Low frequency BOLD oscillations, APOE4, and plasma pTau₂₁₇

Intrinsic low frequency oscillations in BOLD signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs may shed light on cerebrovascular dysfunction and early Alzheimer's disease pathophysiology, but the mechanisms remain unclear. No investigations to date have assessed the relationship between BOLD-LFOs and plasma pTau₂₁₇, or how this relationship differs in apolipoprotein-e4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and predisposed to AD pathophysiology.

Independently living older adults (N=118) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain functional MRI and venipuncture. Total BOLD-LFOs were quantified as signal power within the 0.01-0.10 Hz frequency range. Plasma level of pTau₂₁₇ was assessed and linear regression was used to quantify the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau₂₁₇. 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau₂₁₇ cutoffs.

The interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau₂₁₇ (β=-.65, p=.004). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau₂₁₇ in APOE4 carriers (β=-.49, p=.003). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (-) APOE4 carriers (p=.02) and amyloid-β (+) APOE4 non-carriers (p=.04). All models were adjusted for age and sex.

Present study findings suggests that BOLD-LFOs are implicated early in AD pathophysiology in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.