Associations of infections and vaccines with Alzheimer's disease point to a role of compromised immunity rather than specific pathogen in AD.

INTRODUCTION: Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role in AD by increasing an individual's vulnerability to various infections, which could contribute to neurodegeneration. If true, then vaccines that have heterologous effects on immunity, extending beyond protection against the targeted disease, may hold a potential for AD prevention. METHODS: We evaluated the associations of common adult infections (herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses), and vaccinations against shingles and pneumonia, with the risks of AD and other dementias in a pseudorandomized sample of the Health and Retirement Study (HRS). RESULTS: Shingles, pneumonia and mycoses, diagnosed between ages 65 and 75, were all associated with significantly increased risk of AD later in life, by 16 %-42 %. Pneumococcal and shingles vaccines administered between ages 65-75 were both associated with a significantly lower risk of AD, by 15 %-21 %. These effects became less pronounced when AD was combined with other dementias. DISCUSSION: Our findings suggest that both the pneumococcal polysaccharide vaccine and the live attenuated zoster vaccine can offer significant protection against AD. It remains to be determined if non-live shingles vaccine has a similar beneficial effect on AD. This study also found significant associations of various infections with the risk of AD, but not with the risks of other dementias. This indicates that vulnerability to infections may play a more significant role in AD than in other types of dementia, which warrants further investigation.

Associations of infections and vaccines with Alzheimer's disease point to a major role of compromised immunity rather than specific pathogen in AD.

INTRODUCTION: Diverse pathogens (viral, bacterial, fungal) have been linked to Alzheimer's disease (AD) indicating a possibility that the culprit may be compromised immunity rather than particular microbe. If true, then vaccines with broad beneficial effects on immunity might be protective against AD. METHODS: We estimated associations of common adult infections, including herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses, as well as vaccinations against shingles and pneumonia, with the risk of AD in a pseudorandomized sample of the Health and Retirement Study. RESULTS: Shingles, pneumonia, and mycoses diagnosed between ages 65-75, were all associated with higher risk of AD later in life, by 16%-42%. Pneumococcal and shingles vaccines received between ages 65-75 both lowered the risk of AD, by 15%-21%. DISCUSSION: Our results support the idea that the connection between AD and infections involves compromised immunity rather than specific pathogen. We discuss mechanisms by which the declining immune surveillance may promote AD, and the role of biological aging in it. Repurposing of vaccines with broad beneficial effects on immunity could be a reasonable approach to AD prevention. Pneumococcal and zoster vaccines are promising candidates for such repurposing.

Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease.

Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer's disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.

Differences in Risk of Alzheimer's Disease Following Later-Life Traumatic Brain Injury in Veteran and Civilian Populations.

OBJECTIVE: To directly compare the effect of incident age 68+ traumatic brain injury (TBI) on the risk of diagnosis of clinical Alzheimer's disease (AD) in the general population of older adults, and between male veterans and nonveterans; to assess how this effect changes with time since TBI. SETTING AND PARTICIPANTS: Community-dwelling traditional Medicare beneficiaries 68 years or older from the Health and Retirement Study (HRS). DESIGN: Fine-Gray models combined with inverse-probability weighting were used to identify associations between incident TBI, post-TBI duration, and TBI treatment intensity, with a diagnosis of clinical AD dementia. The study included 16 829 older adults followed over the 1991-2015 period. For analyses of veteran-specific risks, 4281 veteran males and 3093 nonveteran males were identified. Analysis of veteran females was unfeasible due to the age structure of the population. Information on occurrence(s) of TBI, and onset of AD and risk-related comorbidities was constructed from individual-level HRS-linked Medicare claim records while demographic and socioeconomic risk factors were based on the survey data. RESULTS: Later-life TBI was strongly associated with increased clinical AD risk in the full sample (pseudo-hazard ratio [HR]: 3.22; 95% confidence interval [CI]: 2.57-4.05) and in veteran/nonveteran males (HR: 5.31; CI: 3.42-7.94), especially those requiring high-intensity/duration care (HR: 1.58; CI: 1.29-1.91). Effect magnitude decreased with time following TBI (HR: 0.72: CI: 0.68-0.80). CONCLUSION: Later-life TBI was strongly associated with increased AD risk, especially in those requiring high-intensity/duration care. Effect magnitude decreased with time following TBI. Univariate analysis showed no differences in AD risk between veterans and nonveterans, while the protective effect associated with veteran status in Fine-Gray models was largely due to differences in demographics, socioeconomics, and morbidity. Future longitudinal studies incorporating diagnostic procedures and documentation quantifying lifetime TBI events are necessary to uncover pathophysiological mediating and/or moderating mechanisms between TBI and AD.

Understanding Alzheimer's disease in the context of aging: Findings from applications of stochastic process models to the Health and Retirement Study.

There is growing literature on applications of biodemographic models, including stochastic process models (SPM), to studying regularities of age dynamics of biological variables in relation to aging and disease development. Alzheimer's disease (AD) is especially good candidate for SPM applications because age is a major risk factor for this heterogeneous complex trait. However, such applications are largely lacking. This paper starts filling this gap and applies SPM to data on onset of AD and longitudinal trajectories of body mass index (BMI) constructed from the Health and Retirement Study surveys and Medicare-linked data. We found that APOE e4 carriers are less robust to deviations of trajectories of BMI from the optimal levels compared to non-carriers. We also observed age-related decline in adaptive response (resilience) related to deviations of BMI from optimal levels as well as APOE- and age-dependence in other components related to variability of BMI around the mean allostatic values and accumulation of allostatic load. SPM applications thus allow revealing novel connections between age, genetic factors and longitudinal trajectories of risk factors in the context of AD and aging creating new opportunities for understanding AD development, forecasting trends in AD incidence and prevalence in populations, and studying disparities in those.

Does the Chronic Stress of Everyday Discrimination or Race Itself Better Predict AD Onset Risk?

Using evidence from the Health and Retirement Study, we explore racial disparities in Alzheimer's Disease (AD) onset risk. From a stress process perspective, there is substantial evidence in the literature that everyday discrimination is a chronic strain for Black individuals that acts as a social determinant of illness. However, few studies have examined specific relationships between this social stressor, race, and AD onset risk. Using Cox Proportional Hazard Models, we examined racial differences in exposure and vulnerability to everyday discrimination. Findings suggest that everyday discrimination predicts AD onset risk, and Black individuals experience more frequent exposure to everyday discrimination as a chronic strain. However, contrary to the stress process model, Black respondents were not more vulnerable to the effect of everyday discrimination on AD onset risk. Racial bias from medical professionals during the diagnostic process and mortality selection bias may explain this effect. Overall, the results of this study provide further evidence that discrimination is a key factor in predicting AD while also considering that many racial minorities with high rates of this type of social stress may not receive an unbiased diagnosis and/or survive to late life to develop AD.

Epidemiology of geographic disparities in heart failure among US older adults: a Medicare-based analysis.

BACKGROUND: There are prominent geographic disparities in the life expectancy (LE) of older US adults between the states with the highest (leading states) and lowest (lagging states) LE and their causes remain poorly understood. Heart failure (HF) has been proposed as a major contributor to these disparities. This study aims to investigate geographic disparities in HF outcomes between the leading and lagging states. METHODS: The study was a secondary data analysis of HF outcomes in older US adults aged 65+, using Center for Disease Control and Prevention sponsored Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database and a nationally representative 5% sample of Medicare beneficiaries over 2000-2017. Empiric estimates of death certificate-based mortality from HF as underlying cause of death (CBM-UCD)/multiple cause of death (CBM-MCD); HF incidence-based mortality (IBM); HF incidence, prevalence, and survival were compared between the leading and lagging states. Cox regression was used to investigate the effect of residence in the lagging states on HF incidence and survival. RESULTS: Between 2000 and 2017, HF mortality rates (per 100,000) were higher in the lagging states (CBM-UCD: 188.5-248.6; CBM-MCD: 749.4-965.9; IBM: 2656.0-2978.4) than that in the leading states (CBM-UCD: 79.4-95.6; CBM-MCD: 441.4-574.1; IBM: 1839.5-2138.1). Compared to their leading counterparts, lagging states had higher HF incidence (2.9-3.9% vs. 2.2-2.9%), prevalence (15.6-17.2% vs. 11.3-13.0%), and pre-existing prevalence at age 65 (5.3-7.3% vs. 2.8-4.1%). The most recent rates of one- (77.1% vs. 80.4%), three- (59.0% vs. 60.7%) and five-year (45.8% vs. 49.8%) survival were lower in the lagging states. A greater risk of HF incidence (Adjusted Hazards Ratio, AHR [95%CI]: 1.29 [1.29-1.30]) and death after HF diagnosis (AHR: 1.12 [1.11-1.13]) was observed for populations in the lagging states. The study also observed recent increases in CBMs and HF incidence, and declines in HF prevalence, prevalence at age 65 and survival with a decade-long plateau stage in IBM in both leading and lagging states. CONCLUSION: There are substantial geographic disparities in HF mortality, incidence, prevalence, and survival across the U.S.: HF incidence, prevalence at age 65 (age of Medicare enrollment), and survival of patients with HF contributed most to these disparities. The geographic disparities and the recent increase in incidence and decline in survival underscore the importance of HF prevention strategies.

Vulnerability to Hypertension Is a Major Determinant of Racial Disparities in Alzheimer's Disease Risk.

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.

Extended anesthesia exposure for abdominal and pelvic procedures in older adults with colorectal cancer: Associations with chart dementia diagnoses.

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.

Genome-wide analysis of genetic predisposition to common polygenic cancers.

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.

Roles of interacting stress-related genes in lifespan regulation: insights for translating experimental findings to humans.

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.

Epidemiology of Geographic Disparities of Myocardial Infarction Among Older Adults in the United States: Analysis of 2000-2017 Medicare Data.

Background: There are substantial geographic disparities in the life expectancy (LE) across the U.S. with myocardial infarction (MI) contributing significantly to the differences between the states with highest (leading) and lowest (lagging) LE. This study aimed to systematically investigate the epidemiology of geographic disparities in MI among older adults. Methods: Data on MI outcomes among adults aged 65+ were derived from the Center for Disease Control and Prevention-sponsored Wide-Ranging Online Data for Epidemiologic Research database and a 5% sample of Medicare Beneficiaries for 2000-2017. Death certificate-based mortality from MI as underlying/multiple cause of death (CBM-UCD/CBM-MCD), incidence-based mortality (IBM), incidence, prevalence, prevalence at age 65, and 1-, 3-, and 5-year survival, and remaining LE at age 65 were estimated and compared between the leading and lagging states. Cox model was used to investigate the effect of residence in the lagging states on MI incidence and survival. Results: Between 2000 and 2017, MI mortality was higher in the lagging than in the leading states (per 100,000, CBM-UCD: 236.7-583.7 vs. 128.2-357.6, CBM-MCD: 322.7-707.7 vs. 182.4-437.7, IBM: 1330.5-1518.9 vs. 1003.3-1197.0). Compared to the leading states, lagging states had higher MI incidence (1.1-2.0% vs. 0.9-1.8%), prevalence (10.2-13.1% vs. 8.3-11.9%), pre-existing prevalence (2.5-5.1% vs. 1.4-3.6%), and lower survival (70.4 vs. 77.2% for 1-year, 63.2 vs. 67.2% for 3-year, and 52.1 vs. 58.7% for 5-year), and lower remaining LE at age 65 among MI patients (years, 8.8-10.9 vs. 9.9-12.8). Cox model results showed that the lagging states had greater risk of MI incidence [Adjusted hazards ratio, AHR (95% Confidence Interval, CI): 1.18 (1.16, 1.19)] and death after MI diagnosis [1.22 (1.21, 1.24)]. Study results also showed alarming declines in survival and remaining LE at age 65 among MI patients. Conclusion: There are substantial geographic disparities in MI outcomes, with lagging states having higher MI mortality, incidence, and prevalence, lower survival and remaining LE at age 65. Disparities in MI mortality in a great extent could be due to between-the-state differences in MI incidence, prevalence at age 65 and survival. Observed declines in survival and remaining LE require an urgent analysis of contributing factors that must be addressed.

Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation.

A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging - changes in the body and extend limits of human lifespan. However, majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene-environment and gene-gene interactions, among other factors. In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant (FDR < 0.05) effects of interactions between SNPs in IGF1R, TGFBR2, and BCL2 on survival 85+. We validated these findings in the Cardiovascular Health Study sample, with P < 0.05, using survival to age 85+, and to the 90th percentile, as outcomes. Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research.

Analysis of Time Trends in Alzheimer's Disease and Related Dementias Using Partitioning Approach.

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.

Geographic disparities in mortality from Alzheimer's disease and related dementias.

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.

Chemotherapy and the Risk of Alzheimer's Disease in Colorectal Cancer Survivors: Evidence From the Medicare System.

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.

Outcomes and Costs for Women After Breast Cancer: Preparing for Improved Survivorship of Medicare Beneficiaries.

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.

A medicare-based comparative mortality analysis of active surveillance in older women with DCIS.

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.

Partitioning of time trends in prevalence and mortality of bladder cancer in the United States.

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.

The Cost to Medicare of Bladder Cancer Care.

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 ($47533) than for regional ($42403) or localized ($14304) cancer. Bladder cancer survival was highly stage dependent. After an initial spike in costs lasting 1-2yrs, monthly costs dropped in survivors but remained higher than for controls. Long-term survivors in the full sample accrued cumulative Medicare costs of $172426 over 16yrs-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.