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Cited by 142Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Molecular properties underlying regional vulnerability to Alzheimer’s disease pathology

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Grothe, Michel J, Sepulcre, Jorge, Gonzalez-Escamilla, Gabriel, Jelistratova, Irina, Schöll, Michael, Hansson, Oskar, Teipel, Stefan J, Alzheimer’s Disease Neuroimaging Initiative·2018·Brain
DOI 10.1093/brain/awy189PMC PMC6113636
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Abstract

Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.

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  • The finding that PNN CS-GAGs are altered in 9m-PS19 mice agrees with a recent report that identified gene changes in chondroitin sulfate metabolism underlying the vulnerability of pTau (but not Aβ) accumulation and neurodegeneration in human AD brain tissue.

    “The finding that PNN CS-GAGs are altered in 9m-PS19 mice agree with a recent report that identified gene changes in chondroitin sulfate metabolism underlying the vulnerability of pTau (but not Aβ) accumulation and neurodegeneration in human AD brain tissue (Grothe et al. 2018).”

    From Perineuronal net deglycosylation associates with tauopathy‐induced gliosis and neurodegeneration (2024) · cites this paper as Grothe et al. 2018

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Authors
Grothe, M. J., Sepulcre, J., Gonzalez-Escamilla, G., Jelistratova, I., Schöll, M., Hansson, O., Teipel, S. J., & Initiative, A. D. N.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • Harvard University (US)
  • Section of Movement Disorders and Neurostimulation, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg-University Mainz, Germany
  • Lund University (SE)
Corresponding author
Grothe, Michel J
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2018-07-16
Volume
141
Issue
9
Pages
2755-2771
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awy189
PMC
PMC6113636
OpenAlex
W2884934212
Cited by
142
References
20
Citations by year
2026: 4 · 2025: 20 · 2024: 20 · 2023: 9 · 2022: 20 · 2021: 23 · 2020: 24 · 2019: 17 · 2018: 5
FWCI
11.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion)
Funders
  • Alzheimer Forschung Initiative e.V. (#16037)
  • NIH (1K23EB019023, R01AG052653-01A1)
  • Knut and Alice Wallenberg Foundation
  • the Wallenberg Centre for Molecular and Translational Medicine
  • Swedish Research Council
  • National Institutes of Health (U01 AG024904)
  • Department of Defense (W81XWH-12-2-0012)
  • National Institute on Aging
  • the National Institute of Biomedical Imaging and Bioengineering
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, regional brain vulnerability, amyloid deposition, neurofibrillary degeneration, amyloid PET, neurodegeneration, gene expression profiles, amyloid precursor protein, tau protein, MAPT, cyclin-dependent kinase 5, Ras/ERK pathway, neuroplasticity, protein synthesis, mitochondrial respiration, Alzheimer's dementia
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Cohort Studies, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Genetic Predisposition to Disease, Positron-Emission Tomography, Amyloidogenic Proteins, Transcriptome, Neuroimaging

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