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Cited by 32Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Data-Driven Analysis of Age, Sex, and Tissue Effects on Gene Expression Variability in Alzheimer's Disease

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Brooks, Lavida R. K., Mias, George I.·2019·Frontiers in Neuroscience
DOI 10.3389/fnins.2019.00392PMC PMC6491842

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Abstract

ABSTRACT Alzheimer’s disease (AD) has been categorized by the Centers for Disease Control and Prevention (CDC) as the 6 th leading cause of death in the United States. AD is a significant health-care burden because of its increased occurrence (specifically in the elderly population) and the lack of effective treatments and preventive methods. With an increase in life expectancy, the CDC expects AD cases to rise to 15 million by 2060. Aging has been previously associated with susceptibility to AD, and there are ongoing efforts to effectively differentiate between normal and AD age-related brain degeneration and memory loss. AD targets neuronal function and can cause neuronal loss due to the buildup of amyloid-beta plaques and intracellular neurofibrillary tangles. Our study aims to identify temporal changes within gene expression profiles of healthy controls and AD subjects. We conducted a meta-analysis using publicly available microarray expression data from AD and healthy cohorts. For our meta-analysis, we selected datasets that reported donor age and gender, and used Affymetrix and Illumina microarray platforms (8 datasets, 2,088 samples). Raw microarray expression data were re-analyzed, and normalized across arrays. We then performed an analysis of variance, using a linear model that incorporated age, tissue type, sex, and disease state as effects, as well as study to account for batch effects, and including binary interaction between factors. Our results identified 3,735 statistically significant (Bonferroni adjusted p<0.05) gene expression differences between AD and healthy controls, which we filtered for biological effect (10% two-tailed quantiles of mean differences between groups) to obtain 352 genes. Interesting pathways identified as enriched comprised of neurodegenerative diseases pathways (including AD), and also mitochondrial translation and dysfunction, synaptic vesicle cycle and GABAergic synapse, and gene ontology terms enrichment in neuronal system, transmission across chemical synapses and mitochondrial translation. Overall our approach allowed us to effectively combine multiple available microarray datasets and identify gene expression differences between AD and healthy individuals including full age and tissue type considerations. Our findings provide potential gene and pathway associations that can be targeted to improve AD diagnostics and potentially treatment or prevention. (US).

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  • Sex differences in immune response have been reported in AD.

    “Although sex differences in immune response 17 , 18 , 19 and mitochondrial metabolism 79 have been reported in AD, other molecular processes identified here remain understudied.”

    From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [18]

    Results §3.3 reports a significant sex-by-disease interaction for CXCR4, and Discussion §4.2 identifies it as a chemokine receptor involved in inflammatory and neuroinflammatory signaling. This supports a sex difference in an immune-related gene in AD, but the paper does not directly establish a sex difference in immune response more broadly. No page numbers are available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Long-term infection depressed the 26S proteasome ubiquitination system by downregulation of Psmd8 and Psmc6.

    “The long term infection also depressed the 26S proteasome ubiquitination system by downregulation of Psmd883 and Psmc684 leading to persistence of stress-induced protein aggregates.”

    From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [84]

    The Discussion (§4.1; page not supplied) reports that PSMC6 is downregulated in Alzheimer’s disease and is part of the proteasome complex. It does not establish that long-term infection downregulates PSMC6 or depresses the 26S proteasome system; the cited passage does not report PSMD8 downregulation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Limited findings from genome-wide and transcriptome-wide association studies in AD suggest that sample size is a critical consideration when examining sex interactions.

    “Limited findings from genome‐wide 86 and transcriptome‐wide 18 , 22 association studies in AD also suggest that the sample size is a critical consideration when examining sex interactions.”

    From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [18]

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Cited by

Sorted by citations

Authors
Brooks, L. R. K., & Mias, G. I.
Affiliations
Michigan State University (US)
Corresponding author
Mias, George I.
ORCID
Mias, George I.
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2019-04-24
Volume
13
Pages
392-392
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2019.00392
PMC
PMC6491842
OpenAlex
W2953283484
Cited by
32
References
12
Citations by year
2026: 3 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 4 · 2017: 2
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Human Genome Research Institute (R00 HG007065)
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, gene expression variation, age effects, sex differences, tissue type, meta-analysis of microarray data, mitochondrial translation, synaptic vesicle recycling, GABAergic synapses, amyloid plaques, neurofibrillary tangles, Alzheimer's disease diagnosis

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