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Background Higher incidence levels of Alzheimer’s disease (AD) in Black Americans are well documented. However, quantitative explanations of this disparity in terms of risk-factor diseases acting through well-defined pathways are lacking. Methods We applied a Blinder-Oaxaca-based algorithm modified for censored data to a 5% random sample of Medicare beneficiaries age 65+ to explain Black/White disparities in AD risk in terms of differences in exposure and vulnerability to morbidity profiles based on 10 major AD-risk-related diseases. Results The primary contribution to racial disparities in AD risk comes from morbidity profiles that included hypertension with about 1/5th of their contribution due to differences in prevalence (exposure effect) and 4/5ths to differences in the effects of the morbidity profile on AD risk (vulnerability effect). In total, disease-related effects explained a higher proportion of AD incidence in Black Americans than in their White counterparts. Conclusions Disease-related causes may represent some of the most straightforward targets for targeted interventions aimed at the reduction of racial disparities in health among US older adults. Hypertension is a manageable and potentially preventable condition responsible for the majority of the Black/White differences in AD risk, making mitigation of the role of this disease in engendering higher AD incidence in Black Americans a prominent concern.

PURPOSE: Evidence on the nature of the relationship between patients receiving chemotherapy as an essential part of guideline-concordant cancer care and the onset of Alzheimer's Disease (AD) and other adverse cognitive outcomes has been mixed. Biological mechanisms were proposed to support both a potentially beneficial and an adverse role. To explore the relationship between chemotherapy and onset of AD and other neurocognitive disorders (ND) in colorectal cancer survivors. METHODS: We conducted a retrospective cohort study of 135,834 individuals older than 65 years diagnosed with colorectal cancer between 1998 and 2007, using SEER-Medicare data. A proportional hazards model was used before and after the use of inverse probability weighting to account for populational differences between the chemotherapy and nonchemotherapy groups. Weights were normalized to the total sample size. RESULTS: After inverse probability weighting, chemotherapy was associated with decreased AD risk (hazard ratio [HR]: 0.791; 95% CI: 0.758 to 0.824) and lower risk for the majority of other ND including AD-related diseases (HR: 0.823; CI: 0.802 to 0.844), dementia (permanent mental disorder) (HR: 0.807; CI: 0.782 to 0.832), and dementia (senile) (HR: 0.772; CI: 0.745 to 0.801). The only adverse effect to remain significant was cerebral degeneration (excluding AD) (HR: 1.067; CI: 1.033 to 1.102). The effects for AD remained after treatment was stratified by chemotherapy agent type and remained significant for up to 6 years past diagnosis. CONCLUSION: Chemotherapy use in colorectal cancer survivors demonstrated an association with reduced risk for AD and other ND.

Background: Understanding the dynamics of epidemiologic trends in Alzheimer’s disease (AD) and related dementias (ADRD) and their epidemiologic causes is vital to providing important insights into reducing the burden associated with these conditions. Objective: To model the time trends in age-adjusted AD/ADRD prevalence and incidence-based mortality (IBM), and identify the main causes of the changes in these measures over time in terms of interpretable epidemiologic quantities. Methods: Trend decomposition was applied to a 5%sample of Medicare beneficiaries between 1991 and 2017. Results: Prevalence of AD was increasing between 1992 and 2011 and declining thereafter, while IBM increased over the study period with a significant slowdown in its rate of growth from 2011 onwards. For ADRD, prevalence and IBM increased through 2014 prior to taking a downwards turn. The primary determinant responsible for declines in prevalence and IBM was the deceleration in the increase and eventual decrease in incidence rates though changes in relative survival began to affect the overall trends in prevalence/IBM in a noticeable manner after 2008. Other components showed only minor effects. Conclusion: The prevalence and IBM of ADRD is expected to continue to decrease. The directions of these trends for AD are not clear because AD incidence, the main contributing component, is decreasing but at a decreasing rate suggesting a possible reversal. Furthermore, emerging treatments may contribute through their effects on survival. Improving ascertainment of AD played an important role in trends of AD/ADRD over the 1991-2009/10 period but this effect has exhausted itself by 2017.

BACKGROUND: We hypothesized that cumulative anesthesia exposure over the course of routine treatment of colorectal cancer in older adults can increase long-term risk of Alzheimer’s disease (AD), Alzheimer’s disease-related dementias (ADRD), and other chronic neurocognitive disorders (CND). METHODS: We conducted a SEER-Medicare-based retrospective cohort study of 84,770 individuals age 65 years and older diagnosed with colorectal cancer between 1998 and 2007 using a proportional hazards model with inverse probability weighted estimators. The primary exploratory variable was a time-variant measure of cumulative anesthesia exposure for abdominal and pelvic procedures, updated continuously. RESULTS: Our primary outcomes, AD and ADRD, occurred in 6005/84,770 (7.1%) and 14,414/83,444 (17.3%) individuals respectively. No statistically significant association was found between cumulative anesthesia exposure and AD (hazard ratio [HR], 0.993; 95% CI, 0.973–1.013). However, it was moderately associated with the risk of ADRD (HR, 1.016; 95% CI, 1.004–1.029) and some secondary outcomes including most notably: cerebral degeneration (HR, 1.048; 95% CI, 1.033–1.063), hepatic encephalopathy (HR, 1.133; 95% CI, 1.101–1.167), encephalopathy–not elsewhere classified (HR,1.095; 95% CI: 1.076–1.115), and incident/perioperative delirium (HR, 1.022; 95% CI, 1.012–1.032). Furthermore, we observed an association between perioperative delirium and increased risk of AD (HR, 2.05; 95% CI, 1.92–2.09). CONCLUSION: Cumulative anesthesia exposure for abdominal and pelvic procedures was not associated with increased risk of AD directly and had a small but statistically significant association with ADRD and a number of other CNDs. Cumulative anesthesia exposure was also associated with perioperative delirium, which had an independent adverse association with AD risk.

Purpose The aim of the study was to evaluate the relative contributions of incidence, stage-specific relative survival, and stage ascertainment to changes in bladder cancer (BC) prevalence and incidence-based mortality. Methods Partitioning of prevalence and incidence-based mortality trends into their epidemiologic components. Results BC prevalence estimated from our model increased but at monotonically decreasing rates until 2007, after which it decreased again. The main forces underlying observed trends in BC prevalence were relative BC survival, which improved throughout the period, and BC incidence, which increased at a decreasing rate until 2005 and declined thereafter. Mortality of persons ever diagnosed with BC increased at an increasing rate until 1997, increased at a decreasing rate from 1997 to 2005, and decreased thereafter. The primary forces accounting for mortality trends were changes in mortality in the general population, which improved at an increasing rate during most of 1992–2010, the most important factor, and changes in incidence. Stage ascertainment did not improve during 1992–2010. Conclusions Although mortality rates improved, these gains largely reflected improvements in U.S. population survival rather than from improvements in BC-specific outcomes.

Lung, breast, prostate, and colorectal cancers are among the most common and fatal malignancies worldwide. They are mainly caused by multifactorial mechanisms and are genetically heterogeneous. We investigated the genetic architecture of these cancers through genome-wide association, pathway-based, and summary-based transcriptome-/methylome-wide association analyses using three independent cohorts. Our genome-wide association analyses identified the associations of 33 single-nucleotide polymorphisms (SNPs) at P 5E - 06, of which 32 SNPs were not previously reported and did not have proxy variants within their ± 1 Mb flanking regions. Moreover, other polymorphisms mapped to their closest genes were not previously associated with the same cancers at P 5E - 06. Our pathway enrichment analyses revealed associations of 32 pathways; mainly related to the immune system, DNA replication/transcription, and chromosomal organization; with the studied cancers. Also, 60 probes were associated with these cancers in our transcriptome-wide and methylome-wide analyses. The ± 1 Mb flanking regions of most probes had not attained P 5E - 06 in genome-wide association studies. The genes corresponding to the significant probes can be considered as potential targets for further functional studies. Two genes (i.e., CDC14A and PMEL) demonstrated stronger evidence of associations with lung cancer as they had significant probes in both transcriptome-wide and methylome-wide association analyses. The novel cancer-associated SNPs and genes identified here would advance our understanding of the genetic heterogeneity of the common cancers.

Aim: Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods: Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results: Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion: Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.

Background Time trends of lung cancer prevalence and mortality are the result of three competing processes: changes in the incidence rate, stage-specific survival, and ascertainment at early stages. Improvements in these measures act concordantly to improve disease-related mortality, but push the prevalence rate in opposite directions making a qualitative interpretation difficult. The goal of this paper is to evaluate the relative contributions of these components to changes in lung cancer prevalence and mortality. Methods Partitioning of prevalence and mortality trends into their components using SEER data for 1973-2013. Results The prevalence of lung cancer increases for females and decreases for males. In 1998, the former was due to increased incidence (45%-50% of total trend), improved survival (40%-45%), and increased ascertainment at early stages (10%-15%). In males, a rapidly declining incidence rate overpowered the effects of survival and ascertainment resulting in an overall decrease in prevalence over time. Trends in lung cancer mortality are determined by incidence during 1993-2002 with noticeable contribution of survival after 2002. Conclusion Lung cancer incidence was the main driving force behind trends in prevalence and mortality. Improved survival played essential role from 2000 onwards. Trends in stage ascertainment played a small but adverse role. Our results suggest that further improvement in lung cancer mortality can be achieved through advances in early stage ascertainment, especially for males, and that in spite of success in treatment, adenocarcinoma continues to exhibit adverse trends (especially in female incidence) and its role among other histology-specific lung cancers will increase in the near future.

Objectives The regions with highest and lowest Alzheimer's disease (AD) mortality across the United States at state/county levels were identified and their contribution to the differences in total mortality rates between these regions was evaluated. The disease, disease group, sex, race/ethnicity, and place-of-death-related inter-region differences that engender the disparity in mortality were quantitatively described. The hypothesis that inter-regional differences in filling out death certificates are a major contributor to differences in AD mortality was tested. Design Retrospective evaluation of death certificate data. Setting The United States. Participants Deceased US residents, 1999-2018. Methods Region-specific age-adjusted mortality rates and group-specific rate decomposition. Results The county clusters with the highest and lowest AD mortality rates were in Washington (WA) and New York (NY), respectively, with other notable high-mortality clusters on the border of Tennessee, Georgia, and Alabama as well as in North Dakota and South Dakota. These patterns were stable over the 1999-2018 period. AD had the highest contribution to total mortality difference between WA and NY (156%, higher in WA), in contrast circulatory diseases had a contribution of comparable magnitude (154%) but were higher in NY. Differences in cause-of-death certificate coding, either through coding of non-AD dementias, or other conditions accompanying a potential AD death could not account for differences in AD mortality between NY and WA. Conclusions Inter-regional differences in filling out death certificates were not a major contributor to variation in AD mortality between the regions with the highest and lowest rates. The respective mitigation of the effects of neural and circulatory diseases and several other high-impact conditions would not negate the disparity in mortality between NY and WA.

Aim Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.

Over 97% of individuals diagnosed with ductal carcinoma in situ (DCIS) will choose to receive guideline concordant care (GCC), which was originally designed to treat invasive cancers and is associated with treatment related morbidity. An alternative to GCC is active surveillance (AS) where therapy is delayed until medically necessary. Differences in mortality risk between the two approaches in women age 65+ are analyzed in this study. SEER and Medicare information on treatment during the first year after diagnosis was used to identify three cohorts based on treatment type and timing: GCC (N = 21,772; immediate consent for treatment), AS1 (N = 431; delayed treatment within 365 days), and AS2 (N = 205; no treatment/ongoing AS). A propensity score-based approach provided pseudorandomization between GCC and AS groups and survival was then compared. Strong influence of comorbidities on the treatment received was observed for all age-groups, with the greatest burden observed in the AS2 group. All-cause and breast-cancer-specific mortality hazard ratios (HR) for AS1 were not statistically different from the GCC group; AS2 was associated with notably higher risk for both all-cause (HR:3.54; CI:3.29, 3.82) and breast-cancer-specific (HR:10.73; CI:8.63,13.35) mortality. Cumulative mortality was substantially higher from other causes than from breast cancer, regardless of treatment group. Women managed with AS for DCIS had higher all-cause and breast-cancer-specific mortality. This effect declined after accounting for baseline comorbidities. Delays of up to 12 months in initiation of GCC did not underperform immediate surgery.

Emerging evidence from experimental and clinical research suggests that stress-related genes may play key roles in AD development. The fact that genome-wide association studies were not able to detect a contribution of such genes to AD indicates the possibility that these genes may influence AD non-linearly, through interactions of their products. In this paper, we selected two stress-related genes (GCN2/EIF2AK4 and APP) based on recent findings from experimental studies which suggest that the interplay between these genes might influence AD in humans. To test this hypothesis, we evaluated the effects of interactions between SNPs in these two genes on AD occurrence, using the Health and Retirement Study data on white indidividuals. We found several interacting SNP-pairs whose associations with AD remained statistically significant after correction for multiple testing. These findings emphasize the importance of nonlinear mechanisms of polygenic AD regulation that cannot be detected in traditional association studies. To estimate collective effects of multiple interacting SNP-pairs on AD, we constructed a new composite index, called Interaction Polygenic Risk Score, and showed that its association with AD is highly statistically significant. These results open a new avenue in the analyses of mechanisms of complex multigenic AD regulation.

PURPOSE: Increasing health care costs, longer life expectancy, improved breast cancer (BC) survival, and higher levels of complex comorbidities have important implications for future Medicare expenditures. METHODS: Data from the SEER program linked to Medicare claims records were used. Women with BC (cases) were categorized into 3 groups on the basis of their year of diagnosis (1998, 2003, or 2008) and were propensity score matched to women without a BC diagnosis (controls). All stage and stage-specific longitudinal changes in survival, morbidity levels using the Elixhauser index, and Medicare expenditures in 2018 dollars were calculated and compared. RESULTS: More than 15% of BC cases were diagnosed in patients over the age of 85 years. The prevalence of most comorbidities increased over time. Costs among cases increased between 1998 and 2008. Spending directly correlated with the stage of disease at diagnosis, with the lowest per-patient costs in the ductal carcinoma in situ (DCIS) subgroup ($14,792 in 1998 and $19,652 in 2008) and the highest in those with distant cancer ($37,667 in 1998 and $43,675 in 2008). Assuming no significant changes in the distribution of BC stage or age at diagnosis, the total annual costs of caring for patients with BC in women 65 years of age or older at diagnosis increased by at least $1.1 billion between 1998 and 2008. CONCLUSION: Improvements in BC survivorship are associated with intensive use of health care resources and substantially higher downstream costs among Medicare beneficiaries. Appropriate planning, in both the fiscal and the oncology care infrastructure, is required to prepare the health system for these emerging health care trends.

Longer lifespan is accompanied by a larger number of chronic diseases among older adults. Because of a growing proportion of older adults in the U.S., this brings the problem of age-related morbidity to the forefront as a major contributor to rising medical expenditures. We evaluated 15-year time trends (from 1998 to 2013) in the prevalence of 48 acute and chronic non-cancer diseases and cancers in older U.S. adults aged 65+ and estimated the annual percentage changes of these prevalence trends using SEER-Medicare and HRS-Medicare data. We found that age-adjusted prevalence of cancers of kidney, pancreas, and melanoma, as well as diabetes, renal disease, limb fracture, depression, anemia, weight deficiency, dementia/Alzheimer's disease, drug/medications abuse and several other diseases/conditions increased over time. Conversely, prevalence of myocardial infarction, heart failure, cardiomyopathy, pneumonia/influenza, peptic ulcer, and gastrointestinal bleeding, among others, decreased over time. There are also diseases whose prevalence did not change substantially over time, e.g., a group of fast progressing cancers and rheumatoid arthritis. Analysis of trends of multiple diseases performed simultaneously within one study design with focus on the same time interval and the same population for all diseases allowed us to provide insight into the epidemiology of these conditions and identify the most alarming and/or unexpected trends and trade-offs. The obtained results can be used for health expenditures planning for growing sector of older adults in the U.S.

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

Aims To identify how efforts to control the diabetes epidemic and the resulting changes in diabetes mellitus, type II (T2D) incidence and survival have affected the time-trend of T2D prevalence. Methods A newly developed method of trend decomposition was applied to a 5% sample of Medicare administrative claims filed between 1991 and 2012. Results Age-adjusted prevalence of T2D for adults age 65+ increased at an average annual percentage change of 2.31% between 1992 and 2012. Primary contributors to this trend were (in order of magnitude): improved survival at all ages, increased prevalence of T2D prior to age of Medicare eligibility, decreased incidence of T2D after age of Medicare eligibility. Conclusions Health services supported by the Medicare system, coupled with improvements in medical technology and T2D awareness efforts provide effective care for individuals age 65 and older. However, policy maker attention should be shifted to the prevention of T2D in younger age groups to control the increase in prevalence observed prior to Medicare eligibility.

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection–free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection–free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection–free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

BACKGROUND Improvements in breast cancer survival and increasing population life expectancy have resulted in a growing number of women receiving subsequent health care after breast cancer diagnosis and treatment. We sought to determine the magnitude of increases in healthcare costs related to breast cancer survivorship, in anticipation of predicted increases in enrollment, higher intensity utilization, and greater healthcare spending among Medicare beneficiaries. METHODS Women age 65+ diagnosed with stage 0-III breast cancer in 1998, 2003 or 2008, were identified from the SEER database linked to Medicare records. After restrictions they were propensity score matched to a comparable group of non-breast-cancer women on demographic characteristics and co-morbidities at time of diagnosis based on the Elixhauser co-morbidity index. Line payments to care providers were then calculated for the first year of care after diagnosis (cases only) as well as years 2-6, 8-11 and 12-16 post-diagnosis (cases and controls). Direct Medicare costs were adjusted for inflation using the experimental Medicare costs Price Index and compared under real world and alternative survival scenarios. RESULTS Overall, the costs of care were progressively higher in later cohorts across all time periods. Differences in survivorship were the primary driver of differences in costs between breast cancer cases and controls. All-stage costs in years 2-6 were higher in the cancer group ($2,499, $10,261 and $12,029 higher per-person in 1998, 2003 and 2008 respectively), however, higher mortality in the cancer group reduced the costs and quantity of care received in later years [years 7-11 ($2,183 lower per-person in 1998) and 12-16 ($2,431 lower per-person in 1998)]. In pairs with identical survival, costs in the cancer group were significantly higher than in matched non-breast-cancer controls across all time periods (years 2-6: $4,799, $9,545 and $12,245 higher in 1998/2003/2008; years 7-11: $2,922 and $5,597 higher in 1998/2003). Stratification by stage changed the magnitude but not the general pattern of our results. The first year of care in 2003 was on average $4,933 dollars higher than in 1998; in 2008 costs again increased by $4,223 per-person. In years 2-6 the cost of cancer care increased by $12,440 (2003 vs 1998) and $3,456 (2008 vs 2003) per-person; Finally, cancer care for years 7-11 in 2003 $3,964 higher than in 1998 per-person. CONCLUSION Improved breast cancer survival and increased overall life expectancy among women in the United States will contribute to higher Medicare expenditures. Future risk-based capitation schemes should account for these advancements when preparing for healthcare delivery after cancer. Citation Format: Greenup RA, Yashkin A, Gorbunova G, Akusevich I, Hwang ES. Medicare costs for women after breast cancer: Preparing for survivorship [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-08.

The aim of this study was to assess differences in the effect of traumatic brain injury (TBI) on the onset of Alzheimer’s disease (AD) and other dementias between veteran and non-veteran respondents of the Health and Retirement Study as well as to measure the sensitivity of these differences to the introduction of controls for groups of demographic, medical co-morbidity and polygenic risk scores reflecting AD hallmarks. Using the Fine-Gray proportional hazards model we found that TBI was a strong predictor of dementia in community dwelling residents age 65+: for AD associated risk was 181% [Hazard Ratio (HR): 2.81; CI:2.05-3.86] sample-wide and 142% [HR: 2.42; CI:1.31-2.46] in veteran males. Effect magnitude decreased with the addition of risk-related control variables but remained associated with significantly increased risk. Large differences in risk were observed between veteran and non-veteran males for AD, vascular dementia, senile dementia, and dementia with Lewy Bodies

The time trend of prevalence and mortality of major cancers is the result of three competing processes: changes in the incidence rate, stage-specific survival, and ascertainment at early stages. Partitioning approach allows for evaluating the relative contribution of each of these competing processes to the overall trend. In this report we applied the partitioning methodology developed for the SEER registry data for prostate, colorectal, lung, female breast, bladder, ovarian, stomach, pancreas, kidney, liver cancers and melanoma. The analysis involves the design and estimation of four models for each cancer site: i) incidence rate using the Armitage-Doll model with individual predisposition modeled by the gamma distribution, ii) probability of relative survival after cancer diagnosis using the Weibull model for time after disease onset, iii) frequencies of stage at onset, and iv) mortality in the general population using the Gompertz model. B-splines are used to fit the time patterns of model parameters obtained for each year Relative contributions of the partitioning components were evaluated for individual cancers (e.g., increase of prevalence in prostate cancer in 2000 was due to increased incidence (59%), improved survival (29%), and improve stage ascertainment (12%)) and compared among all considered cancers. The results were discussed in the light of the effect of the accumulation of survivors occurring in early years (due to improving survival) and their higher mortality (because of higher prevalence of survivors) in later years (i.e., mortality is transferred to latter time periods due to overall improvements in survival).

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder caused by the interplay of multiple genetic and non-genetic factors. Hypertension is one of the AD risk factors that has been linked to underlying pathological changes like senile plaques and neurofibrillary tangles formation as well as hippocampal atrophy. In this study, we investigated the differences in the genetic architecture of AD between hypertensive and non-hypertensive subjects in four independent cohorts. Our genome-wide association analyses revealed significant associations of 15 novel potentially AD-associated polymorphisms (P

Persistent stress of external or internal origin accelerates aging, increases risk of aging related health disorders, and shortens lifespan. Stressors activate stress response genes, and their products collectively influence traits. The variability of stressors and responses to them contribute to trait heterogeneity, which may cause the failure of clinical trials for drug candidates. The objectives of this paper are: to address the heterogeneity issue; to evaluate collective interaction effects of genetic factors on Alzheimer’s disease (AD) and longevity using HRS data; to identify differences and similarities in patterns of genetic interactions within two genders; and to compare AD related genetic interaction patterns in HRS and LOADFS data. To reach these objectives we: selected candidate genes from stress related pathways affecting AD/longevity; implemented logistic regression model with interaction term to evaluate effects of SNP-pairs on these traits for males and females; constructed the novel interaction polygenic risk scores for SNPs, which showed strong interaction potential, and evaluated effects of these scores on AD/longevity; and compared patterns of genetic interactions within the two genders and within two datasets. We found there were many genes involved in highly significant interactions that were the same and that were different within the two genders. The effects of interaction polygenic risk scores on AD were strong and highly statistically significant. These conclusions were confirmed in analyses of interaction effects on longevity trait using HRS data. Comparison of HRS to LOADFS data showed that many genes had strong interaction effects on AD in both data sets.

The aim of this study was to identify the differences in terms of demographics, socioeconomic status and overall levels of morbidity-related health burden between population strata characterized by high levels of adherence to American Diabetes Association screening guidelines and their low-adherence counterparts. Factor analysis was used to create a single continuous measure of adherence which was stratified and analyzed using the Cox proportional hazards model to identify adherence levels associated with protective effects for mortality. Based on the results, the entire population of Health and Retirement Study respondents newly diagnosed with diabetes mellitus, type II was then stratified into four levels of adherence – excellent, sufficient, insufficient, poor – based on the strength of the protective effect associated with that level of the adherence factor and compared. Mortality in the group associated with excellent adherence was 41 to 57 percentage points lower than among their counterparts. High levels of adherence were associated with White and Hispanic race, low morbidity burden, high education and economic status, and low levels of functioning limitations. Based on race-specific survival function estimates we found that the life expectancy at age 65 of an individual newly diagnosed with type II diabetes mellitus could be improved from 14.97 to 19.64 years for whites, 13.36 to 19.58 years for African Americans and 14.92 to 21.28 for Hispanics if average adherence levels are increased to the highest levels observed in our study. Finally, we found that adherence levels were improving over the 1991-2015 period suggesting successful diabetes awareness efforts.

The aim of this paper is to assess the extent of the potential bias introduced by the exclusion of the Medicare Advantage (MA) population– an increasingly sizeable (31% of all beneficiaries in 2017) subset of the Medicare population which does not provide claims data to the Centers for Medicare and Medicaid Services– from Medicare-based health outcomes and epidemiologic analyses. Using self-reported data from the Health and Retirement Study together with monthly information on Medicare enrollment, we compared MA enrollees with individuals enrolled in traditional Medicare (TM) on 42 variables representing demographic, socioeconomic, adverse health behavior and health status-related characteristics over the 1991-2015 period. We used both univariate analysis (t-tests and standardized differences) and multivariate logistic regression to compare the two groups. We found that apart from differences in economic (higher in TM group) and education status (lower in MA group) – which have been increasing in magnitude over the 1991-2015 period– the MA subset was highly comparable with the traditional Medicare (TM) population. Even though the TM population was characterized by slightly higher levels of morbidity, the resulting crude prevalence rates for common age-related diseases in the TM/MA groups were within each other’s 95% confidence intervals and did not represent a major source of bias. MA membership was not associated with increased mortality at any point over the 1991-2015 period. We conclude that exclusion of the MA population will not lead to notable bias in health outcome analyses apart from those for which income and education are important explanatory factors.

Purpose To assess the effect of availability of anti-vascular endothelial growth factor (VEGF) therapy on mortality and hospitalizations for acute myocardial infarction (AMI) and stroke over a 5-year follow-up period in United States Medicare beneficiaries newly diagnosed with exudative age-related macular degeneration (AMD) in 2006 compared with control groups consisting of beneficiaries (1) newly diagnosed with exudative AMD at a time when anti-VEGF therapy was not possible and (2) newly diagnosed with nonexudative AMD. Design Retrospective cohort study. Participants Beneficiaries newly diagnosed with exudative and nonexudative AMD in 2000 and 2006 selected from a random longitudinal sample of Medicare 5% claims and enrollment files. Methods Beneficiaries with a first diagnosis of exudative AMD in 2006 were the treatment group; beneficiaries newly diagnosed with exudative AMD in 2000 or nonexudative AMD in 2000 or 2006 were control groups. To deal with potential selection bias, we designed an intent-to-treat study, which controlled for nonadherence to prescribed regimens. The treatment group consisted of patients with clinically appropriate characteristics to receive anti-VEGF injections given that the therapy is available, bypassing the need to monitor whether treatment was actually received. Control groups consisted of patients with clinically appropriate characteristics but first diagnosed at a time when the therapy was unavailable (2000) and similar patients but for whom the therapy was not clinically indicated (2000, 2006). We used a Cox proportional hazard model. Main Outcome Measures All-cause mortality and hospitalization for AMI and stroke during follow-up. Results No statistically significant changes in probabilities of death and hospitalizations for AMI and stroke within a 5-year follow-up period were identified in exudative AMD beneficiaries newly diagnosed in 2006, the beginning of widespread anti-VEGF use, compared with 2000. As an alternative to our main analysis, which excluded beneficiaries from nonexudative AMD group who received anti-VEGF therapies during follow-up, we performed a sensitivity analysis with this group of individuals reincluded (11% of beneficiaries newly diagnosed with nonexudative AMD in 2006). Results were similar. Conclusions Introduction of anti-VEGF agents in 2006 for treating exudative AMD has not posed a threat of increased risk of AMI, stroke, or all-cause mortality.

Background Bladder cancer (BC) is highly prevalent and costly. This study documented cost and use of services for BC care and for other (non-BC) care received over a 15-year follow-up period by a cohort of Medicare beneficiaries diagnosed with BC in 1998. Methods Data came from the Surveillance, Epidemiology and End Results Program linked to Medicare claims. Medicare claims provided data on diagnoses, services provided, and Medicare Parts A and B payments. Cost was actual Medicare payments to providers inflated to 2018 US$. Cost and utilization were BC-related if the claim contained a BC diagnosis code. Otherwise, costs were for “other care.” For utilization, we grouped Part B-covered services into 6 mutually-exclusive categories. Utilization rates were ratios of the count of claims in a particular category during a follow-up year divided by the number of beneficiaries with BC surviving to year-end. Results Cumulatively over 15-years, for all stages combined, total BC-related cost per BC beneficiary was $42,011 (95% Confidence Interval (CI): $42,405–$43,417); other care cost was about twice this number. Cumulative total BC-related cost of 15-year BC survivors for all stages was $43,770 (CI: $39,068–$48,522), intensity of BC-related care was highest during the first year following BC diagnosis, falling substantially thereafter. After follow-up year 5, there were few statistically significant changes in BC-related utilization. Utilization of other care remained constant during follow-up or increased. Conclusions Substantial costs were incurred for non-BC care. While increasing BC survivorship is an important objective, non-BC care would remain a burden to Medicare.

In this paper we evaluated the effect of a series of diseases previously reported to be associated with increased risk of Alzheimer’s disease and related dementia (AD/ADRD) when this information is supplemented by self-reported data on demographics, behavior and socio-economic status. Medicare Claims data from SEER-Medicare and the Health and Retirement Study (HRS) were analyzed using a newly developed approach for evaluating the effect of diseases from eleven groups: cardiovascular, cerebrovascular, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus, thyroid dysfunction, metabolic syndrome, obstructive sleep apnea, depression, and traumatic brain injury and/or head trauma. The HRS provided data on the second component of our study including demographics, self-reported health status, disability, smoking, alcohol consumption, BMI, and depression as defined by the CESD scale. We identified the effects of Medicare-based disease indicators on AD/ADRD risk in uni- and multivariate analyses with and without use of lag effects and, observed changes in these estimates in response to time and the addition of self-reported data. With the exception of solid cancers the hazard ratios (HRs) for all included disease groups were positive (e.g., HR=2.47 for depression and 2.12 for hemorrhagic stroke). No modifying lag-effects were observed. The addition of self-reported data showed that they do not significantly modify the effects of the disease indicators even when they are statistically significant. The analyses show the extent to which links between the distinct differences in comorbidities, behavioral and socioeconomic factors can predict the risk for AD/ADRD.

Background Bladder cancer care is costly, including cost to Medicare, but the medical cost associated with bladder cancer patients relative to identical persons without bladder cancer is unknown. Objective To determine incremental bladder cancer cost to Medicare and the impact of diagnosis stage and bladder cancer survival on cost. Design, setting, and participants A case–control study was conducted using 1998–2013 Surveillance, Epidemiology and End Results–Medicare data. Controls were propensity score matched for diagnosis year, age, gender, race, and 31 Elixhauser Comorbidity Index values. Three incident cohorts, 1998 (n = 3136), 2003 (n = 7000), and 2008 (n = 7002), were compared. Outcome measurements and statistical analysis Survival following diagnosis and Medicare payments (in 2018 dollars) were tabulated, and compared between cases and controls. Results and limitations From 1998 to 2008, bladder cancer patients became older and had more comorbidities at diagnosis, although no stage migration or change in survival occurred. Incremental costs (above those associated with controls) were highest during the 1st year after diagnosis and were higher for distant ($47 533) than for regional ($42 403) or localized ($14 304) cancer. Bladder cancer survival was highly stage dependent. After an initial spike in costs lasting 1–2 yrs, monthly costs dropped in survivors but remained higher than for controls. Long-term survivors in the full sample accrued cumulative Medicare costs of $172 426 over 16 yrs—46% higher than for controls. Limitations include omission of indirect costs and reliance on traditional Medicare. Conclusions While a bladder cancer diagnosis incurs initial high Medicare cost, particularly in patients with advanced cancers, the cumulative costs of bladder cancer in long-term survivors are higher still. Bladder cancer prevention saves Medicare money. However, while early detection, better therapies, and life extension of bladder cancer patients are worthwhile goals, they come at the cost of higher Medicare outlays. Patient summary The lifetime cost of bladder cancer, reflecting surveillance, treatment, and management of complications, is substantial. Since care is ongoing, cost increases with the length of life after diagnosis as well as the severity of initial diagnosis.

BACKGROUND Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records. OBJECTIVE We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon. METHODS Using Medicare data linked to the Health and Retirement Study (1992-2012), we performed a joint analysis of trends in CI and ND to test our hypothesis. RESULTS We identified two major contributors to the divergent directions in CI and ND trends: reductions in disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals. DISCUSSION Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic.

A new model for disease prevalence based on the analytical solutions of McKendrick-von Foerster’s partial differential equations is developed. Derivation of the model and methods to cross check obtained results are explicitly demonstrated. Obtained equations describe the time evolution of the healthy and unhealthy age-structured sub-populations and age patterns of disease prevalence. The projection of disease prevalence into the future requires estimates of time trends of age-specific disease incidence, relative survival functions, and prevalence at the initial age and year available in the data. The computational scheme for parameter estimations using Medicare data, analytical properties of the model, application for diabetes prevalence, and relationship with partitioning models are described and discussed. The model allows natural generalization for the case of several diseases as well as for modeling time trends in cause-specific mortality rates.

Aims Analyze relationships between adherence to guidelines for diabetes care – regular screening; physical activity; and medication – and diabetes complications and mortality. Methods Outcomes were onset of congestive heart failure (CHF), stroke, renal failure, moderate complications of lower extremities, lower-limb amputation, proliferative diabetic retinopathy (PDR), and mortality during follow-up. Participants were persons aged 65 + in the Health and Retirement Study (HRS) 2003 Diabetes Study and had Medicare claims in follow-up period (2004–8). Results Adherence to screening recommendations decreased risks of developing CHF (odds ratio (OR) = 0.83; 95% confidence interval (CI): 0.72–0.96), stroke (OR = 0.80; 95% CI: 0.68–0.94); renal failure (OR = 0. 82; 95% CI: 0.71–0.95); and death (OR = 0.86; 95% CI: 0.74–0.99). Adherence to physical activity recommendation reduced risks of stroke (OR = 0.64; 95% CI: 0.45–0.90), renal failure (OR = 0.71; 95% CI: 0.52–0.97), moderate lower-extremity complications (OR = 0.71; 95% CI: 0.51–0.99), having a lower limb amputation (OR = 0.31, 95% CI: 0.11–0.85), and death (OR = 0.56, 95% CI: 0.41–0.77). Medication adherence was associated with lower risks of PDR (OR = 0.35, 95% CI: 0.13–0.93). Conclusions Adherence to screening, physical activity and medication guidelines was associated with lower risks of diabetes complications and death. Relative importance of adherence differed among outcome measures.

BACKGROUND To determine if Type 2 diabetes mellitus (DM) is protective against giant cell arteritis (GCA) and to estimate the incidence of GCA diagnosis from Medicare claims. METHODS Medicare 5% claims files from 1991 to 2011 were used to identify beneficiaries diagnosed with DM, but not GCA, within a 3-year ascertainment period. Propensity score matching was used to define a control group of nondiabetics with comparable demographic covariates. Competing risk regression was then used to assess the impact of DM diagnosis on GCA diagnosis. To allow for a 3-year ascertainment period, the analysis sample was limited to beneficiaries older than 68 years at baseline. RESULTS A total of 151,041 beneficiaries diagnosed with DM were matched to an equal number of controls. Mean study follow-up was 67.75 months. GCA was diagnosed among 1116 beneficiaries with DM (0.73%) vs 465 (0.30%) controls. The risk of receiving a GCA diagnosis among patients with DM was increased by 100% (subhazard ratio, 2.00; 95% confidence interval, 1.78-2.25). The annual incidence of GCA diagnosis among claims for US Medicare beneficiaries older than 68 years old was 93 in 100,000. CONCLUSIONS A DM diagnosis is not protective against a GCA diagnosis in the Medicare population. Our data suggest that a DM diagnosis increases the risk of GCA diagnosis within 5.7 years for Medicare beneficiaries older than 68 years.

Objective To quantify the causes of the changes in the rates of mortality and select severe complications of diabetes mellitus, type 2 (T2D) among the elderly between 1992 and 2012. Research design A retrospective cohort study design based on Medicare 5% administrative claims data from 1992 to 2012 was used. Traditional fee-for-service Medicare beneficiaries, age 65 and older, diagnosed with T2D and living in the United States between 1992 and 2012 were included in the study. Blinder-Oaxaca decomposition was used to quantify the potential causes of the change in the rates of death, congestive heart failure and/or acute myocardial infarction, stroke, amputation of lower extremity and end-stage renal disease between 1992 and 2012. Results The number of beneficiaries in the analysis sample diagnosed with T2D increased from 152,191 in 1992 to 289,443 in 2012. Over the same time period, rates of mortality decreased by 1.2, congestive heart failure and/or acute myocardial infarction by 2.6, stroke by 1.6, amputation by 0.6 while rates of end-stage renal disease increased by 1.5 percentage points. Improvements in the management of precursor conditions and utilization of recommended healthcare services, not population composition, were the primary causes of the change. Conclusions With the exception of end-stage renal disease, outcomes among Medicare beneficiaries diagnosed with T2D improved. Analysis suggests that persons diagnosed with T2D are living longer with fewer severe complications. Much of the improvement in outcomes likely reflects more regular contact with health professionals and better management of care.

Direct evaluation of lung cancer mortality from SEER data is challenging because of uncertainties in evaluating the population at risk at the time of death We overcome this problem by proposing a new approach for the calculation of cancer-specific mortality rates through the evaluation of multiple components contributing to total mortality and applying it to lung cancer patients. Specifically, the time-trend of lung cancer mortality is the result of three competing processes: changes in incidence rate, stage-specific survival, and ascertainment at early stages. Our approach estimates the contribution of each of the above components to the overall mortality trend. Using SEER data, we found that lung cancer mortality increases in females and decreases in males over the study period (1988–2012). The main contributions to the change in mortality trends for both genders are incidence rates (increasing in females and decreasing in males). Trends in incidence explain more than 50% of total lung cancer mortality trend. The remaining percentages are explained by increased ascertainment at early stages, improved survival, and prevailing trends in mortality for the general population. These patterns held for analysis of histotype-specific groups (adenocarcinoma, squamous-cell carcinoma, and small-cell carcinoma) with the exception of the increased role of incidence in adenocarcinoma in males and ascertainment at early stages for squamous-cell and small-cell carcinoma. The methodology developed in this study increases the range of analysis that can be accomplished with SEER data and can serve as an additional tool for improvement in the quality of health outcomes research.

Diabetes Mellitus (DM) is a chronic disease that is highly prevalent in the U.S. and is associated with multiple co-morbidities as well as reduced physical and cognitive function. When admitted to nursing homes, beneficiaries with DM are characterized by comparatively high levels of functional disability, the presence of many co-morbid conditions, and could represent a sub-population of residents requiring especially intensive care and representing a dis-proportional social and financial burden. Adherence to diabetes management guidelines such as those provided by the American Diabetes Association (ADA) have been shown to be protective against many diabetes-related adverse health outcomes, but the role of adherence in reducing the risk of requiring nursing home care and/or improving the overall health status at time of admission has not been fully addressed. The purpose of this paper is to identify how adherence to ADA guidelines in U.S. Medicare beneficiaries age 65+ affects the risk of nursing home entry and functional, cognitive and co-morbidity status at the time of admission. Data from the Health and Retirement Study, linked to Medicare administrative claims was used to identify the presence of a new diagnosis of DM, the presence of co-morbidities and adherence to guidelines. Data on new nursing home admissions as well as detailed, professional in-person new resident assessments were drawn from the HRS-linked Minimum Dataset. The results of this study will aid in public health awareness efforts aimed at combating the diabetes pandemic and reducing the burden of DM to both the patient and society.

Objective: The objective of this study is to investigate relationships between adherence to recommended screening and medication use and severe macrovascular complications and all-cause mortality among persons aged above 68 years with diabetes mellitus (DM). Method: Data came from a 5% Medicare claims sample of beneficiaries initially diagnosed with DM during 2006-2008; follow-up was up to 7 years. Results: Adherence to screening guidelines led to reduced mortality—hazard ratio (HR) = 0.57, 95% confidence interval [CI] = [0.56, 0.58]; congestive heart failure [CHF], HR = 0.89, CI = [0.87, 0.91]; acute myocardial infarction [AMI], HR = 0.90, CI = [0.85, 0.95]; and stroke/transient ischemic attack [Stroke/TIA], HR = 0.92, CI = [0.87, 0.97]—during follow-up. Recommended medication use led to lower mortality: HR = 0.72, CI = [0.70, 0.73]; CHF, HR = 0.67, CI = [0.66, 0.69]; AMI, HR = 0.68, CI = [0.65, 0.71]; and Stroke/TIA, HR = 0.79, CI = [0.76, 0.83]. Discussion: Elderly persons newly diagnosed with diabetes who adhered to recommended care experienced reduced risk of mortality and severe macrovascular complications.

BACKGROUND This study identifies the effect of intensive drug therapy (IDT) in individuals age 65+ with diabetes (type 2 diabetes mellitus (T2D)) and hypertension on all-cause death, congestive heart failure (CHF), hospitalization for myocardial infarction (MI), and stroke or transient ischemic attack (TIA). METHODS Individuals from the Medicare 5% dataset with hypertension and T2D undergoing IDT for these conditions were propensity score matched to a nonintensive drug-therapy group. Hazard ratios (HRs) were obtained using the Cox proportional hazard model. RESULTS IDT was associated with increased risk of CHF (HR 2.32; 95% confidence interval (CI) 2.32–2.38), MI (HR 4.27; 95% CI 4.05–4.52), and stroke or TIA (HR 1.80; 95% CI 1.70–1.89) but decreased risk of death (HR 0.95; 95% CI 0.93–0.97). Risk for CHF (HR 0.73; 95% CI 0.71–0.73), MI (HR 0.64; 95% CI 0.62–0.67), stroke or TIA (HR 0.82; 95% CI 0.78–0.86), and death (HR 0.29; 95% CI 0.28–0.29) was decreased by adherence to diabetes management guidelines. CONCLUSIONS Use of IDT in a high-risk population delays death but not severe macrovascular outcomes. Protective effects of IDT in high-risk patients likely outweigh polypharmacy-related health concerns.

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.

We demonstrate how application of analytic approaches developed in demography, biodemography, epidemiology, and population studies to Medicare and Medicare-linked data allows to identify causes and mechanisms of disparities in AD/ADRD. Our studies i) confirmed geographic disparities in AD mortality (e.g., existence of hot spots, West-East gradient) but did not detect them in Medicare data, ii) confirmed racial disparities in AD/ADRD incidence and survival (e.g., higher incidence and better survival in Black population) and demonstrated that they can be partly explained by heterogeneity in diagnosis severity and partly by genetic factors, iii) detected unexpectedly strong effects of systemic hypotension, chronic kidney and liver diseases on the risk of AD/ADRD. We concluded that further progress in understanding of mechanisms and causes of the disparities in AD/ADRD is possible by clarifying the role of cause-of-death coding, the effects of comorbidity and their treatment, dynamics in cognition scores before AD/ADRD diagnosis, and genetic factors.