EXOME-WIDE STUDY IDENTIFIED 12 PLEIOTROPIC LOCI ASSOCIATED WITH ALZHEIMER’S AND CARDIOVASCULAR DISEASE RISKS

Abstract Health of brain, heart and blood vessels are closely connected, which means that Alzheimer’s (AD) and cardiovascular (CVD) diseases may have overlapping etiologies including genetic component. Most of previous genetic association studies considered different traits (AD, CVD, and their risk factors) separately. The analysis of pleiotropic predisposition to these traits may shed light on the trait-specific mechanisms in protection against AD. We carried out pair-wise pleiotropic exome-wide association study (~250K common genetic variants) in predisposition to AD and each of 17 traits in a sample of 118K individuals from UK biobank. The analysis included seven qualitative traits (CVD, coronary-heart disease, type 2 diabetes, stroke, myocardial infarction, heart failure and hypertension), as well as their 10 risk factors (blood glucose, body-mass index, height, weight, 4 lipid traits, systolic and diastolic blood pressure). Fisher’s method and omnibus test were used in pleiotropic analyses. In addition to the APOE-TOMM40 locus, the analysis identified 12 genetic loci in which genetic polymorphisms demonstrated significant associations with AD at p≤5×10-4 and pleiotropic associations at genome-wide level, p≤5×10-8. The identified genes are involved in processes of phosphorylation; regulation of cell growth, differentiation, and brain development; signal transduction and neurotransmission; mitochondrial and cytoskeleton organization; regulation of gene expression, apoptotic processes, and adaptive immune response. Our results provide novel evidence supporting the hypothesis of complex pleiotropic mechanisms contributing to the development and progression of AD and provide more insights into understanding of underlying biological functions and regulatory mechanisms behind these effects.

Palo Alto Healthcare System, Palo Alto, California, United States Brain-derived neurotrophic factor (BDNF) has a demonstrated role in promoting memory functions and neuronal survival.A common variant in the BDNF gene, the Val66Met polymorphism, has been found to reduce BDNF expression and increase vulnerability to neurocognitive impairments and age-related cognitive declines.Research suggests that BDNF Val66Met may be associated with hypertension, a well-established risk factor for health and brain functioning across the lifespan.While BDNF is most studied for its effect on learning and memory, its role in moderating other cognitive domains is not as well understood, especially those most affected by hypertension.Furthermore, no study to date has investigated these relationships exclusively with older adults and those at increased risk for cognitive decline.Therefore, the aim of this study was to investigate the effect of BDNF Val66Met and hypertension on the executive function ability of older adults (mean age 71.3±9.2 years) diagnosed with amnestic Mild Cognitive Impairment (aMCI) (N = 108).Results showed that BDNF Val66Met moderated the relationship between hypertension and executive functioning, such that hypertensive carriers of the BDNF Met allele performed significantly worse compared to Val-Val homozygotes, and independent to the effects of aging.These results indicate that genetic and vascular risk interactions can predispose older adults with aMCI to impairments in multiple cognitive domains, and potentially increase susceptibility to further declines or conversion to dementia.These findings have implications for future research on dementia disease pathology, and highlight the importance of strategies that target fixed and modifiable risk factors to promote cognitive resilience.

EXOME-WIDE STUDY IDENTIFIED 12 PLEIOTROPIC LOCI ASSOCIATED WITH ALZHEIMER'S AND CARDIOVASCULAR DISEASE RISKS
Yury Loika, Elena Loiko, Konstantin Arbeev, Eric Stallard, Anatoliy Yashin, Irina Culminskaya, and Alexander Kulminski, Duke University, Durham, North Carolina, United States Health of brain, heart and blood vessels are closely connected, which means that Alzheimer's (AD) and cardiovascular (CVD) diseases may have overlapping etiologies including genetic component.Most of previous genetic association studies considered different traits (AD, CVD, and their risk factors) separately.The analysis of pleiotropic predisposition to these traits may shed light on the traitspecific mechanisms in protection against AD.We carried out pair-wise pleiotropic exome-wide association study (~250K common genetic variants) in predisposition to AD and each of 17 traits in a sample of 118K individuals from UK biobank.The analysis included seven qualitative traits (CVD, coronary-heart disease, type 2 diabetes, stroke, myocardial infarction, heart failure and hypertension), as well as their 10 risk factors (blood glucose, body-mass index, height, weight, 4 lipid traits, systolic and diastolic blood pressure).Fisher's method and omnibus test were used in pleiotropic analyses.In addition to the APOE-TOMM40 locus, the analysis identified 12 genetic loci in which genetic polymorphisms demonstrated significant associations with AD at p≤5×10-4 and pleiotropic associations at genome-wide level, p≤5×10-8.The identified genes are involved in processes of phosphorylation; regulation of cell growth, differentiation, and brain development; signal transduction and neurotransmission; mitochondrial and cytoskeleton organization; regulation of gene expression, apoptotic processes, and adaptive immune response.Our results provide novel evidence supporting the hypothesis of complex pleiotropic mechanisms contributing to the development and progression of AD and provide more insights into understanding of underlying biological functions and regulatory mechanisms behind these effects.
ted significant associations with AD at p≤5×10-4 and pleiotropic associations at genome-wide level, p≤5×10-8.The identified genes are involved in processes of phosphorylation; regulation of cell growth, differentiation, and brain development; signal transduction and neurotransmission; mitochondrial and cytoskeleton organization; regulation of gene expression, apoptotic processes, and adaptive immune response.Our results provide novel evidence supporting the hypothesis of complex pleiotropic mechanisms contributing to the development and progression of AD and provide more insights into understanding of underlying biological functions and regulatory mechanisms behind these effects.


REGULATION OF NEURONAL MITOCHONDRIAL BIOENERGETICS BY LIPID METABOLITES UPREGULATED IN DEMENTIA

Stephanie Heimler 1 , K. Allison Amick 2 , Jaclyn Bergstrom 3 , Mohit Jain 3 , and Anthony Molina Mitochondrial dysfunction occurs early in Alzheimer's disease (AD) progression and is evident in the Central Nervous System (CNS) and peripheral circulating cells.While there is evidence indicating that bioenergetic decline can drive the early pathogenesis of AD, little is known about the extracellular factors that alter neuronal bioenergetic capacity.We hypothesized that circulating metabolites contribute to neuronal bioenergetic decline associated with AD.Using a cohort comprised of participants with normal cognition, mild cognitive impairment, and dementia, we show that human serum harbors circulating, non-cellular factors capable of mediating neuronal bioenergetic differences according to the cognitive status of the serum donor.We developed a novel screeningbased approach to identify candidate "mito-active" lipid metabolites in human serum that could mediate differences in bioenergetic capacity.Among these, Nervonic Acid and 15-epi-PGA1 were predicted to be mitochondrial inhibitors upregulated in participants with dementia.Neurons exposed to physiologically-relevant ranges of these molecules in-vitro exhibited a dose-dependent reduction in maximal mitochondrial respiration.We found that 500ug/mL of Nervonic Acid and 9ug/mL of 15-epi-PGA1 reduced maximal mitochondrial respiration by 62.3% and 63.3%, respectively, thereby validating our screening and prediction approach.Future experiments may be directed towards investigating if and how these and other mito-active metabolites of interest cross the blood-brain barrier to meaningfully affect AD.Furthermore, identified mito-active molecules can be investigated in other clinical cohorts to examine their role/s in multiple age-related or neurological conditions.This work expands our mechanistic understanding of how extrinsic factors associated with age and cognitive status contribute to neuronal bioenergetic decline.


AN OPTIMIZED MOUSE PARABIOSIS PROTOCOL FOR INVESTIGATION OF AGING AND REJUVENATIVE MECHANISMS

Sonia Rodriguez, Chase Carver, Katayoun Ayasoufi, Felicia Duke Boynton, and Marissa Schafer, Mayo Clinic, Rochester, Minnesota, United States Surgical parabiosis is widely used to study the mechanistic influence of the circulating milieu on aging and regeneration.

Innovation in Aging, 2022, Vol. 6, No. S1

REGULATION OF NEURONAL MITOCHONDRIAL BIOENERGETICS BY LIPID METABOLITES UPREGULATED IN DEMENTIA
Stephanie Heimler 1 , K. Allison Amick 2 , Jaclyn Bergstrom 3 , Mohit Jain 3 , and Anthony Molina Mitochondrial dysfunction occurs early in Alzheimer's disease (AD) progression and is evident in the Central Nervous System (CNS) and peripheral circulating cells.While there is evidence indicating that bioenergetic decline can drive the early pathogenesis of AD, little is known about the extracellular factors that alter neuronal bioenergetic capacity.We hypothesized that circulating metabolites contribute to neuronal bioenergetic decline associated with AD.Using a cohort comprised of participants with normal cognition, mild cognitive impairment, and dementia, we show that human serum harbors circulating, non-cellular factors capable of mediating neuronal bioenergetic differences according to the cognitive status of the serum donor.We developed a novel screeningbased approach to identify candidate "mito-active" lipid metabolites in human serum that could mediate differences in bioenergetic capacity.Among these, Nervonic Acid and 15-epi-PGA1 were predicted to be mitochondrial inhibitors upregulated in participants with dementia.Neurons exposed to physiologically-relevant ranges of these molecules in-vitro exhibited a dose-dependent reduction in maximal mitochondrial respiration.We found that 500ug/mL of Nervonic Acid and 9ug/mL of 15-epi-PGA1 reduced maximal mitochondrial respiration by 62.3% and 63.3%, respectively, thereby validating our screening and prediction approach.Future experiments may be directed towards investigating if and how these and other mito-active metabolites of interest cross the blood-brain barrier to meaningfully affect AD.Furthermore, identified mito-active molecules can be investigated in other clinical cohorts to examine their role/s in multiple age-related or neurological conditions.This work expands our mechanistic understanding of how extrinsic factors associated with age and cognitive status contribute to neuronal bioenergetic decline.

AN OPTIMIZED MOUSE PARABIOSIS PROTOCOL FOR INVESTIGATION OF AGING AND REJUVENATIVE MECHANISMS
Sonia Rodriguez, Chase Carver, Katayoun Ayasoufi, Felicia Duke Boynton, and Marissa Schafer, Mayo Clinic, Rochester, Minnesota, United States Surgical parabiosis is widely used to study the mechanistic influence of the circulating milieu on aging and regeneration.


