OSCR

Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia.

Overview

Authors: Lei Guo1,2,3, Nicholas Grimaldi4, Minghui Wang1,2,3, Lap Ho1,2,3, Ben Shackleton5, Ryan Neff1,2,3, Erming Wang1,2,3, Zhidong Tu1,3, Sam Gandy5,6,7,8, Vahram Haroutunian4,6,7,8, Michelle E Ehrlich1,5,9, Charles Mobbs4,5, Bin Zhang1,2,3
ORCID iDs: Minghui Wang
  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
  2. Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
  3. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
  4. Nash Family Department of Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
  5. Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
  6. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
  7. Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, 1399 Park Ave, New York, NY 10029, USA
  8. James J Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA
  9. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA
Institutions: Icahn School of Medicine at Mount Sinai (United States); James J. Peters VA Medical Center (United States)
Journal: Biomolecules, volume 16, issue 7, article 992
Dates: received 12 April 2026; accepted 16 June 2026; published online 6 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3390/biom16070992 · PMID 42509786 · PMCID PMC13406847 · OpenAlex W7167478429
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), C. elegans (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: brain resilience, gene coexpression network, dementia, Alzheimer’s disease
MeSH: Aging*, Alzheimer Disease*, Brain*, Dementia*, Gene Regulatory Networks*, Animals, Caenorhabditis elegans, Gene Expression Profiling, Humans (* major topic)
Topic: Genetics, Aging, and Longevity in Model Organisms (Aging, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: NIA NIH HHS (R01 AG057907, U01 AG052411, RF1 AG054014, RF1 AG057440, U01 AG046170); NIH HHS (5R01AG057907-05)
Citations: not cited yet (Europe PMC); 82 references in the paper

Abstract

Alzheimer’s disease (AD) is an aging-related neurodegenerative disease characterized by an initial memory impairment that progresses to a widespread cerebrocortical failure, culminating in death. Understanding the molecular mechanisms that protect brain function during aging may help reveal novel targets for the development of effective treatments for the memory and cognitive deficits associated with AD. In this study, we analyzed a gene expression dataset generated from the prefrontal cortices of individuals showing no neurological or cognitive abnormalities. The gene expression profiles were used to identify candidate protective genes. We then compared the expression patterns of these genes in aging with their expression patterns in AD, thereby enabling us to pinpoint the genes that potentially contribute to brain resilience that delays or prevents aging-related dementia. We selected seven genes that are potentially protective for aging and AD, and have known homologues in Caenorhabditis elegans (C. elegans). Among these genes, SRPK2, AAK1, EFR3A and MAPK10 were previously implicated in attenuating AD-related cognitive decline. Our experiments demonstrated that all seven genes prioritized by our resilience model significantly extended the lifespan of C. elegans. Given the important relationship between neuronal functional integrity and lifespan (i.e., lifespan vs. brain health span), this work suggests the predicted AD resilience genes could serve as important candidate targets for therapeutic intervention.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data Availability Statement

The microarray gene expression profile used in this work is publicly available on NCBI Gene Expression Omnibus (GSE53890 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53890)): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53890, accessed on 10 September 2018. The RNAseq data used in this work were developed through the Religious Orders Study and Memory and Aging Project (ROSMAP) study [14] and are available at (https://www.synapse.org/#!Synapse:syn3505720, accessed on 10 September 2018) via the AD Knowledge Portal (https://adknowledgeportal.synapse.org, accessed on 10 September 2018). The AD Knowledge Portal is a platform for accessing data, analyses, and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open-science practices and accelerate translational learning. Data is available for general research use according to the following requirements for data access and data attribution (https://adknowledgeportal.synapse.org/#/DataAccess/Instructions, accessed on 10 September 2018).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 4 keywords, 9 MeSH terms, 2 funders, 77 references.

Cite

This paper

Guo, L., Grimaldi, N., Wang, M., Ho, L., Shackleton, B., Neff, R., Wang, E., Tu, Z., Gandy, S., Haroutunian, V., Ehrlich, M. E., Mobbs, C., & Zhang, B. (2026). Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia. Biomolecules, 16(7), 992. https://doi.org/10.3390/biom16070992

BibTeX

@article{guo2026molecular,
author = {Guo, Lei and Grimaldi, Nicholas and Wang, Minghui and Ho, Lap and Shackleton, Ben and Neff, Ryan and Wang, Erming and Tu, Zhidong and Gandy, Sam and Haroutunian, Vahram and Ehrlich, Michelle E and Mobbs, Charles and Zhang, Bin},
title = {{Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia}},
journal = {Biomolecules},
year = {2026},
month = jul,
volume = {16},
number = {7},
pages = {992},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {2218-273X},
doi = {10.3390/biom16070992},
url = {https://doi.org/10.3390/biom16070992},
pmid = {42509786},
pmcid = {PMC13406847}
}

RIS

TY - JOUR
AU - Guo, Lei
AU - Grimaldi, Nicholas
AU - Wang, Minghui
AU - Ho, Lap
AU - Shackleton, Ben
AU - Neff, Ryan
AU - Wang, Erming
AU - Tu, Zhidong
AU - Gandy, Sam
AU - Haroutunian, Vahram
AU - Ehrlich, Michelle E
AU - Mobbs, Charles
AU - Zhang, Bin
TI - Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia
T2 - Biomolecules
J2 - Biomolecules
PY - 2026
DA - 2026/07/06
VL - 16
IS - 7
SP - 992
SN - 2218-273X
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/biom16070992
UR - https://doi.org/10.3390/biom16070992
LA - en
ER -

CSL-JSON

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