27 Sep 2024

When Aβ aggregates stoke synaptic fires, tau tangles put them out. This phenomenon, demonstrated in animal models, now gains support in a human study, published September 18 in Nature Neuroscience. Led by Sylvain Baillet at McGill University in Montreal, scientists used magnetoencephalography to tap into neural rhythms in the brains of cognitively normal people at risk for AD. In regions where amyloid plaques showed up on PET scans, the amplitude of fast-frequency alpha waves soared. In contrast, tau tangles acted more like a wet blanket, dousing alpha oscillations in favor of slower delta and theta rhythms. This synaptic snuffing correlated with cognitive decline.

The findings indicate that early changes in brain activity—happening in parallel with Aβ and tau accumulation—can predict future cognitive decline. “This suggests that we may be able to detect Alzheimer’s earlier than previously thought from brain activity patterns, using tools like MEG to identify subtle shifts in brain function,” Baillet wrote to Alzforum.

Synaptic Roller Coaster. In this model of AD progression, Aβ deposition strengthens fast-frequency brain rhythms early in disease (blue line going up), while tau deposition douses neurophysiological activity later on (blue line going down). Dashed arrows represent uncertainty around when these brain rhythm changes occur with respect to neuropathological progression. [Courtesy of Gallego-Rudolf et al., Nature Neuroscience, 2024.]

Scientists have long recognized that the emergence of Aβ and tau pathology in the brain messes with neuronal signaling, both at the level of individual synapses and neural networks (Palop and Mucke, 2010; May 2017 news). In transgenic mice, Aβ and tau aggregates appear to exert opposing effects on synapses, with the former pushing them into overdrive and the latter quieting them down (Dec 2018 conference news; Aug 2019 news).

In people, functional MRI suggests that Aβ provokes hyperactivity in the hippocampus (Huijbers et al., 2015; Leal et al., 2017). On a larger scale, magnetoencephalography studies of brain-wide electrical oscillations in people with AD support a model whereby Aβ stokes fast-frequency, alpha waves early in disease, while tau deposition enhances slower, delta-theta rhythms later on (Ranasinghe et al., 2021; Wiesman et al., 2022; Alexandersen et al., 2023).

How might these potentially oppositional influences play out during the long preclinical phase of AD, and how might their interaction relate to impending cognitive decline? First author Jonathan Gallego-Rudolf and colleagues used a combination of magnetoencephalography, Aβ-PET, and tau-PET scans to correlate neural activity to each proteinopathy in 104 cognitively normal volunteers in the PREVENT-AD study. Each had a family history of sporadic AD.

First, they separated participants into three groups based on their PET positivity for Aβ and tau pathologies: those who were negative for both; those who were positive for Aβ only; or positive for both Aβ and tau deposition. Relative to people with no pathology or only plaques, those with both plaques and tangles had signs of flagging circuitry brain-wide. Fast-frequency alpha rhythms, which wash across the brain at 8-12 Hz, were weaker; slower delta and theta rhythms, which pulse at 2-4 Hz and 5-7 Hz, respectively, were enhanced.

Next, the scientists zeroed in on spatial relationships between Aβ aggregates and neural oscillations. Across the cohort, the more Aβ plaques inundated a given region, the faster neurons there seemed to fire. In other words, Aβ revved alpha rhythms, and put the kibosh on slow-frequency delta and theta waves.

Calm Before Storm? MEG charted the power of fast-frequency alpha oscillations across the brain (left). Aβ aggregation co-localized with stronger alpha rhythms (right), but tau pathology dampened this. [Courtesy of Gallego-Rudolf et al., Nature Neuroscience, 2024.]

Tangles tempered this. As more tangles inundated the entorhinal cortex, the relationship between Aβ aggregates and neural activity weakened. This was true whether the researchers considered the burden of tangles in the entorhinal cortex, or more broadly in the medial temporal lobe. Baillet pointed out that the entorhinal cortex is a hub for neural communication between memory and cognitive networks. “Essentially, tangles interfere with the brain’s ability to maintain the same levels of connectivity and excitation that Aβ aggregation alone might induce, leading to a shift from hyperactivity to hypoactivity,” he said.

What’s more, it seemed that the tangle effect brought on cognitive decline. The extent to which tau pathology countered Aβ’s excitatory boost correlated with steeper declines on tests of attention and memory. The researchers think that once that happens, cognitive impairment is just around the corner. “Tau-driven hypoactivity likely reflects a tipping point where the brain’s compensatory mechanisms can no longer keep up, resulting in the cognitive symptoms we see in Alzheimer’s disease,” Baillet said.

Marc Aurel Busche of University College London agreed, noting that the new study provides evidence in the human brain that supports what his lab and others have reported in mice. He commented that the findings emphasize an urgent need to characterize the underlying mechanisms that determine this neurophysiological transition, and to develop quantifiable predictors of this tipping point (see comment below).

Along those lines, Baillet proposed that, in combination with blood-based AD biomarkers, non-invasive measures of neurophysiological activity such as MEG might one day be used to gauge whether a person is on the cusp of cognitive decline.—Jessica Shugart

Comments

1. • Marc Aurel Busche
     University College London
   • Posted: 01 Oct 2024

   This study provides important evidence supporting a biphasic neurophysiological model of Alzheimer’s disease (AD) progression, as previously proposed by Harris et al., 2020. Several studies from multiple laboratories have established a clear sequence in mouse models in which Aβ accumulation causes neuronal hyperactivity/hypersynchrony, while tau pathology subsequently leads to neuronal silencing. This framework suggests the existence of a critical tipping point in AD progression, where tau pathology shifts neuronal dynamics from a hyperactive to a hypoactive state.

   Employing MEG to analyse whole-brain spectral band power alongside quantitative PET imaging of Aβ and tau, the current study extends these findings to a human cohort. Cognitively unimpaired individuals with high Aβ deposition, but no significant tau pathology, exhibited enhanced fast-frequency (alpha-beta) oscillatory activity along with reduced slow-frequency (delta-theta) activity. In contrast, subjects with both high Aβ and tau burden demonstrated a clear shift toward slower neuronal oscillations, indicative of neurophysiological slowing. This shift was associated with a longitudinal decline in cognitive domains related to attention and memory.

   These novel findings emphasize the urgent need to more precisely characterise the spatiotemporal neurophysiological changes and cellular/molecular mechanisms that determine this transition, and to develop quantifiable predictors for this “real-world” tipping-point of accelerated neural system failure, to inform early intervention strategies aimed at slowing disease progression.

   References:

   Harris SS, Wolf F, De Strooper B, Busche MA. Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease. Neuron. 2020 Aug 5;107(3):417-435. Epub 2020 Jun 23 PubMed.

   View all comments by Marc Aurel Busche

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References

News Citations

1. What Lies Beneath: Intracranial Probes Pick Up Hippocampal Seizures in AD 5 May 2017
2. Tau Silences, Aβ Inflames; Hitting Excitatory Synapses Hardest 20 Dec 2018
3. Aβ Dimers Block Glutamate Uptake, Fire Up Synapses 9 Aug 2019

Paper Citations

1. Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci. 2010 Jul;13(7):812-8. PubMed.
2. Huijbers W, Mormino EC, Schultz AP, Wigman S, Ward AM, Larvie M, Amariglio RE, Marshall GA, Rentz DM, Johnson KA, Sperling RA. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression. Brain. 2015 Apr;138(Pt 4):1023-35. Epub 2015 Feb 11 PubMed.
3. Leal SL, Landau SM, Bell RK, Jagust WJ. Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline. Elife. 2017 Feb 8;6 PubMed.
4. Ranasinghe KG, Petersen C, Kudo K, Mizuiri D, Rankin KP, Rabinovici GD, Gorno-Tempini ML, Seeley WW, Spina S, Miller BL, Vossel K, Grinberg LT, Nagarajan SS. Reduced synchrony in alpha oscillations during life predicts post mortem neurofibrillary tangle density in early-onset and atypical Alzheimer's disease. Alzheimers Dement. 2021 Apr 21; PubMed.
5. Wiesman AI, Murman DL, Losh RA, Schantell M, Christopher-Hayes NJ, Johnson HJ, Willett MP, Wolfson SL, Losh KL, Johnson CM, May PE, Wilson TW. Spatially resolved neural slowing predicts impairment and amyloid burden in Alzheimer's disease. Brain. 2022 Jun 30;145(6):2177-2189. PubMed.
6. Alexandersen CG, de Haan W, Bick C, Goriely A. A multi-scale model explains oscillatory slowing and neuronal hyperactivity in Alzheimer's disease. J R Soc Interface. 2023 Jan;20(198):20220607. Epub 2023 Jan 4 PubMed.

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