Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene
Open accessAbstract
The vascular hypothesis of Alzheimer's disease (AD) has proposed the involvement of brain hypoperfusion in AD pathogenesis, where cognitive decline and dysfunction result from dwindling cerebral blood flow (CBF). Based on the vascular hypothesis of Alzheimer's disease, we focused on exploring how genetic factors influence AD pathogenesis via the cerebrovascular system. To investigate the role of CBF endophenotypes in AD pathogenesis, we performed a targeted genetic analysis of 258 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort to examine associations between 4033 single-nucleotide polymorphisms of 24 AD genes and CBF measures in 4 brain regions. A novel association with CBF measure in the left angular gyrus was identified in an INPP5D single-nucleotide polymorphism (i.e., rs61068452; p = 1.48E-7; corrected p = 2.39E-3). The gene-based analysis discovered both INPP5D and CD2AP associated with the left angular gyrus CBF. Further analyses on nonoverlapping samples revealed that rs61068452-G was associated with lower CSF t-tau/Aβ 1-42 ratio. Our findings suggest a protective role of rs61068452-G in an AD-relevant cerebrovascular endophenotype, which has the potential to provide novel insights for better mechanistic understanding of AD.
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The INPP5D variant rs61068452 is protective against Alzheimer's disease and is significantly associated with lower cerebrospinal fluid total tau/Aβ42 ratio.
“A second variant in INPP5D, rs61068452, was found to be protective against AD, and was significantly associated with lower cerebrospinal fluid (CSF) total tau (t-tau)/amyloid beta (Aβ)42 ratio.8”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [8]
rs61068452 is apparently protective against AD.
“while rs61068452 is apparently protective against AD.8”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [8]
Variant rs35349669 is proposed to confer increased risk for AD, and rs61068452 is proposed to confer protection.
“While variant rs35349669 is proposed to confer increased risk for AD, rs61068452 is proposed to confer protection [166, 167].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [167]
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- Authors
- Yao, X., Risacher, S. L., Nho, K., Saykin, A. J., Wang, Z., & Shen, L.
- Affiliations
- University of Pennsylvania (US)
- Indiana University School of Medicine (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Wang, Ze
- Shen, Li
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 81
- Pages
- 213-221
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC6732252
- OpenAlex
- W2949384336
- Cited by
- 40
- References
- 9
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 10 · 2021: 7 · 2020: 4 · 2019: 2
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurobiology of Aging (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Publisher
- Funders
- National Institute on Aging
- National Science Foundation
- U.S. National Library of Medicine
- National Institute of Biomedical Imaging and Bioengineering
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, cerebral blood flow, INPP5D, CD2AP, single nucleotide polymorphisms, cerebral hypoperfusion, angular gyrus, genetic association
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Aged, Aged, 80 and over, Alzheimer Disease, Cerebrovascular Circulation, Female, Humans, Male, Parietal Lobe, Peptide Fragments, Amyloid beta-Peptides, tau Proteins, Polymorphism, Single Nucleotide, Endophenotypes, Neuroimaging
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