Synergistic effects of APOE ϵ4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults

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.

doi:10.1101/2025.06.20.660774

bioRxiv · 10.1101/2025.06.20.660774

Synergistic effects of APOE ϵ4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults

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.

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Abstract

Amyloid-{beta} (A{beta}) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE {varepsilon}4, a key genetic risk factor for Alzheimers disease (AD). Although the presence of A{beta}, tau, and APOE {varepsilon}4 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. A{beta} was measured using CSF A{beta}42/A{beta}40 or Florbetaben-PET imaging and tau was measured using CSF pTau181. 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 {varepsilon}4 was independently associated with greater A{beta} and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE {varepsilon}4. Among APOE {varepsilon}4 non-carriers, A{beta} burden was linked to a pattern of hippocampal hyperactivity. Among APOE {varepsilon}4 carriers, CSF pTau181 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 {varepsilon}4 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. Significance StatementHippocampus-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 Alzheimers 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 {varepsilon}4 in cognitively unimpaired older adults. Amyloid-{beta}-related hyperactivity was observed in the hippocampus among APOE {varepsilon}4 non-carriers, while CSF pTau181 was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among APOE {varepsilon}4 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.

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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.. 2025-06-25. Synergistic effects of APOE ϵ4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults. https://doi.org/10.1101/2025.06.20.660774

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