Biology subjects

Kehoe, P. G.

Publications and source records attributed to Kehoe, P. G..

4 recordsLinked to original sources

bioRxiv2025

Elevated Na+/K+ Ratio in Alzheimers Disease: A Potential Biomarker for Braak Stage

Alzheimers disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and the accumulation of amyloid plaques and neurofibrillary tangles. While prior research has focused mainly on protein aggregation and neuroinflammation, emerging evidence suggests that ionic imbalances, particularly involving sodium (Na+) and potassium (K+), may contribute to AD progression. Na+ and K+ are critical for maintaining neuronal membrane potential, regulating action potential firing, and supporting neurotransmitter function. Although studies primarily focused on absolute Na+ concentrations, the Na+/K+ ratio may provide a more sensitive marker of ionic dysregulation. Given that the Na+/K+ gradient is actively maintained by the Na/K-ATPase pump, a target known to be vulnerable in AD, we hypothesized that the Na+/K+ ratio is altered in AD. We analyzed postmortem tissue from the prefrontal cortex, thalamus, and cerebrospinal fluid (CSF) of 97 human subjects (67 AD, 30 controls). AD cases exhibited a significant increase in the Na+/K+ ratio in the thalamus and CSF, driven primarily by elevated Na+ levels. The Na+/K+ ratio positively correlated with Braak tangle stage, suggesting an association with AD progression. These findings provide novel insights into ionic dysregulation in AD and suggest that the CSF Na+/K+ ratio may serve as a valuable biomarker of disease severity and progression. Future research should explore the potential of targeting ionic homeostasis as a therapeutic strategy in AD.

biochemistry↗

bioRxiv2022

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses to prioritize genes that are likely functionally relevant, and shared with closely related traits and risk factors. For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Our study identified genetic risks underlying all-cause dementia, demonstrating overlap with neurodegenerative processes, vascular risk factors (Type-II diabetes, blood pressure, lipid) and cerebral small vessel disease. These novel insights could lead to new prevention and treatment strategies for all dementias.

genetics↗

bioRxiv2020

Evidence for unique small RNA modifications in Alzheimers disease

BackgroundWhile significant advances have been made in uncovering the aetiology of Alzheimers disease and related dementias at the genetic level, molecular events at the epigenetic level remain largely undefined. Emerging evidence indicates that small non-coding RNAs (sncRNAs) and their associated RNA modifications are important regulators of complex physiological and pathological processes, including aging, stress responses, and epigenetic inheritance. However, whether small RNAs and their modifications are altered in dementia is not known. MethodsWe performed LC-MS/MS-based, high-throughput assays of small RNA modifications in post-mortem samples of the prefrontal lobe cortices of Alzheimers disease (AD) and control individuals. We noted that some of the AD patients has co-occurring vascular cognitive impairment-related pathology (VaD). FindingsWe report altered small RNA modifications in AD samples compared with normal controls. The 15-25-nucleotide (nt) RNA fraction of these samples was enriched for microRNAs, whereas the 30-40-nt RNA fraction was enriched for tRNA-derived small RNAs (tsRNAs), rRNA-derived small RNAs (rsRNAs), and YRNA-derived small RNAs (ysRNAs). Interestingly, most of these altered RNA modifications were detected both in the AD and AD with co-occurring vascular dementia subjects. In addition, sequencing of small RNA in the 30-40-nt fraction from AD cortices revealed reductions in rsRNA-5S, tsRNA-Tyr, and tsRNA-Arg. InterpretationThese data suggest that sncRNAs and their associated modifications are novel signals that may be linked to the pathogenesis and development of Alzheimers disease. FundingNIH grants (R01HL122770, R01HL091905, 1P20GM130459, R01HD092431, P50HD098593, GM103440), AHA grant (17IRG33370128), Sigmund Gestetner Foundation Fellowship to P Kehoe. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSAlzheimers disease (AD) and vascular dementia (VaD) are marked by cognitive impairment and neuropathologies caused by significant neuronal death. Associated gene mutations are rare in subjects with dementia, and the aetiology of these diseases is still not completely understood. Recent emerging evidence suggests that epigenetic changes are risk factors for the development of dementia. However, studies assessing small RNA modifications--one of the features of epigenetics--in dementia are lacking. Added value of this studyWe used high-throughput liquid chromatography-tandem mass spectrometry and small RNA sequencing to profile small RNA modifications and the composition of small RNAs in post-mortem samples of the prefrontal cortex of AD and control subjects. We detected and quantified 16 types of RNA modifications and identified distinct small non-coding RNAs and modification signatures in AD subjects compared with controls. Implications of all the available evidenceThis study identified novel types and compositions of small RNA modifications in the prefrontal cortex of AD patients compared with control subjects in post-mortem samples. The cellular locations of these RNA modifications and whether they are drivers or outcomes of AD are still not known. However, results from the present study may open new possibilities for dissecting the dementia pathology.

cell biology↗

bioRxiv2018

Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian Randomization study

BackgroundEvidence concerning the potential repurposing of antihypertensives for Alzheimers disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure (SBP), via different antihypertensive drug classes, on Alzheimers disease.\n\nMethodsWe used summary statistics from genome wide association studies of SBP (from UK Biobank) and Alzheimers disease (from the International Genomics of Alzheimers Project) in a two-sample Mendelian randomization analysis. We identified single nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive targets and estimated the effect of lowering SBP, via antihypertensive drug classes, on Alzheimers disease. We also report the effect of lowering SBP on Alzheimers disease by combining all drug targets and without consideration of the associated drugs.\n\nResultsThere was limited evidence that lowering SBP, via antihypertensive drug classes, affected Alzheimers disease risk. For example, calcium channel blockers had an odds ratio (OR) per 10mmHg lower SBP of 1.53 (95% confidence interval (CI): 0.94 to 2.49; p=0.09; SNPs=17). We also found limited evidence for an effect of lowering SBP on Alzheimers disease when combining all drug targets (OR per 10mmHg lower SBP: 1.14; 95%CI: 0.83 to 1.56; p=0.41; SNPs=59) and without consideration of the associated drug targets (OR per 10mmHg lower SBP: 1.04; 95%CI: 0.95 to 1.13; p=0.45; SNPs=153).\n\nConclusionsLowering SBP itself is unlikely to affect risk of developing Alzheimers disease. Consequently, if specific antihypertensive drug classes do affect risk of Alzheimers disease, they are unlikely to do so via SBP.\n\nKEY MESSAGESO_LIThis is the first study to use Mendelian randomization to estimate the effects of the twelve most common antihypertensive drug classes on Alzheimers disease.\nC_LIO_LILowering systolic blood pressure itself is unlikely to affect risk of developing Alzheimers disease.\nC_LIO_LIIf specific antihypertensive drug classes do affect Alzheimers disease risk, they are unlikely to do so via systolic blood pressure.\nC_LI

genetics↗