Eoin N. Molloy

The medial temporal lobe (MTL) is crucial for episodic memory. Tau pathology is a hallmark of Alzheimer's disease (AD) and accumulates in layer-specific patterns in the MTL during aging. It is, however, unclear whether early AD pathology relates to mesoscale network signatures distinct from non-pathological aging. To address this gap, we acquired 7 Tesla submillimeter-resolution resting-state fMRI, plasma-based AD biomarkers, glial fibrillary acidic protein (GFAP) levels, APOE genotype, regional [18F]PI-2620 tau PET burden, and longitudinal episodic memory data in 75 cognitively unimpaired older adults. Older age was associated with lower perirhinal-hippocampal connectivity and lower network segregation, whereas higher plasma-based AD pathology was associated with higher perirhinal-hippocampal connectivity. Furthermore, temporal-lobe tau burden was related to altered connectivity patterns in tau-vulnerable MTL subfields and layers, dependent on GFAP levels. Retrosplenial tau burden was associated with higher hippocampal-retrosplenial connectivity consistent with tau spread along canonical hippocampal output pathways. Finally, higher connectivity within the hippocampus attenuated the negative association between temporal-lobe tau burden and memory performance but predicted unfavorable memory trajectories. Our findings show differential associations of age and AD pathology with mesoscale MTL-connectivity patterns. Importantly, increased hippocampal connectivity may support memory function in the short term while contributing to subsequent memory decline.

BACKGROUND: Episodic memory declines early with aging, reflecting reduced neural resources and diminished memory specificity. However, few studies have created a cognitive challenge with multiple levels of task demand to investigate this early subtle decline. Furthermore, it is unclear whether the genetic Alzheimer’s disease risk factor APOE4 and early Alzheimer’s pathology constrain the neural resources required to cope with increasing task demands. METHODS: In this preregistered behavioral study named EMCOMP (Episodic Memory & COMPensation), we conducted a semantic episodic memory retrieval task using a sentence-based task demand manipulation with five demand levels at recognition (novel foils, “old” target sentences, and three lure levels) and two demand levels at free and cued recall (gist and details). We collected data from 100 cognitively unimpaired adults (37 young (mean age 24 years), 63 older (mean age 72 years)) with additional neuropsychological testing and blood-based measures available for the older group. First, we investigated differences in EMCOMP episodic memory retrieval accuracy and confidence between young and older adults in linear mixed-effects models. Second, we investigated differences associated with the APOE4 genotype and plasma-derived Alzheimer’s pathology. Third, we assessed correlations between EMCOMP recognition and recall and established cognitive tests. RESULTS: Young adults showed higher recognition accuracy and confidence as well as a higher recall score and a lower recall error rate compared to older adults. As recognition-task demand increased there was a steeper decline in recognition accuracy and a steeper increase in high-confidence errors in older compared to younger adults and in older APOE4 carriers compared to older non-carriers. However, we found no associations with Alzheimer’s pathology. EMCOMP performance was positively correlated with established cognitive tests. CONCLUSION: Our study demonstrates age– and APOE4 -related differences in episodic memory retrieval under increasing task demands – differences that may not be detectable in paradigms with only one or two levels of task demand. By manipulating semantic retrieval specificity, we provide a novel approach to detect subtle cognitive deficits and potential functional compensation in cognitively unimpaired older adults with risk factors or early Alzheimer’s pathology. Future research should extend this work to more diverse samples and combine behavioral assessment with fMRI to examine underlying brain activation patterns and functional connectivity.

Background: Cognitive reserve (CR) and brain maintenance (BM) support preserved cognition by mitigating or slowing neural decline in aging. Physical fitness represents a plausible pathway to both CR and BM, yet the underlying neurobiological mechanisms remain insufficiently understood. This study examined the role of physical fitness in BM and CR by testing its associations with Alzheimer's disease related brain pathology and by assessing its moderating and mediating effects on the relationship between pathology and cognition. Methods: Data were obtained from 345 cognitively unimpaired older adults (mean age = 73.11, SD 8.03 years; 177 females) participating in the ongoing SFB1436 study. We assessed global cognition and delayed verbal memory performance, aerobic fitness (VO2max), and muscular capacity. Blood biomarkers included plasma Aβ1-42/Aβ1-40, p-tau217, and GFAP (glial fibrillary acidic protein), as well as serum BDNF (brain derived neurotrophic factor), VEGF (vascular endothelial growth factor), and Cathepsin-B (plasticity). Neuroimaging measures comprised medial temporal lobe (MTL) tau burden ([18F]PI-2620 PET), MRI-derived hippocampal volumes, white matter hyperintensities, perivascular spaces (PVS) in basal ganglia (BG) and centrum semiovale, total gray matter volume (GMV), and MTL thickness. To examine BM, we tested associations between fitness and brain pathology. To examine CR, we conducted moderation analyses assessing whether fitness attenuated the negative impact of MTL tau burden on cognition. Mediation analyses further evaluated whether hippocampal volume, total GMV, or MTL thickness mediated a potential association between fitness and cognition. All models controlled for age and sex (and education in mediation analyses), and multiple comparisons were FDR-corrected. Results: Physical fitness was not related to cognitive performance. Higher muscular capacity was associated with lower BG PVS volumes, while higher aerobic fitness was related to higher MTL thickness and total GMV. Elevated MTL tau burden was associated with poorer verbal memory performance. Although physical fitness did not significantly moderate the tau-memory relationship, model comparison indicated weak evidence for CR effects (p = .015). Conclusion: Muscular capacity was linked to lower BG PVS volumes, supporting resistance against pathology, while aerobic fitness related to preserved cortical integrity and tended to act as a CR proxy against MTL tau pathology. Physical fitness may support cerebrovascular and glymphatic function, providing weak CR-like protection against tau-related cognitive decline.

Changes in functional connectivity (FC) strength involving the medial temporal lobe (MTL) and posteromedial cortex (PMC) are related to early Alzheimer’s pathology and alterations in episodic memory performance in cognitively unimpaired older adults, but their dynamics remain unclear. We examined how longitudinal changes in FC involving MTL and PMC during resting-state, episodic memory encoding, and retrieval relate to subsequent amyloid- and tau-PET burden, longitudinal episodic memory performance, and the APOE4 genotype in 152 cognitively unimpaired older adults from the PREVENT-AD cohort. We found APOE4- and fMRI paradigm-dependent associations of change in FC strength with pathology burden and change in episodic memory performance. Decreasing FC over time, or “hypoconnectivity”, within PMC during rest in APOE4 carriers and during retrieval in APOE4 non-carriers was related to more amyloid and tau, respectively. Conversely, increasing FC over time, or “hyperconnectivity”, within MTL during encoding in APOE4 carriers and between MTL and PMC during retrieval independent of APOE4 status was related to more tau. Further, increasing FC between MTL and PMC during rest, unlike during encoding, was beneficial for episodic memory. Our study highlights that pathology-related episodic memory network changes manifest differently during rest and task and have differential implications for episodic memory trajectories.

Resistance to age-related pathological changes (brain maintenance), including Alzheimer’s disease, cerebrovascular disease, and neurodegeneration may promote cognitive resilience in aging. However, how lifestyle and health profiles relate to successful cognitive and brain aging remains poorly understood. In a novel, deeply phenotyped cohort of 211 cognitively unimpaired older adults (age = 71.0 ± 7.4 years, 46% female), we characterized principal components of lifestyle and health using questionnaire, fitness, and blood data. We estimated cognitive age gap (CAG) based on comprehensive neuropsychological data and brain age gap (BAG) based on brain-pathology markers, including plasma biomarkers of Alzheimer’s pathology (pTau ₂₁₇ and Aβ _1-42 /Aβ _1-40 ), MRI-based measures of white matter hyperintensities, perivascular spaces, and brain atrophy. Regression analyses tested how the observed lifestyle-health profiles were related to CAG and BAG. Seven principal components explained 49% of the variance in health and lifestyle. The second component, characterized by a mentally and physically active life and low cardiovascular risk, was associated with lower CAG ( β = − 0.66, p < 0.001) and BAG ( β = − 0.52, p = 0.003), reflecting a younger-than-expected brain and cognitive age, respectively. The association of an active lifestyle and lower CAG was partially mediated by BAG. Higher CAG was also associated with other lifestyle components characterized by low mental stimulation. APOE-ε4 carriers exhibited higher BAG. In conclusion, a lifestyle combining low cardiovascular risk, high mental engagement throughout life and high physical activity/fitness is jointly associated with less-than-expected brain pathology and better-than-expected cognitive performance, supporting its involvement in brain maintenance and cognitive resilience to aging.

Changes in functional connectivity (FC) strength involving the medial temporal lobe (MTL) and posteromedial cortex (PMC) are related to early Alzheimer’s pathology and alterations in episodic memory performance in cognitively unimpaired older adults, but their dynamics remain unclear. We examined how longitudinal changes in FC involving MTL and PMC during resting-state, episodic memory encoding, and retrieval relate to subsequent amyloid- and tau- PET burden, longitudinal episodic memory performance, and the APOE4 genotype in 152 cognitively unimpaired older adults from the PREVENT-AD cohort. We found APOE4- and fMRI paradigm-dependent associations of change in FC strength with pathology burden and change in episodic memory performance. Decreasing FC over time, or “hypoconnectivity”, within PMC during rest in APOE4 carriers and during retrieval in APOE4 non-carriers was related to more amyloid and tau, respectively. Conversely, increasing FC over time, or “hyperconnectivity”, within MTL during encoding in APOE4 carriers and between MTL and PMC during retrieval independent of APOE4 status was related to more tau. Further, increasing FC between MTL and PMC during rest, unlike during encoding, was beneficial for episodic memory. Our study highlights that pathology-related episodic memory network changes manifest differently during rest and task and have differential implications for episodic memory trajectories.

Background: Both aging and Alzheimer's disease (AD) affect brain networks, with early disruptions occurring in regions involved in episodic memory. Few studies have, however, focused on distinguishing region-specific effects of AD-biomarker negative “normal” aging and early amyloid- and tau pathology on functional connectivity. Further, longitudinal studies combining imaging, biomarkers, and cognition are rare. Methods: We assessed resting-state functional connectivity (rsFC) strength and graph measures in the episodic memory network including the medial temporal lobe (MTL), posteromedial cortex (PMC), and medial prefrontal cortex alongside cognition over two years. For this preregistered study, we included 100 older adults who were amyloid- and tau-negative using CSF and PET measurements to investigate “normal” aging, and 70 older adults who had longitudinal CSF data available to investigate functional changes related to early AD pathology. All participants were cognitively unimpaired older adults from the PREVENT-AD cohort. We used region of interest (ROI)-to-ROI bivariate correlations, graph analysis, and multiple regression models. Results: In the amyloid- and tau-negative sample, rsFC strength within PMC, between parahippocampal cortex and inferomedial precuneus, and between posterior hippocampus and inferomedial precuneus decreased over time. Additionally, we observed a longitudinal decrease in global efficiency. Further, there was a steeper longitudinal decrease in rsFC and global efficiency with higher baseline age particularly of parahippocampal-gyrus regions. Further, lower rsFC strength within PMC was associated with poorer longitudinal episodic memory performance. In the sample with available CSF data, a steeper increase in rsFC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher MTL-PMC rsFC strength was differentially associated with episodic memory trajectories depending on APOE4 genotype. Conclusions: Our findings suggest differential effects of aging and AD pathology. Hypoconnectivity within PMC was related to aging and cognitive decline. MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. Future studies should investigate more diverse samples, nonetheless, our approach allowed us to identify longitudinal functional changes related to aging and early AD pathology, enhancing cross-sectional research. Hyperconnectivity has been proposed as a mechanism related to early AD pathology before, we now contribute specific functional connections to focus on in future research. Graphical A) “Normal aging” in cognitively unimpaired older adults with a negative amyloid- and tau- biomarker status was characterized by a longitudinal decrease in functional connectivity strength. B) Cognitively unimpaired older adults with more Alzheimer’s pathology at baseline (measured via cerebrospinal fluid) exhibited a longitudinal increase in functional connectivity strength.

Mnemonic discrimination (MD) is the ability to distinguish current experiences from similar memories. Research on the brain correlates of MD has focused on how regional neural responses are linked to MD. Here we go beyond this approach to investigate inter-regional functional connectivity patterns related to MD, its inter-individual variability and training-related improvement. Based on prior work we focused on medial temporal lobe (MTL), prefrontal cortex (PFC) and visual regions. We used fMRI to determine how functional connectivity patterns between these regions are related to MD before and after 2-weeks of web-based cognitive training. We identified a functional connectivity signature involving MTL-PFC-visual areas during successful MD. We found that hippocampal-PFC connectivity was negatively associated with interindividual variability in MD performance across two different tasks. Hippocampal-PFC connectivity decrease was also linked to interindividual variability in post-training MD improvement. Additionally, training led to increased connectivity from the lateral occipital cortex to the occipital pole area. Our results point to a hippocampal-PFC connectivity pattern which is a reliable, task-invariant, marker of MD performance. This pattern is further related to MD training gains providing causal evidence for its relevance in distinguishing similar memories. Overall, we show that hippocampal-PFC connectivity constitutes a neural resource for MD that enables training-related improvements and could be targeted in future research to enhance cognition.

The precuneus is a site of early amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E (APOE) genotype is unclear. Investigating the PREVENT-AD dataset, we assessed how baseline and longitudinal precuneus activity during successful memory retrieval relates to future Aβ and tau burden and change in memory performance. We further studied the moderation by APOE4 genotype. We included 165 older adults (age, 62.8 ± 4.4 years; 113 female; 66 APOE4 carriers) who were cognitively normal at baseline with a family history of AD. All participants performed task-fMRI at baseline and underwent ¹⁸F-flortaucipir-PET and ¹⁸F-NAV4694-Aβ-PET on average 5 years later. We found that higher baseline activity and greater longitudinal increase in precuneus activity were associated with higher Aβ burden in APOE4 carriers but not noncarriers. We observed no effects of precuneus activity on tau burden. Finally, APOE4 noncarriers with low baseline precuneus activity exhibited better longitudinal performance in an independent memory test compared with (1) noncarriers with higher baseline activity and (2) APOE4 carriers. Our findings suggest that higher task-related precuneus activity during memory retrieval at baseline and over time are associated with greater Aβ burden in cognitively normal APOE4 carriers. Our results further indicate that the absence of “hyperactivation” and the absence of the APOE4 allele is related with better future cognitive outcomes in cognitively normal older adults at risk for AD.

INTRODUCTION: Both aging and Alzheimer’s disease (AD) affect episodic memory networks. How this relates to region-specific early differences in functional connectivity (FC), however, remains unclear. METHODS: We assessed resting-state FC strength in the medial temporal lobe (MTL) - posteromedial cortex (PMC) - prefrontal network and cognition over two years in cognitively normal older adults from the PREVENT-AD cohort. RESULTS: FC strength within PMC and between posterior hippocampus and inferomedial precuneus decreased in “normal” aging (amyloid- and tau-negative adults). Lower FC strength within PMC was associated with poorer longitudinal episodic memory performance. Increasing FC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher FC strength was differentially associated with memory trajectories depending on APOE4 genotype. DISCUSSION: Findings suggest differential effects of aging and AD pathology on longitudinal FC. MTL-PMC hypoconnectivity was related to aging and cognitive decline. Furthermore, MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers. Graphical A) “Normal aging” is characterized by a longitudinal decrease in functional connectivity. B) Cognitively unimpaired older adults with more Alzheimer’s pathology at baseline (measured via cerebrospinal fluid) exhibit a longitudinal increase in functional connectivity.