Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov 1;79(11):glae211.
doi: 10.1093/gerona/glae211.

Network Analysis of Brain and Bone Tissue Transcripts Reveals Shared Molecular Mechanisms Underlying Alzheimer's Disease and Related Dementias and Osteoporosis

Archana Nagarajan  1   2 , Jason Laird  3 , Obiadada Ugochukwu  4 , Sjur Reppe  5   6 , Kaare Gautvik  5 , Ryan D Ross  7 , David A Bennett  8 , Clifford Rosen  9 , Douglas P Kiel  10   11 , Lenora A Higginbotham  4 , Nicholas T Seyfried  4 , Christine W Lary  1   9
Affiliations

Network Analysis of Brain and Bone Tissue Transcripts Reveals Shared Molecular Mechanisms Underlying Alzheimer's Disease and Related Dementias and Osteoporosis

Archana Nagarajan et al. J Gerontol A Biol Sci Med Sci. .

Abstract

Background: Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are 2 prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown.

Methods: We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these 2 diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in 5 ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of coexpressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms.

Results: We discovered 3 modules in ROSMAP that showed significant associations with ADRD and bone-related traits and 4 modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the 2 networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest.

Conclusions: These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.

Keywords: Alzheimer’s disease; Genetics; Osteoporosis.

PubMed Disclaimer

Conflict of interest statement

N.T.S. is a co-founder and consultant of Emtherapro and co-founder of Arc Proteomics. D.P.K. serves on scientific advisory boards for Pfizer and Solarea Bio, has received royalty payments from Wolters Kluwer for authoring a chapter in UpToDate on Falls, and received grant funding through a grant to his Institute by the Dairy Council, Amgen, and Radius Health. The other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
ROSMAP subgroup and Oslo network module-trait associations. Dotplot of module eigengene correlation with ADRD and bone traits in ROSMAP network (A) and with osteoporotic and bone traits in Oslo network (B). In each plot, the x-axis is the trait and the y-axis is the module, and correlation values are noted through dot color and p value through dot size. Values shown are for −log(p), where p < .1. Modules of interest are highlighted in color-coded rectangles, and traits showing strong module correlations for ROSMAP are highlighted in black rectangles.
Figure 2.
Figure 2.
ROSMAP and Oslo modules show correspondence in enriched pathways with a specific enrichment in Wnt signaling. (A) Venn diagram of the GO term overlap between the ROSMAP subgroup red module and the Oslo pink module. (B) Venn diagram of the GO term overlap between the ROSMAP subgroup red module and the Oslo turquoise module. (C) Modules of interest (modules correlating with multiple ADRD and/or bone traits) are shown for ROSMAP subgroup, ROSMAP full, and Oslo networks, and bidirectional arrows are placed between modules from different networks where there is correspondence in GO term annotation for those modules.
See this image and copyright information in PMC

References

    1. Zhao Y, Shen L, Ji HF.. Alzheimer’s disease and risk of hip fracture: a meta-analysis study. Sci World J. 2012;2012:872173. 10.1100/2012/872173 - DOI - PMC - PubMed
    1. Xia T, Zhang J, Guo Y, et al. Humulus lupulus L. extract protects against senior osteoporosis through inhibiting amyloid beta deposition and oxidative stress in APP/PS1 mutated transgenic mice and osteoblasts. Molecules. 2023;28(2):583. 10.3390/molecules28020583 - DOI - PMC - PubMed
    1. LLabre JE, Gil C, Amatya N, Lagalwar S, Possidente B, Vashishth D.. Degradation of bone quality in a transgenic mouse model of Alzheimer’s disease. J Bone Miner Res. 2022;37(12):2548–2565. 10.1002/jbmr.4723 - DOI - PMC - PubMed
    1. Porter T, Sim M, Prince RL, et al. Abdominal aortic calcification on lateral spine images captured during bone density testing and late-life dementia risk in older women: a prospective cohort study. Lancet Reg Health West Pac. 2022;26:100502. 10.1016/j.lanwpc.2022.100502 - DOI - PMC - PubMed
    1. Tsai YL, Yen CT, Wang YF.. Astrocyte dysregulation and calcium ion imbalance may link the development of osteoporosis and Alzheimer’s disease. J Alzheimers Dis. 2022;88(2):439–445. 10.3233/JAD-220218 - DOI - PubMed