Neurophysiological changes associated with plasma p‐tau represent functional effects of amyloid accumulation and are modulated by APOE.

Abstract

AbstractBackgroundAlzheimer disease (AD) is defined by the presence of cerebral amyloid‐β plaques and tau neurofibrillary tangles (NFT). Neurophysiological manifestations which depict the functional changes of neurons and circuits, demonstrate that amyloid‐β and tau have distinct effects—high cerebral amyloid‐β burden is associated with increased neural oscillatory activity while high tau burden with decreased activity. With the recent proliferation of fluid biomarkers, plasma p‐tau181 is known to reflect accumulation of amyloid‐β as well as tau, detected from molecular imaging and neuropathological analyses. It remains unknown whether the neurophysiological consequences of soluble p‐tau reflects the effects of amyloid‐β or those of NFT.MethodWe used multimodal imaging combining magnetoencephalography (MEG) to cross‐sectionally study the spectral signatures and positron emission tomography with Aβ binding tracers to define the global amyloid burden in early‐stage neuropathological spectrum including Aβ+ cognitively‐unimpaired (CU, n = 9), Aβ+ mild‐cognitive‐impairment (MCI, n = 20), and Aβ‐negative CU controls (n = 45). Plasma p‐tau181 and neurofilament light (NFL) were measured with Simoa. Using statistical mixed models we examined the associations of neural oscillatory signatures with plasma p‐tau181 and NFL.ResultThe characteristic oscillatory signature of increased delta‐theta and reduced alpha spectrum were detectable even in the earliest stages of global amyloid accumulation (Aβ+CU vs. Aβ‐CU; Fig.1). Increased p‐tau181 was associated with increased spectral signatures across the frequency spectrum in Aβ+ individuals (Fig.2). These positive correlations were more robust within delta‐theta (2‐7Hz) than alpha (8‐12 Hz) spectrum. Plasma NFL in Aβ+ individuals, in contrast, was associated with reduced spectral signatures. We also found APOE‐ɛ4 carriers have greater degree of neurodegeneration which modulated the associations between p‐tau181 and neural oscillations (Fig.3).ConclusionPrevious neurophysiological studies have demonstrated that Aβ accumulation is associated with increased oscillatory activity while tau accumulation is associated with reduced oscillatory activity. Positive correlations of p‐tau181 across the spectrum is therefore consistent with the effects of Aβ accumulation and not with tau accumulation. Plasm NFL may represent early effects of neurodegeneration. Collectively our findings indicate that p‐tau181 reflects earliest functional effects of Aβ rather than tau and have implications for the interpretation of plasma p‐tau along the AT(N) stages.