Abstract
Two neuropathological hallmarks of Alzheimer’s disease (AD) are the accumulation of amyloid-β (Aβ) proteins and alterations in cortical neurophysiological signaling. Despite parallel research indicating disruption of multiple neurotransmitter systems in AD, it has been unclear whether these two phenomena are related to the neurochemical organization of the cortex. We leveraged task-free magnetoencephalography and positron emission tomography, with a cortical atlas of 19 neurotransmitters to study the alignment and interactions between alterations of neurophysiological signaling, Aβ deposition, and the neurochemical gradients of the human cortex. In patients with amnestic mild cognitive impairment (N = 18) and probable AD (N = 20), we found that changes in rhythmic, but not arrhythmic, cortical neurophysiological signaling relative to healthy controls (N = 20) are topographically aligned with cholinergic, serotonergic, and dopaminergic neurochemical systems. These neuro-physio-chemical alignments are related to the severity of cognitive and behavioral impairments. We also found that cortical Aβ plaques are preferentially deposited along neurochemical boundaries, and mediate how beta-band rhythmic cortical activity maps align with muscarinic acetylcholine receptors. Finally, we show in an independent dataset that many of these alignments manifest in the asymptomatic stages of cortical Aβ accumulation (N = 33; N = 71 healthy controls), particularly the Aβ-neurochemical alignments (57.1%) and neuro-physio-chemical alignments in the alpha frequency band (62.5%). Overall, the present study demonstrates that the expression of pathology in pre-clinical and clinical AD aligns topographically with the cortical distribution of chemical neuromodulator systems, scaling with clinical severity and with implications for potential pharmacotherapeutic pathways.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This work was supported to AIW by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research (CIHR; BPF-186555) and grant F32-NS119375 from the United States National Institutes of Health (NIH); to JGR from the Mexican National Council of Science and Technology (CONACyT; 2020-000017-02EXTF-00402) and the Healthy Brains Healthy Lives program at McGill University; to SV from the Alzheimer Society of Canada, the Alzheimer Association, the Canadian Institutes of Health Research (CIHR, 438655), and a CIHR Canada Research Chair Tier 2 and a Brain Canada Platform grant; to SB from a NSERC Discovery grant (RGPIN-2020-06889), the CIHR Canada Research Chair (Tier 1; CRC-2017-00311) of Neural Dynamics of Brain Systems, a grant from the NIH (R01-EB026299), and by the Canada Brain Research Fund (CBRF), an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada Foundation, and Alzheimer's Association; and to TWW from the NIH (R01-MH116782-S1; R01-MH118013-S1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. Private sector contributions are facilitated by the Development Office of the McGill University Faculty of Medicine and by the Douglas Hospital Research Centre Foundation (http://www.douglas.qc.ca/).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Data from patients with aMCI and probable AD were included via the Dynamic Mapping of Alzheimer's disease Pathology (DMAP) study. The Institutional Review Board at the University of Nebraska Medical Center reviewed and approved this investigation, and all research protocols complied with the Declaration of Helsinki. Written informed consent was obtained from each participant (as well as, for participants in the patient group, from their spouse/child informant) following detailed description of the study. For individuals with diminished capacity to make an informed decision regarding research participation, educated assent was acquired from the participant, in addition to informed consent of their legally authorized representative. Data from asymptomatic older adults with elevated familial risk of sporadic AD were included via the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) cohort. The Institutional Review Board at McGill University reviewed and approved this investigation, and all research protocols complied with the Declaration of Helsinki. Written informed consent was obtained from each participant following detailed description of the study.
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Footnotes
↵‡ Data used in preparation of this article were obtained from the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD) program (https://douglas.research.mcgill.ca/stop-ad-centre). A complete listing of PREVENT-AD Research Group can be found in the PREVENT-AD database: https://preventad.loris.ca/acknowledgements/acknowledgements.php?date=[2024-04-02]. The investigators of the PREVENT-AD program contributed to the design and implementation of PREVENT-AD and/or provided data but did not participate in analysis or writing of this report.