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 alters brain activity patterns in older adults, providing key insights into early Alzheimer’s disease progression.

In a recent study published in the journal Nature Neuroscience, a group of researchers investigated how early amyloid-β (Aβ) and tau depositions synergistically affect cortical neurophysiology and cognitive decline in cognitively unimpaired older adults with a family history of Alzheimer's disease (AD) (a brain disorder causing memory loss and cognitive decline).

Background 

Together, Aβ and tau lead to synaptic loss, brain atrophy, and eventual cognitive decline. Animal models indicate that this two-pronged effect, where Aβ causes hyperactivity, and tau suppresses it, needs further research to clarify how these processes interact to drive 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 with an elevated familial risk of sporadic AD, defined by having at least one parent or multiple siblings affected.

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

Cognitive function was assessed using standardized tools like 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 also had to score ≥ 24 on the Mini-Mental State Examination to ensure cognitive normalcy.

Synergistic effect of Aβ and tau: The study highlights how amyloid-β deposits initially accelerate brain activity, but as tau accumulates, it shifts brain function towards slower, dysfunctional activity, leading to cognitive decline.

Study results 

To compare whole-brain cortical neurophysiological activity, Analysis of Covariance (ANCOVAs) was used across 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 exhibited increased slow-wave activity (delta-theta bands), characteristic of tau-driven neurophysiological slowing, and reduced 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 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 employed 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. Greater tau levels shifted neurophysiological activity toward slower frequencies.

The results were consistent when tau was assessed across a broader set of temporal regions (meta-ROI), and removing the entorhinal cortex from the ROI did not alter 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 deterioration in the presence of Aβ. A stronger moderating effect of tau on the Aβ-neurophysiology relationship was linked to steeper cognitive declines, especially in attention.

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

Familial Alzheimer’s risk: This research focuses on cognitively unimpaired individuals with a family history of Alzheimer’s, providing key insights into how proteinopathies may trigger the earliest neurophysiological disruptions in at-risk populations.

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

The interactive effects of Aβ and tau on alpha-band activity in asymptomatic participants aligned 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 clinical symptoms emerge.

Conclusions 

To summarize, 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 reveal that Aβ deposits initially cause an increase in fast-frequency neurophysiological activity, while tau accumulation shifts this activity towards slower frequencies. This shift corresponds to cognitive declines in attention and memory.

These observations support the hypothesis that Aβ and tau interact dynamically to differentially affect neural activity across the progression of AD, offering valuable insights for future research into AD-related neurophysiology and potential biomarkers.

Journal reference:

• Gallego-Rudolf, J., Wiesman, A.I., Pichet Binette, A. et al. Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults. Nat Neurosci (2024), DOI - 10.1038/s41593-024-01763-8, https://www.nature.com/articles/s41593-024-01763-8