Neurochemical organization of cortical proteinopathy and neurophysiology along the Alzheimer's disease continuum

Abstract

INTRODUCTIONDespite parallel research indicating amyloid‐β accumulation, alterations in cortical neurophysiological signaling, and multi‐system neurotransmitter disruptions in Alzheimer's disease (AD), the relationships between these phenomena remains unclear.METHODSUsing magnetoencephalography, positron emission tomography, and an atlas of 19 neurotransmitters, we studied the alignment between neurophysiological alterations, amyloid‐β deposition, and the neurochemical gradients of the cortex.RESULTSIn patients with mild cognitive impairment and AD, changes in cortical rhythms were topographically aligned with cholinergic, serotonergic, and dopaminergic systems. These alignments correlated with the severity of clinical impairments. Additionally, cortical amyloid‐β plaques were preferentially deposited along neurochemical boundaries, influencing how neurophysiological alterations align with muscarinic acetylcholine receptors. Most of the amyloid‐β‐neurochemical and alpha‐band neuro‐physio‐chemical alignments replicated in an independent dataset of individuals with asymptomatic amyloid‐β accumulation.DISCUSSIONOur findings demonstrate that AD pathology aligns topographically with the cortical distribution of chemical neuromodulator systems and scales with clinical severity, with implications for potential pharmacotherapeutic pathways.Highlights Changes in cortical rhythms in Alzheimer's are organized along neurochemical boundaries. The strength of these alignments is related to clinical symptom severity. Deposition of amyloid‐β (Aβ) is aligned with similar neurotransmitter systems. Aβ deposition mediates the alignment of beta rhythms with cholinergic systems. Most alignments replicate in participants with pre‐clinical Alzheimer's pathology.