Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity

Journal article

INTRODUCTION: Alzheimer's disease (AD) affects neurophysiology by loss of neurons, synapses, and neurotransmitters. A mechanistic understanding of the human disease will facilitate new treatments. METHODS: Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from healthy adults (n = 14) and people with symptomatic AD (n = 45, amyloid biomarker positive) at baseline and after 16 months. Fourteen people with AD had repeat magnetoencephalography at 2 weeks to assess test–retest reliability. Dynamic causal models were fitted to the evoked responses and analyzed using parametric empirical Bayes. RESULTS: Sensor data confirmed that AD and its progression reduce the mismatch negativity amplitude, which had excellent test–retest reliability. Parametric empirical Bayes analyses confirmed that AD progressively reduces extrinsic connectivity between pyramidal cells and superficial pyramidal cell gain modulation. DISCUSSION: Dynamic causal modeling revealed cellular‐level causes of the neurophysiological deficits observed in AD. This approach may help facilitate experimental medicine studies of candidate treatments. Highlights: Magnetoencephalography scanning provides reliable biomarkers that are sensitive to Alzheimer's disease (AD) and its progression, and informative about disease mechanisms underlying cognitive decline. In vivo assays of pyramidal cell function during cognitive processes in humans improve our understanding of AD mechanisms. The amplitude of the mismatch negativity response is progressively reduced in AD. Reduced pyramidal cell gain and connectivity underlie this neurophysiological deficit. These measures are potential biomarkers for interventional studies.

Authors: Lanskey, JH; Jafarian, A; Karadag, M; Kocagoncu, E; Williams, RS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association
• Volume: 21
• Issue: 10
• Article number: e70805
• Publication date: 2025-10-25
• Acceptance date: 2025-09-19
• DOI: 10.1002/alz.70805
• EISSN: 1552-5279
• ISSN: 1552-5260
• Language: English
• Keywords: canonical microcircuit; mismatch negativity; dynamic causal modeling; connectivity; magnetoencephalography; dementia