Amyloid-β and tau disrupt brain activity, driving early cognitive decline in Alzheimer’s risk

New research reveals how the combined impact of amyloid-β and tau deposits changes brain activity patterns in older adults, providing important insights into the early progression of Alzheimer’s disease.

Study: Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults. Image credits: Juan Gaertner / Shutterstock

This is evident from a recent study published in the journal Nature Neurosciencea group of researchers investigated how early deposits of amyloid-β (Aβ) and tau synergistically influence cortical neurophysiology and cognitive decline in cognitively healthy older adults with a family history of Alzheimer’s disease (AD) (a brain disorder that causes memory loss and cognitive decline) .

Background

AD develops gradually, with Aβ plaques initially driving neurons into a hyperactive state, while tau deposits gradually lead to reduced neuronal activity and cognitive dysfunction. Aβ deposits typically begin in cortical areas with high basal activity and spread over time. Tau pathology follows a predictable trajectory, first appearing in the entorhinal cortex before spreading to other brain areas, contributing to hypoactivity at a later stage.

Together, Aβ and tau lead to synaptic loss, brain atrophy and eventual cognitive decline. Animal models indicate that this dual effect, with Aβ causing hyperactivity and tau suppressing it, needs further study to clarify how these processes interact to cause neural dysfunction and cognitive decline.

About the study

Participants from the PRe-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) cohort were middle-aged and older individuals at increased familial risk for sporadic AD, defined by having at least one parent or more brothers and sisters.

To be included in the study, participants had to meet several criteria: they had to be 60 years or older (or 55-59 if their age was 15 years younger than the age of the first affected relative at the onset of dementia) , have no history of dementia. severe neurological or psychiatric disorders, and normal cognitive function.

Cognitive function was assessed using standardized tools such as the Montreal Cognitive Assessment (score ≥ 26) and the Clinical Dementia Rating scale (score 0). At the time of the magnetoencephalography (MEG)-Positron Emission Tomography (PET) sessions, participants were also required to score ≥ 24 on the Mini-Mental State Examination to ensure cognitive normality.

The study collected data from 124 PREVENT-AD participants, all of whom underwent Aβ and tau PET imaging and MEG to measure resting-state brain activity. Due to data quality issues, participants were excluded and the final sample consisted of 104 participants. A notable aspect of this study is the use of advanced MEG and PET imaging to map both neurophysiological changes and the distribution of protein pathology across brain regions. All participants gave informed consent and the protocols complied with the ethical guidelines of the Declaration of Helsinki.

Study results

To compare whole-brain cortical neurophysiological activity, Analysis of Covariance (ANCOVAs) was used in three PET-defined subgroups: (1) individuals without Aβ or tau pathology (Aβ−/Tau−), (2) those with high global Aβ but no tau (Aβ+/Tau−), and (3) those with both high Aβ and tau (Aβ+/Tau+).

Participants with higher levels of Aβ and tau showed increased slow wave activity (delta-theta bands), characteristic of tau-driven neurophysiological slowing, and decreased fast wave activity (alpha-beta bands), which is typically enhanced by Aβ-driven hyperactivity. This finding suggests that tau pathology moderates the effects of Aβ, shifting its activity from a hyperactive to a hypoactive state. Statistical differences were significant for delta and alpha bands, even after removing outliers.

Given the sample size imbalance and the limitations of using a positivity cutoff, nested linear mixed effects (LME) models were used to account for regional variability in Aβ, tau, and neurophysiological activity. Aβ deposition was strongly associated with increased fast frequency activity (increased alpha band and decreased delta band), but this effect was significantly reduced as tau levels increased, indicating a synergistic interaction between the two pathologies. Higher tau levels shifted neurophysiological activity to slower frequencies.

The results were consistent when tau was assessed over a broader range of temporal areas (meta-ROI), and removing the entorhinal cortex from the ROI did not change the findings. Crucially, the tau-mediated shift in activity represents a transition from an initial state of Aβ-induced hyperactivity to a later stage of tau-induced slowing.

To assess the relationship between neurophysiological shifts and cognitive outcomes, longitudinal cognitive data were analyzed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Participants with high levels of both Aβ and tau experienced greater declines in attention and memory scores, further supporting the hypothesis that tau accelerates cognitive decline in the presence of Aβ. A stronger moderating effect of tau on the Aβ neurophysiological relationship was linked to steeper cognitive decline, especially in attention.

These results were replicated using the temporal meta-ROI instead of the entorhinal cortex tau, supporting the robustness of the findings.

Finally, the study examined whether the observed neurophysiological changes could predict later disease stages, particularly in individuals with mild cognitive impairment (MCI) and probable AD.

The interactive effects of Aβ and tau on alpha band activity in asymptomatic participants were consistent with independent observations from individuals with mild cognitive impairment (MCI) and probable AD, suggesting that these early proteinopathy-related changes could serve as predictive markers for disease progression.

This finding highlights the potential for identifying at-risk individuals based on early neurophysiological patterns before the onset of clinical symptoms.

Conclusions

In summary, this study reports the synergistic effects of early Aβ and tau pathology on cortical neurophysiological activity in asymptomatic individuals with a family history of sporadic AD. Using MEG and PET imaging, the findings show that Aβ deposits initially cause an increase in high-frequency neurophysiological activity, while tau accumulation shifts this activity to slower frequencies. This shift corresponds to cognitive decline in attention and memory.

These observations support the hypothesis that Aβ and tau interact dynamically to differentially influence neural activity during AD progression, providing valuable insights for future research on AD-related neurophysiology and potential biomarkers.