieval show similarities or differences. Assessing network dynamics over time during different fMRI paradigms and their associations with pathology and cognitive performance measures could help to better understand the complex functional brain changes that are involved in aging and disease, which cross-sectional studies cannot offer42.

Thus, in the present preregistered study we investigated (a) how longitudinal changes in FC within and between MTL and PMC regions are related to AD pathology and the APOE4 genotype in the aging brain, (b) how these changes are related to changes in episodic memory performance, and (c) whether similar changes in FC occur during resting-state and episodic memory task fMRI. We assessed FC at rest, task-state FC during object-location episodic memory encoding and retrieval, subsequent Aβ- and tau-PET, APOE4 status, and cognitive data from the PREVENT-AD cohort of cognitively unimpaired older adults. We focused on FC strength within the MTL, within the PMC, and between the MTL and the PMC. Further information regarding the project is provided in the preregistration focusing on resting-state[43](https://www.nature.com/articles/s41598-025-21596-0#ref-CR43 “Fischer, L. Preregistration: Longitudinal and cross-sectional changes in resting-state functional connectivity of episodic memory brain areas related to ageing and risk factors for Alzheimer’s disease. Open Sci. Framew. https://doi.org/10.17605/OSF.IO/BGNY5

(2023).“) and task[44](https://www.nature.com/articles/s41598-025-21596-0#ref-CR44 “Fischer, L. Preregistration: Longitudinal and cross-sectional changes in task functional connectivity of episodic memory brain areas related to ageing and Alzheimer’s pathology. Open Sci. Framew. https://doi.org/10.17605/OSF.IO/NFRB5

(2024).“) fMRI. “FC” in the following hypotheses refers to both FC during rest and task states.

Regarding longitudinal FC strength of the episodic memory network and AD pathology, we hypothesized that i) FC shows an age-related decrease, however, ii) FC shows an increase related to higher subsequent Aβ and tau burden, especially in APOE4 carriers. Regarding longitudinal FC strength of the episodic memory network and longitudinal episodic memory performance, we hypothesized that iii) increasing FC strength could be an initial beneficial or compensatory process if predicting maintained episodic memory performance or a detrimental process if predicting decline in performance.

Results

Demographics

One hundred fifty-two cognitively unimpaired older adults (63 ± 5 years, 102 female, 59 APOE4), from the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) cohort[45](https://www.nature.com/articles/s41598-025-21596-0#ref-CR45 “Breitner, J. C. S., Poirier, J., Etienne, P. E. & Leoutsakos, J. M. Rationale and structure for a new center for studies on prevention of Alzheimer’s disease (StoP-AD). J. Prev. Alzheimers Dis. https://doi.org/10.14283/jpad.2016.121

(2016).“),46 were included. Demographics are presented in Table 1. In the current study, we focused on a subsample of PREVENT-AD participants with available longitudinal fMRI data and cross-sectional PET data. In particular, participants completed at least a baseline session of resting-state and episodic memory task fMRI, cognitive testing, and up to four years of follow-up sessions. Additionally, participants underwent PET imaging to measure Aβ using 18F-NAV4694 (NAV) and tau using 18F-flortaucipir (FTP). PET was conducted on average 63 months after the baseline session (see Fig. 1a for an overview).

Fig. 1

Study design and a priori defined regions of interest (ROIs). (a) Each participant underwent at least one baseline resting-state and task fMRI session and between 1 and 3 follow-up fMRI examinations, with the last scan taking place 4 years (48 months) after baseline. Similarly, neuropsychological RBANS assessments were conducted at baseline and at follow-up sessions. Participants also underwent PET scanning to quantify amyloid using 18F-NAV4694 and tau using 18F-flortaucipir. This took place between 7 months and 10 years after the baseline session. Numbers (N) of data for each session and modality describe the cohort after exclusions due to MRI quality control. (b) The posteromedial cortex (PMC) ROI (light green) consisted of the retrosplenial cortex, posterior cingulate cortex, and four subregions of the precuneus. The medial temporal lobe (MTL) ROI (dark green) consisted of the anterior and posterior perirhinal cortex, entorhinal cortex, lateral and medial parahippocampal cortex, and anterior and posterior hippocampus. Regions were defined using the Brainnetome atlas. fMRI, Functional Magnetic Resonance Imaging; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; PET, Positron Emission Tomography.

Functional connectivity change over time and relation to APOE4 status, age, sex, and education

Values for FC strength between each pair of regions of interest (ROIs) were derived by extracting the respective BOLD time-series and conducting ROI-to-ROI functional connectivity analysis. See Fig. 1b for details on the 13 included ROIs from the Brainnetome atlas47. We calculated the mean FC strength for each participant and session for three meta-ROIs, i.e. (i) all ROIs within MTL, ii) all ROIs within PMC, and iii) between MTL and PMC ROIs. We followed this procedure for the resting-state fMRI session and the encoding and retrieval session from an object-location episodic memory fMRI task48. During encoding, participants were presented with 48 objects on either the left or right side of the screen and indicated the side via button press. During retrieval 20 min later, participants were presented with 48 old (previously encoded) and 48 new (not previously encoded) objects. They were instructed to give one of the four following forced-choice retrieval responses: familiar object, remembered left, remembered right, or new object. Exploratory analyses were False-discovery-rate (FDR)-corrected, while preregistered analyses were not.

First, we investigated whether meta-ROI (i.e. within MTL, within PMC and between MTL and PMC) FC strength changed over time for the different fMRI paradigms (resting-state, rsFC; encoding task, encoding-FC; retrieval task, retrieval-FC). We included a time by APOE4 group interaction, age at baseline, sex, and education as covariates in linear mixed models. These models revealed that rsFC decreased within MTL (β = −0.10 [95% CI −0.19, −0.01], t = −2.199, p = 0.029), within PMC (β = −0.13 [95% CI −0.21, −0.04], t = −2.904, p = 0.004), and between MTL and PMC (β = −0.09 [95% CI −0.18, −0.00], t = −1.988, p = 0.048) over time. In contrast, encoding-FC and retrieval-FC did not change significantly over time (all p > 0.05).

There were no significant effects of APOE4 group or time by APOE4 group interactions (all p > 0.05). Higher baseline age was related to lower retrieval-FC within MTL (β = −0.18 [95% CI −0.32, −0.05], t = −2.728, p = 0.007). Further, in all models except for two — encoding-FC and retrieval-FC between the MTL and PMC — significant sex effects were observed, with females showing lower FC strength than males. See Supplementary Tables S1-9 for all models.

Exploratively, we compared the trajectories of FC strength between resting-state, encoding and retrieval. The slopes of FC strength, derived from linear mixed models including time as predictor, within MTL were positively correlated between all three fMRI paradigms and changes in FC strength within PMC were positively correlated between resting-state and encoding (r-values between 0.30 and 0.67). Interestingly, changes in MTL-PMC FC strength during rest versus encoding were negatively correlated (r = −0.19). See Table 2 for statistics.

Relationship between functional connectivity change and subsequent Aβ and tau burden

We then investigated the association of the slopes of MTL and PMC FC strength and subsequent AD pathology (i.e. Aβ- and tau-PET burden) using linear models including the interaction of FC slope by APOE4 group, age, sex, education, and time between baseline session and PET.

Regarding global neocortical Aβ burden, we found an effect of rsFC slope within PMC that differed by APOE4 group (β = −0.42 [95% CI −0.81, −0.02], t = −2.100, p = 0.038, Cohen’s f2 = 0.032; see Fig. 2a and Supplementary Table S10). Specifically, APOE4 carriers showed a steeper decrease of rsFC within PMC with more Aβ (β = −0.35 [95% CI −0.70, −0.01], t = −1.970, p = 0.054; see Supplementary Table S11), while APOE4 non-carriers had no association between rsFC slope and Aβ (β = 0.01 [95% CI −0.27, 0.29], t = 0.071, p = 0.944; see Supplementary Table S12).

Fig. 2

Change in functional connectivity (FC) strength during rest, encoding, and retrieval over time and the relationship with Alzheimer’s pathology measured via PET imaging. (a) The slope of mean resting-state FC (rsFC) strength within the posteromedial cortex (PMC), meaning the mean FC strength between PMC subregions, was differentially related to subsequent global neocortical amyloid depending on APOE genotype, with APOE4 carriers showing more amyloid with declining rsFC within PMC but not APOE4 non-carriers. (b) The slope of mean FC strength during intentional encoding within medial temporal lobe (MTL) was differentially related to subsequent entorhinal tau depending on APOE, with APOE4 carriers showing more subsequent tau with increasing encoding-FC within MTL but not APOE4 non-carriers. (c) The slope of mean FC strength during retrieval within the PMC was differentially related to subsequent entorhinal tau depending on APOE, with APOE4 carriers showing more subsequent tau with increasing retrieval-FC within PMC, and APOE4 non-carriers showing more subsequent tau with decreasing retrieval-FC within PMC. (d) The slope of mean FC strength during retrieval between MTL and PMC was related to subsequent entorhinal tau, with more subsequent tau with increasing retrieval-FC between MTL and PMC. PET, Positron Emission Tomography; FC, functional connectivity; APOE, apolipoprotein E.

There was no significant association between global Aβ burden and the slope of task-state FC strength within PMC during encoding or retrieval and no significant association between Aβ burden and the slope of FC within MTL or between MTL and PMC for any of the three paradigms (all p > 0.05; see Supplementary Tables S10 and S13—14).

Regarding entorhinal tau burden, we found an effect of encoding-FC within MTL depending on APOE4 group (β = 0.34 [95% CI 0.00, 0.68], t = 1.980, p = 0.0497, Cohen’s f2 = 0.028; see Fig. 2b and Supplementary Table S15). Specifically, APOE4 carriers showed a steeper increasing slope of encoding-FC within MTL with more entorhinal tau (β = 0.27 [95% CI −0.02, 0.55], t = 1.876, p = 0.066; see Supplementary Table S16), while APOE4 non-carriers showed no association (β = −0.04 [95% CI −0.25, 0.17], t = −0.396, p = 0.693; see Supplementary Table S17).

Across both APOE4 groups, there was a main effect of retrieval-FC within PMC, with a steeper decreasing slope being related to more entorhinal tau (β = −0.35 [95% CI −0.54, −0.15], t = −3.540, p < 0.001; see Supplementary Table S18). This effect was driven by APOE4 non-carriers, as we also found a significant interaction between retrieval-FC within PMC and APOE4 group (β = 0.58 [95% CI 0.23, 0.94], t = 3.259, p = 0.001, Cohen’s f2 = 0.105; see Fig. 2c and Supplementary Table S18). APOE4 carriers tended to show an increasing slope of retrieval-FC within PMC with more entorhinal tau (β = 0.20 [95% CI −0.07, 0.47], t = 1.459, p = 0.151; see Supplementary Table S19), while APOE4 non-carriers showed a decreasing slope of retrieval-FC within PMC with more entorhinal tau (β = −0.41 [95% CI −0.62, −0.20], t = −3.943, p < 0.001; see Supplementary Table S20). Finally, there was a main effect of retrieval-FC between MTL and PMC, with an increasing slope being related to more entorhinal tau burden (β = 0.28 [95% CI 0.06, 0.50], t = 2.540, p = 0.012; see Fig. 2d and Supplementary Table S18).

In summary, we observed distinct associations between change in FC and subsequent AD pathology burden depending on APOE4 genotype and fMRI paradigm (i.e. rest, encoding, and retrieval). In APOE4 carriers, decreasing rsFC within PMC was related to more subsequent global Aβ burden, and increasing encoding-FC within MTL was related to more subsequent entorhinal tau burden. Decreasing retrieval-FC within PMC was related to more entorhinal tau, especially in APOE4 non-carriers. Finally, increasing retrieval-FC between MTL and PMC was related to more entorhinal tau independent of APOE4 status.

Relationship between functional connectivity change and change in episodic memory performance

Finally, we investigated the association of the slopes of meta-ROI FC strength and the slopes of episodic memory performance using linear models including the interaction of FC slope by APOE4 group, age, sex, and education. Episodic memory performance was measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory index score and the corrected hit rate from the object-location episodic memory fMRI retrieval session. With respect to changes in performance over time, we observed that the RBANS delayed memory index score increased over time (β = 0.14 [95% CI 0.07, 0.21], t = 4.199, p < 0.001; see Supplementary Table S21), while the corrected hit rate decreased over time (β = −0.09 [95% CI −0.17, 0.01], t = −2.278, p = 0.023; see Supplementary Table S22).

There was a main effect of encoding-FC within PMC for both measures of memory performance. Specifically, a decrease in PMC encoding-FC over time was related to an increase in the RBANS delayed memory index score (β = −0.27 [95% CI −0.50, −0.05], t = −2.412, p = 0.017; see Supplementary Table S23) and the corrected hit rate (β = −0.37 [95% CI −0.59, −0.15], t = −3.355, p = 0.001; see Supplementary Table S24).

Further, there was a main effect of rsFC between MTL and PMC on the RBANS delayed memory index score, with an increase in FC being related to an increase in RBANS memory performance (β = 0.31 [95% CI 0.02, 0.60], t = 2.141, p = 0.043; see Supplementary Table S25 and Fig. 3a). Conversely, there was a main effect of encoding-FC between MTL and PMC, with a decrease in FC being related to an increase in the corrected hit rate performance (β = −0.26 [95% CI −0.47, 0.06], t = −2.519, p = 0.013; see Supplementary Table S24 and Fig. 3b).

Fig. 3

Episodic memory performance over time and the relationship with functional connectivity (FC) strength over time during rest and encoding. (a) Increasing resting-state FC (rsFC) between MTL and PMC was related to an increasing RBANS delayed memory index score. The slope of cognitive performance was used for visualization. (b) Increasing encoding-FC between MTL and PMC was related to decreasing encoding-task recognition performance. The slope of cognitive performance was used for visualization. RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; FC, functional connectivity; fMRI, Functional Magnetic Resonance Imaging; APOE, apolipoprotein E.

There was no association between the slope of FC strength within MTL during any of the three paradigms and memory performance (all p > 0.05), no effect of retrieval-FC strength for any region (all p > 0.05), and no effects of APOE4 genotype (all p > 0.05). Further, there were no effects of the slope of FC strength on the slope of RBANS attention index score performance (all p > 0.05). In summary, we observed differential associations between change in FC and change in episodic memory performance depending on the paradigm (i.e. rest, encoding, and retrieval) and region, with even opposing directions of associations for change in FC between MTL and PMC during rest versus during encoding (see Fig. 3).

Discussion

By analyzing longitudinal data across rest and task states, this study offers novel insights into FC changes within the episodic memory network and emphasizes differential associations with Alzheimer’s pathology and episodic memory in cognitively unimpaired older adults.

Our first aim was to study how changes in FC strength are linked to subsequent AD pathology burden. Within the PMC, decreasing FC was generally linked to more subsequent AD pathology, with decreasing FC at rest being associated with higher Aβ burden, and decreasing task-state FC during retrieval being associated with higher tau burden. While prior studies reported higher PMC task activation and higher FC between the PMC and other brain regions with more Aβ49,50,51,52, there is also evidence for hypoconnectivity within the PMC with more Aβ27,28,53. The PMC is a highly connected hub region with the highest level of basal glucose energy consumption in the brain54,55. Beside hypoconnectivity, hypometabolism within the PMC has been linked to Aβ burden. For instance, Pascoal and colleagues showed that higher global Aβ burden was related to FDG-PET measured hypometabolism in the PMC and both interacted to predict subsequent cognitive decline26. PMC hypoconnectivity is less often reported in relation to tau pathology, however, lower FC strength within the default mode network (DMN), which includes the PMC, during rest was associated with more inferotemporal tau burden in cognitively unimpaired older adults56 and FDG-PET measured hypometabolism within the PMC was related to higher local tau burden in cognitively unimpaired57 and impaired58 individuals.

Importantly, we found that the APOE4 genotype moderated the associations of FC and pathology with small to medium effect sizes, as reported in previous studies39,[59](https://www.nature.com/articles/s41598-025-21596-0#ref-CR59 “Quevenco, F. C. et al. Functional brain network connectivity patterns associated with normal cognition at Old-Age, local β-amyloid, Tau, and APOE4. Front. Aging Neurosci. https://doi.org/10.3389/fnagi.2020.00046

(2020).“). In our study, decreasing FC strength within the PMC during rest was associated with more Aβ in APOE4 carriers, while the association of decreasing task-state FC strength within the PMC during retrieval with more tau was driven by APOE4 non-carriers. The APOE4 genotype is more strongly related to Aβ60,61,62 than to tau pathology[63](https://www.nature.com/articles/s41598-025-21596-0#ref-CR63 “Cicognola, C. et al. APOE4 impact on soluble and insoluble tau pathology is mostly influenced by amyloid-beta. Brain https://doi.org/10.1093/brain/awaf016

(2025).“), and APOE4 carriers in our cohort showed significantly higher Aβ, but not tau burden. The APOE4 genotype may predispose to vulnerability for greater activity-dependent pathology accumulation15,64. A recent study in the PREVENT-AD cohort hints towards this mechanism, showing that increasing PMC activity during retrieval was related to more subsequent global Aβ burden in APOE4 carriers but not in non-carriers[65](https://www.nature.com/articles/s41598-025-21596-0#ref-CR65 “Fischer, L. et al. Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older APOE4 carriers. J. Neurosci. https://doi.org/10.1523/JNEUROSCI.1408-24

(2025).“). It is, however, unclear if there is a joint mechanism of simultaneously increasing PMC retrieval activity and decreasing FC within the PMC network, which may be pronounced in APOE4 carriers. Further, our finding of decreasing retrieval-FC within PMC being associated with more entorhinal tau specifically in APOE4 non-carriers in our sample should be investigated in future studies. This finding might be specific to primary age-related tauopathy (PART) in older individuals at low risk for AD66,67.

Overall, our results on longitudinal hypoconnectivity within the PMC suggest that disconnection or desynchronization among PMC subregions may be detrimental in the context of Aβ and tau pathology. This was previously reported for Aβ, we contribute novel evidence for this dynamic also for tau. Further, the APOE4 genotype plays a critical but complex role in these associations that warrants further investigation.

Within the MTL, we report an association of increasing task-state FC strength during encoding and more subsequent entorhinal tau burden in APOE4 carriers. A recent study found higher FC during rest within the anterior-temporal network (including the perirhinal cortex and anterior hippocampus) with advancing age in a sample of cognitively unimpaired participants and impaired patients, however, the study did not have measures for tau specifically[68](https://www.nature.com/articles/s41598-025-21596-0#ref-CR68 “Chauveau, L. et al. Anterior-temporal network hyperconnectivity is key to Alzheimer’s disease: from ageing to dementia. Brain https://doi.org/10.1093/brain/awaf008

(2025).“). In non-demented APOE4 carriers, increasing FC at rest within the hippocampus was reported in association with elevated plasma p-tau levels39. While prior research suggests that higher or increasing MTL activity during encoding is linked to more tau burden69, less is known about FC during encoding in relationship to tau.

Moreover, we found that increasing task-state FC between the MTL and the PMC during retrieval was related to higher subsequent entorhinal tau burden. As FC between these regions is generally higher during retrieval and memory formation70,71,72, our findings suggest that hyperconnectivity specifically during task engagement may be related to detrimental pathological processes. Prior resting-state studies reported higher FC between the hippocampus and the retrosplenial cortex with more medial-parietal tau burden25 and higher FC strength seems to accelerate tau spread from the MTL to the PMC23,24. Higher or increasing retrieval activity of the MTL and the PMC was further reported in association with more Aβ pathology[65](https://www.nature.com/articles/s41598-025-21596-0#ref-CR65 “Fischer, L. et al. Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older APOE4 carriers. J. Neurosci. https://doi.org/10.1523/JNEUROSCI.1408-24

(2025).“),73,74, but studies on the association with tau and investigating FC during retrieval are lacking. Interestingly, in APOE4 carriers, we observed further associations of increasing FC in task-engaged regions and higher tau pathology, i.e. within the MTL during encoding and within the PMC during retrieval. This supports the theory that hyperconnectivity particularly of task-engaged regions is detrimental regarding pathology, potentially especially pronounced in APOE4 carriers who are at higher risk for AD. The underlying mechanism, e.g. heightened tau spread and accumulation specifically under these circumstances, needs to be determined using study designs including longitudinal tau-PET.

Our second aim was to investigate the association of change in FC strength in episodic memory regions with change in episodic memory performance. Our findings regarding episodic memory performance differed between the two memory measures. Improvements over time