Prevalence Of Alzheimer's Disease Research Articles

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aβ) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aβ oligomer injection as well as the combined stress and Aβ i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aβ-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aβ-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.

Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases.

Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy associated, among others, with mitochondrial dysfunction. Similar molecular features are found in Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM), underlying potential comorbidity. This study aims to evaluate common clinical and molecular hallmarks among sIBM, AD, and T2DM. Comorbidity with AD was assessed in n = 14 sIBM patients by performing neuropsychological and cognitive tests, cranial magnetic resonance imaging, AD cerebrospinal fluid biomarkers (levels of amyloid beta, total tau, and phosphorylated tau at threonine-181), and genetic apolipoprotein E genotyping. In the same sIBM cohort, comorbidity with T2DM was assessed by collecting anthropometric measures and performing an oral glucose tolerance test and insulin determinations. Results were compared to the standard population and other myositis (n = 7 dermatomyositis and n = 7 polymyositis). Mitochondrial contribution into disease was tested by measurement of oxidative/anaerobic and oxidant/antioxidant balances, respiration fluxes, and enzymatic activities in sIBM fibroblasts subjected to different glucose levels. Comorbidity of sIBM with AD was not detected. Clinically, sIBM patients showed signs of misbalanced glucose homeostasis, similar to other myositis. Such misbalance was further confirmed at the molecular level by the metabolic inability of sIBM fibroblasts to adapt to different glucose conditions. Under the standard condition, sIBM fibroblasts showed decreased respiration (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O2/min; p = 0.024) and increased anaerobic metabolism (5.76 ± 0.52 vs. 3.79 ± 0.35 mM lactate; p = 0.052). Moreover, when glucose conditions were changed, sIBM fibroblasts presented decreased fold change in mitochondrial enzymatic activities (−12.13 ± 21.86 vs. 199.22 ± 62.52 cytochrome c oxidase/citrate synthase ratio; p = 0.017) and increased oxidative stress per mitochondrial activity (203.76 ± 82.77 vs. −69.55 ± 21.00; p = 0.047), underlying scarce metabolic plasticity. These findings do not demonstrate higher prevalence of AD in sIBM patients, but evidences of prediabetogenic conditions were found. Glucose deregulation in myositis suggests the contribution of lifestyle conditions, such as restricted mobility. Additionally, molecular evidences from sIBM fibroblasts confirm that mitochondrial dysfunction may play a role. Monitoring T2DM development and mitochondrial contribution to disease in myositis patients could set a path for novel therapeutic options.

Patients with Alzheimer's Disease Have Increased Levels of Insulin-like Growth Factor-I in Serum but not in Cerebrospinal Fluid.

Insulin-like growth factor-I (IGF-I) is important for amyloid-β (Aβ) metabolism, and also interacts with the brain vasculature. In previous IGF-I studies, it has not been evaluated whether Alzheimer's disease (AD) patients had vascular comorbidities. A cross-sectional study of 40 consecutive non-diabetic AD patients and 36 healthy controls. We measured IGF-I in serum and cerebrospinal fluid (CSF) and also serum insulin. Mixed forms of AD and vascular dementia were excluded. After adjustment for covariates including age, serum IGF-I level was higher in the AD group than in the controls, whereas CSF IGF-I and serum insulin were unchanged. Binary logistic regression confirmed that high serum IGF-I was associated with increased prevalence of AD [adjusted Odds Ratio (OR) = 1.83, 95% confidence interval (CI): 1.005-3.32 per standard deviation (SD) increase in serum IGF-I]. This association was more robust after exclusion of patients receiving treatment with acetylcholinesterase inhibitors or N-methyl D-aspartate (NMDA) receptor antagonists (OR = 2.23, 95 % CI: 1.10-4.48). In the total study population (n = 76) as well in the AD group (n = 40), serum IGF-I correlated negatively with CSF Aβ1-42, and CSF IGF-I correlated positively with CSF/serum albumin ratio, CSF total tau, and CSF phosphorylated tau. In AD patients without major brain vascular comorbidities, serum but not CSF levels of IGF-I were increased after correction for covariates. This association was strengthened by exclusion of patients receiving medical treatment. Overall, the results support the notion of IGF-I resistance in mild AD dementia.

Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.

Approximately two-thirds of those suffering with Alzheimer's disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD.

Type 3 diabetes (Alzheimer's disease): new insight for promising therapeutic avenues.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) are two of the most commonly occurring diseases worldwide, especially among the elderly population. In particular, the increased prevalence of AD has imposed tremendous psychological and financial burdens on society. Growing evidence suggests both AD and T2D share many similar pathological traits. AD is characterized as a metabolic disorder whereby the glucose metabolism in the brain is impaired. This closely resembles the state of insulin resistance in T2D. Insulin resistance of the brain has been heavily implicated two prominent pathological features of AD, Aβ plaques and neurofibrillary tangles. Brain insulin resistance is known to elicit a positive feed-forward loop towards the formation of AD pathology in which they affect each other in a synergistic manner. Other physiological traits shared between the two diseases include inflammation, oxidative stress and autophagic dysfunction, which are also closely associated with brain insulin resistance. In this review and depending on these underlying pathways that link these two diseases, we have discussed the potential therapeutic implications of AD. By expanding our knowledge of the overlapping pathophysiology involved, we hope to provide scientific basis to the discovery of novel therapeutic strategies to improve the clinical outcomes of AD in terms of diagnosis and treatment.

TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

TREATMENT PARAMETERS AND RATIONALE FOR THE USE OF ELECTROCONVULSIVE THERAPY FOR THE MANAGEMENT OF TREATMENT-REFRACTORY AGITATION IN ALZHEIMER'S DISEASE

Predisposition to Alzheimer's and Age-Related Brain Pathologies by PM2.5 Exposure: Perspective on the Roles of Oxidative Stress and TRPM2 Channel.

Accumulating epidemiological evidence supports that chronic exposure to ambient fine particular matters of <2.5 μm (PM2.5) predisposes both children and adults to Alzheimer’s disease (AD) and age-related brain damage leading to dementia. There is also experimental evidence to show that PM2.5 exposure results in early onset of AD-related pathologies in transgenic AD mice and development of AD-related and age-related brain pathologies in healthy rodents. Studies have also documented that PM2.5 exposure causes AD-linked molecular and cellular alterations, such as mitochondrial dysfunction, synaptic deficits, impaired neurite growth, neuronal cell death, glial cell activation, neuroinflammation, and neurovascular dysfunction, in addition to elevated levels of amyloid β (Aβ) and tau phosphorylation. Oxidative stress and the oxidative stress-sensitive TRPM2 channel play important roles in mediating multiple molecular and cellular alterations that underpin AD-related cognitive dysfunction. Documented evidence suggests critical engagement of oxidative stress and TRPM2 channel activation in various PM2.5-induced cellular effects. Here we discuss recent studies that favor causative relationships of PM2.5 exposure to increased AD prevalence and AD- and age-related pathologies, and raise the perspective on the roles of oxidative stress and the TRPM2 channel in mediating PM2.5-induced predisposition to AD and age-related brain damage.

Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer's Disease.

As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer's disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body's diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain's metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

Ovariectomy Influences Cognition and Markers of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner.

Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer's Disease.

Alzheimer’s disease (AD) is a type of incurable neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ; plaques) and tau hyperphosphorylation as neurofibrillary tangles (NFTs) in the brain followed by neuronal death, cognitive decline, and memory loss. The high prevalence of AD in the developed world has become a major public health challenge associated with social and economic burdens on individuals and society. Due to there being limited options for early diagnosis and determining the exact pathophysiology of AD, finding effective therapeutic strategies has become a great challenge. Several possible risk factors associated with AD pathology have been identified; however, their roles are still inconclusive. Recent clinical trials of the drugs targeting Aβ and tau have failed to find a cure for the AD pathology. Therefore, effective preventive strategies should be followed to reduce the exponential increase in the prevalence of cognitive decline and dementia, especially AD. Although the search for new therapeutic targets is a great challenge for the scientific community, the roles of lifestyle interventions and nutraceuticals in the prevention of many metabolic and neurodegenerative diseases are highly appreciated in the literature. In this article, we summarize the molecular mechanisms involved in AD pathology and the possible ameliorative action of lifestyle and nutritional interventions including diet, exercise, Calorie restriction (CR), and various bioactive compounds on cognitive decline and dementia. This article will provide insights into the role of non-pharmacologic interventions in the modulation of AD pathology, which may offer the benefit of improving quality of life by reducing cognitive decline and incident AD.

New Insights Into the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.

Association of Vitamin D Receptor Polymorphisms with Amyloid-β Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort.

Amyloid-β peptide (Aβ) deposition in Alzheimer's disease (AD) is due to an imbalance in its production/clearance rate. Aβ is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aβ-transporters in peripheral blood mononuclear cells (PBMCs). VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aβ-transporters were evaluated in subgroups by qPCR. Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1, while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aβ-transporters in both groups. We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism.

Comparison of male and female patients with amnestic mild cognitive impairment: Hippocampal hyperactivity and pattern separation memory performance.

Recent studies have suggested that sex confers a differential risk in the incidence and prevalence of Alzheimer's disease (AD) thought to be the result of the increased lifespan of women compared to men. However, other factors may contribute to risk beyond the effect of increased lifespan. This study examined the role of sex in hippocampal hyperactivity localized to the dentate gyrus (DG)/CA3 subregion of the hippocampus and associated episodic memory impairment, considered a characteristic feature of AD in patients with amnestic mild cognitive impairment (aMCI). While participants with aMCI showed decreased memory performance and increased activation in the DG/CA3 when compared to controls, no significant sex-related differences in performance or activation were observed. Although other factors may contribute to sex differences in the prevalence of AD these findings show that no sex differences are observed in hippocampal dysfunction characteristic of the aMCI phase of AD.

Evidence against a geographic gradient of Alzheimer's disease and the hygiene hypothesis

A significant positive correlation was previously reported (Fox et al.Evol Med Public Health 2013; 2013:173–86) between hygiene and the global prevalence of Alzheimer's disease (AD) based on World Health Organization (2004) data. These data have now been updated by the Global Burden of Disease (GBD; 2016) dataset that takes into account under-registration and other potential confounds. We therefore addressed whether the association between hygiene and AD is maintained in light of these more recent data. We report a significant positive correlation between GBD AD prevalence rates and parasite burden, and a negative association with hygiene. These newer data argue that hygiene is not a risk factor for AD, and instead suggest that parasite burden may increase AD risk.Lay summary: It was previously hypothesized that hygeine might be a risk factor for the development of Alzheimer disease (AD), based on a global gradient of dementia. Newer data that correct global AD rates for under-reporting now demonstrate that parasite burden is positively correlated with AD.

Effect of atorvastatin on Aβ1–42-induced alteration of SESN2, SIRT1, LC3II and TPP1 protein expressions in neuronal cell cultures

Sestrins (SESNs) and sirtuins (SIRTs) are antioxidant and antiapoptotic genes and crucial mediators for lysosomal autophagy regulation that play a pivotal role in the Alzheimer's disease (AD). Recently, statins have been linked to the reduced prevalence of AD in statin-prescribed populations yet molecular basis for the neuroprotective action of statins is still under debate. This study was undertaken whether Aβ-induced changes of SESN2 and SIRT1 protein expression, autophagy marker LC3II and lysosomal enzyme TPP1 affected by atorvastatin (Western blot) and its possible role in Aβ neurotoxicity (ELISA). We showed that SESN2 and LC3II expressions were elevated, whereas SIRT1 and TPP1 expressions were decreased in the Aβ1-42 -exposed human neuroblastoma cells (SH-SY5Y). Co-administration of atorvastatin with Aβ1-42 compensates SESN2 increase and recovers SIRT1 decline by reducing oxidative stress, decreasing SESN2 expression and increasing SIRT1 expression by its neuroprotective action. Atorvastatin induced LC3II but not TPP1 level in the Aβ1-42 -exposed cells suggested that atorvastatin is effective in the formation of autophagosome but not on the expression of the specific lysosomal enzyme TPP1. Together, these results indicate that atorvastatin induced SESN2, SIRT1 and LC3II levels play a protective role against Aβ1-42 neurotoxicity.

Joint Multi-Modal Longitudinal Regression and Classification for Alzheimer's Disease Prediction.

Alzheimer's disease (AD) is a serious neurodegenerative condition that affects millions of individuals across the world. As the average age of individuals in the United States and the world increases, the prevalence of AD will continue to grow. To address this public health problem, the research community has developed computational approaches to sift through various aspects of clinical data and uncover their insights, among which one of the most challenging problem is to determine the biological mechanisms that cause AD to develop. To study this problem, in this paper we present a novel Joint Multi-Modal Longitudinal Regression and Classification method and show how it can be used to identify the cognitive status of the participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the underlying biological mechanisms. By intelligently combining clinical data of various modalities (i.e., genetic information and brain scans) using a variety of regularizations that can identify AD-relevant biomarkers, we perform the regression and classification tasks simultaneously. Because the proposed objective is a non-smooth optimization problem that is difficult to solve in general, we derive an efficient iterative algorithm and rigorously prove its convergence. To validate our new method in predicting the cognitive scores of patients and their clinical diagnosis, we conduct comprehensive experiments on the ADNI cohort. Our promising results demonstrate the benefits and flexibility of the proposed method. We anticipate that our new method is of interest to clinical communities beyond AD research and have open-sourced the code of our method online.11 The code package for the proposed Joint Multi-Modal Longitudinal Regression and Classification model have been made publicly available online at https://github.com/minds-mines/jmmlrc.

Gender and Age Differences and the Trend in the Incidence and Prevalence of Dementia and Alzheimer's Disease in Taiwan: A 7-Year National Population-Based Study.

Background Very few nationwide studies have focused on the variations in the incidence and prevalence of dementia and Alzheimer's disease (AD) in Asian countries. This study aims to describe the gender and age differences in the incidence and prevalence of dementia and AD in Taiwan. Methods The data on dementia and AD were acquired from the Taiwan National Health Insurance Research Database from 2004 to 2010. The sex and age-specific rates were standardized, and the differences of gender and age on dementia or AD were assessed using Poisson regression analysis. Results Over seven years, the prevalence of dementia and AD significantly increased from 4.7 to 7.6 per hundred people (β = 0.0784, p < 0.0001) and 2.3 to 3.5 per hundred people (β = 0.0696, p < 0.0001), respectively. However, the incidence of both dementia and AD decreased but not significantly from 10.9 to 10.7 and 4.9 to 4.6 per thousand person-years, respectively. Noticeably, both incidence and prevalence increased with age and were higher in women than in men. Conclusions The standardized incidence rates of dementia and AD are much lower than the data reported in some studies from Europe, the US, and Japan. Further studies are warranted to explore which factors are associated with the differences in the incidence of dementia and AD in Taiwan.

GEOGRAPHIC DISPARITIES IN COUNTY-LEVEL PREVALENCE OF ALZHEIMER’S DISEASE ACROSS THE UNITED STATES

Small-area geographic disparities in health care delivery have been observed across multiple disorders, but remain poorly studied for Alzheimer’s disease (AD) and other dementias. While national and state estimates of the prevalence and incidence of AD are available, estimates across finer geographic regions offer an opportunity to tailor programs to the needs of the local population. We estimated prevalence of AD at the county level across the continental United States. We used prevalence rates of AD by age category and race among Medicare fee-for-service beneficiaries published by the Centers for Disease Control (CDC). These prevalence rates were projected onto bridged-race county-level population data for 2017 from the National Center for Health Statistics, with empirical Bayes spatial smoothing to reduce variability in rates due to small population sizes. Estimated prevalence of AD varied more than threefold across counties, from a low of 51.8 per 1,000 persons in Loving County, Texas to a high of 169.6 per 1,000 persons in Kalawao County, Hawaii. Higher prevalence of AD was seen in the Southeastern and Midwestern United States. However, we observed specific counties with low prevalence of AD within regions with high prevalence of AD, and vice versa. These small-area geographic variations may provide vital information about social and environmental influences on dementia care, yet little data have been available to date. Understanding geographic disparities in prevalence will be critical for addressing practice variation in the prevention and diagnosis of dementia.

NEW APPROACH TO STUDYING COLLECTIVE EFFECTS OF GENETIC FACTORS ON ALZHEIMER’S DISEASE

Despite the wide recognition of the multifactorial nature of Alzheimer’s disease (AD), mechanisms of the collective influence of genetic and environmental factors on AD remain poorly understood. We used the Cardiovascular Health Study (CHS) and Framingham Heart Study (FHS) data to investigate the effects of genetic and gene-environment interactions on AD prevalence in the association analysis using logistic regression. Based on results of this analysis, we developed several new measures of integrated effects of SNPs, including for specific gene or group of genes, by constructing SNP-specific Interaction Polygenic Risk Scores (SIPRSs), Gene-specific Interaction Polygenic Risk Scores (GIPRS), and Trait-specific Interaction Polygenic Risk Scores (TIPRS), and tested them in the above data. We found strong interaction effects on AD among the SNPs in NRG3 gene and smoking, and among the SNPs in ATM and creatinine. In summary, we developed a new approach to measuring the collective impact of SNPs on complex traits, and discovered significant effects of the newly constructed SIPRS, GIPRS, and TIPRS on AD prevalence. The results of this study open a new opportunity of investigating the joint impacts of genetic and environmental factors on AD and other phenotypes of aging and health.

SERUM 25(OH)D SIGNIFICANTLY IMPACTS ALZHEIMER’S DISEASE IN OLDER ADULTS LIVING IN LONG-TERM CARE COMMUNITIES.

6.08 million Americans suffer from Alzheimer’s Disease (AD), with some estimating diagnoses will reach 15.0 million by 2060. Age is the strongest risk factor for AD, and the prevalence of AD among older adults necessitates investigation into preventable risk factors. 25-hydroxyvitamin D [25(OH)D] deficiency is more prevalent in older adults than other age demographics. Research shows a strong correlation between deficient 25(OH)D serum levels (≤20ng/ml) and AD diagnosis. The association with insufficient (≤30 ng/ml) levels remains unclear. Older adults (age > 65 yo) of five LTC communities in Texas participated in the cross-sectional study. One-year medical history and demographics were abstracted from medical records using double-blinded data abstraction and entry. Blood draws measured 25(OH)D serum levels. Adjusted logistic regression models examined if insufficient 25(OH)D serum levels (≤30 ng/ml) are associated with AD diagnosis. Confounders were total daily vitamin D supplementation, BMI, race, gender, age, years in community, and diagnosis of liver and renal disease. Participants (n=174, mean age: 83 yo) consisted of 63% female and 89% Caucasian. Fifty five percent had insufficient serum 25(OH)D levels (mean level: 32.6 ng/ml; mean supplementation rate: 1,138 IU per/d), and 20% had diagnosis of AD. 25% had both insufficient serum levels and AD, while 12.6% had adequate serum levels and AD. Those with insufficient 25(OH)D serum levels had elevated odds (OR=2.8; CL: 1.14, 7.02; p=0.024) of having AD after adjusting for confounders. Insufficient serum 25(OH)D levels (≤30 ng/ml) are associated with increased diagnoses of AD, indicating the importance of adequate levels among LTC residents.