Biomarkers.

Background: The posterior-medial network is crucial for episodic memory. However, the medial temporal lobe (MTL) and posteromedial cortex (PMC) regions are vulnerable to aging and early Alzheimer's disease (AD). Both processes might elicit distinct early functional connectivity (FC) changes which could be detrimental or protective/ compensatory regarding cognition. However, this is not well understood. We hypothesized that resting-state FC strength between key regions (Figure 1a) would decrease with age and memory decline without AD pathology (AT) but increase with early AD pathology.

Method: We analysed longitudinal 3-Tesla resting-state fMRI data from cognitively unimpaired older adults (OA; PREVENT-AD cohort). We assessed FC at baseline and after 24 months (FU24) in i) CSF or PET Aβ- and tau-negative OA (AT, N=96, 63±5years, 70 female, 28 APOE4) and ii) Aβ and p-tau CSF-characterized OA with available longitudinal p-tau/Aβ ratio (N=65, 63±5years, 45 female, 22 APOE4). First, we investigated effects of age, APOE genotype and p-tau/Aβ ratio on FC controlling for sex and education. Second, we tested the association between baseline FC or change in FC and change in delayed memory recall in multiple regression analyses.

Result: In AT OA, FC decreased mainly between regions within the PMC subnetwork over 24 months (Figure 1b). Higher baseline FC was related to increasing memory performance over time (p = 0.047; Figure 2a). Longitudinally, increasing FC was associated with increasing memory in APOE4 non-carriers and decreasing memory in APOE4 carriers (p = 0.016; Figure 2b). In CSF-characterized OA, p-tau/Aβ ratio at baseline and FU24 was related to increasing FC over time (Figure 3a). Higher baseline FC was associated with longitudinally increasing memory in APOE4 non-carriers and decreasing memory in APOE4 carriers (p = 0.028; Figure 3b).

Conclusion: Our results provide novel longitudinal evidence incorporating age, APOE, Aβ and tau indicating specific memory-related FC changes in cognitively unimpaired OA. APOE moderated the effects of FC strength on change in episodic memory performance. Higher FC and increasing FC seem to be detrimental in APOE4 carriers but beneficial in APOE4 non-carriers. Importantly, this effect was observed in AT OA, hinting that APOE genotype may affect FC earlier than AD-related pathology.