Greater tau pathology is associated with altered predictive coding
Open accessAbstract
Altered predictive coding may underlie the reduced auditory mismatch negativity amplitude observed in patients with dementia. We hypothesized that accumulating dementia-associated pathologies, including amyloid and tau, lead to disturbed predictions of our sensory environment. This would manifest as increased reliance on ‘observed’ sensory information with an associated increase in feedforward, and decrease in feedback, signalling. To test this hypothesis, we studied a cross-sectional cohort of participants who underwent PET imaging and high-density EEG during an oddball paradigm, and used dynamic casual modelling and Bayesian statistics to make inferences about the neuronal architectures (generators) and mechanisms (effective connectivity) underlying the observed auditory-evoked responses. Amyloid-β imaging with [C-11] Pittsburgh Compound-B PET was qualitatively rated using established criteria. Tau-positive PET scans, with [F-18]MK-6240, were defined by an MK-6240 standardized uptake value ratio positivity threshold at 2 standard deviations above the mean of the Amyloid(–) group in the entorhinal cortex (entorhinal MK-6240 standardized uptake value ratio > 1.27). The cross-sectional cohort included a total of 56 participants [9 and 13 participants in the Tau(+) and Amyloid(+) subgroups, respectively: age interquartile range of (73.50–75.34) and (70.5–75.34) years, 56 and 69% females, respectively; 46 and 43 participants in the Tau(−) and Amyloid(−) subgroups, respectively: age interquartile range of (62.72–72.5) and (62.64–72.48) years, 67 and 65% females, respectively]. Mismatch negativity amplitudes were significantly smaller in Tau+ subgroup than Tau− subgroup (cluster statistics corrected for multiple comparisons: P = 0.028). Dynamic causal modelling showed that tau pathology was associated with increased feedforward connectivity and decreased feedback connectivity, with increased excitability of superior temporal gyrus but not inferior frontal regions. This effect on superior temporal gyrus was consistent with the distribution of tau disease on PET in these participants, indicating that the observed differences in mismatch negativity reflect pathological changes evolving in preclinical dementia. Exclusion of participants with diagnosed mild cognitive impairment or dementia did not affect the results. These observational data provide proof of concept that abnormalities in predictive coding may be detected in the preclinical phase of Alzheimer’s disease. This framework also provides a construct to understand how progressive impairments lead to loss of orientation to the sensory world in dementia. Based on our modelling results, plus animal models indicating that Alzheimer’s disease pathologies produce hyperexcitability of higher cortical regions through local disinhibition, mismatch negativity might be a useful monitor to deploy as strategies that target interneuron dysfunction are developed.
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AD pathology has been associated with connectivity changes to the default-mode network, frontoparietal network, and networks responding in mismatch paradigms.
“For example, AD pathology has been associated with connectivity changes to the default‐mode network, frontoparietal network, 46 , 47 and networks responding in mismatch paradigms. 48 , 49”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [48]
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- Authors
- Gjini, K., Casey, C., Tanabe, S., Bo, A., Parker, M., White, M., Kunkel, D., Lennertz, R., Pearce, R. A., Betthauser, T., Christian, B. T., Johnson, S. C., Bendlin, B. B., & Sanders, R. D.
- Affiliations
- University of Wisconsin–Madison (US)
- The University of Sydney (AU)
- Corresponding author
- Sanders, Robert D
- ORCID
- Venue
- Brain Communications
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-08-17
- Volume
- 4
- Issue
- 5
- Pages
- fcac209-fcac209
- ISSN
- 2632-1297 (ISSN-L)
- PMC
- PMC9547525
- OpenAlex
- W4292264198
- Cited by
- 9
- References
- 22
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Health (P30AG062715, 1R01AG063849-01)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- tau pathology, predictive coding, mismatch negativity, Alzheimer's disease, preclinical dementia, amyloid-beta, superior temporal gyrus, entorhinal cortex, auditory evoked potentials, dynamic causal modeling, Bayesian inference, effective connectivity, oddball paradigm
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