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AAIC 2013 press room, July 13-18: 617.954.3414

Cancer and Chemotherapy Linked with Decreased Risk of
Alzheimer's Disease in Veterans

Three other studies reported at AAIC 2013 illuminate Alzheimer's risk factors, point to potential new strategies for treatment, prevention

BOSTON, July 15, 2013 – Most kinds of cancer are associated with a significantly decreased risk of Alzheimer's disease, according to a study of 3.5 million veterans reported today at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) in Boston. In addition, the study suggested that chemotherapy treatment for almost all of those cancers conferred an additional decrease in Alzheimer's risk.

Three other researchers presented results of epidemiologic studies that uncovered risk factors and/or possible therapies for Alzheimer's disease. The results indicated that:

"With these large-cohort studies and others, we are beginning to see the outlines of a broad picture of Alzheimer's disease risk and prevention factors," said Maria Carrillo, Ph.D., vice president of medical and scientific relations at the Alzheimer's Association.

"However, we need to know even more about what specific factors actually raise and lower risk for cognitive decline and Alzheimer's. To do that, we need longer-term studies in larger and more diverse populations, and more research funding is required to make that happen. Alzheimer's research would benefit from its own version of the Framingham Study, which has taught us so very much about preventable risk factors for heart disease and stroke," Carrillo said.

"With funding of research being a critical need for progress, the National Plan to Address Alzheimer's Disease must be fully implemented and the $100 million identified for Alzheimer's and dementia research this fiscal year needs to be funded," Carrillo concluded.

Cancer history and chemotherapy are associated with decreased risk of Alzheimer's

A growing body of evidence suggests a possible association of cancer with reduced risk for Alzheimer's disease; until now, whether the association differs between cancer types or is modified by cancer treatment is unknown.

Laura Frain, M.D., a geriatrician at VA Boston Healthcare System, and colleagues analyzed the health records of 3,499,378 veterans age 65 and older who were seen in the VA health care system between 1996 and 2011 and who were free of dementia at baseline. The objective was to evaluate the relationship between a history of 19 different cancers, cancer treatment and subsequent Alzheimer's disease.

Over a median follow-up of 5.65 years, 82,028 veterans were diagnosed with Alzheimer's. Twenty-four (24) percent of those veterans with Alzheimer's had a history of cancer, while 76 percent did not.

The researchers found that most types of cancer were associated with reduced Alzheimer's risk, ranging from 9 percent to 51 percent. Reduced risk was greatest among survivors of liver cancer (51 percent lower risk), cancer of the pancreas (44 percent), cancer of the esophagus (33 percent), myeloma (26 percent), lung cancer (25 percent) and leukemia (23 percent). Cancers that did not confer a reduced Alzheimer's risk, or were associated with an increased risk, included melanoma, prostate and colorectal cancers.

The researchers found no association between cancer history and reduced risk of any other typical age-related health outcome; in fact, cancer was associated with an increased risk of stroke, osteoarthritis, cataracts and macular degeneration. Most cancer survivors were also at increased risk for non-Alzheimer's dementia.

"Together, these findings indicate that the protective relationship between most cancers and Alzheimer's disease is not simply explained by increased mortality among cancer patients," said Frain. "More research is needed to determine if these results have therapeutic implications for Alzheimer's."

Among veterans with a cancer history, treatment with chemotherapy but not radiation reduced Alzheimer's risk by 20 to 45 percent, depending on cancer type, with the exception of prostate cancer.

"The potential protective effect of chemotherapy is supported by recent experimental studies," Frain observed. "The results of this study are interesting because they could help focus future research onto the specific pathways and treatment agents involved in the individual cancers that are associated with a reduced risk of Alzheimer's. This could potentially open new therapeutic strategies for Alzheimer's prevention and treatment."

Metformin is linked with lower dementia risk than other type 2 diabetes therapies

Type 2 diabetes doubles the risk of dementia. However, until recently, little research has been done to examine the association between type 2 diabetes treatments and dementia risk. Rachel Whitmer, Ph.D., and colleagues at Kaiser Permanente Division of Research studied a cohort of 14,891 type 2 diabetes patients age 55 and older who began diabetes therapy between October 1999 and November 2001. Only patients who started a single therapy (metformin, sulfonylureas, thiazolidinediones (TZDs) or insulin) were included. The patients were followed for up to five years.

Patients initiating metformin, an insulin sensitizer, had a significantly reduced risk of developing dementia compared with patients on other diabetes therapies. Compared with those taking sulfonylureas, those initiating metformin had a 20 percent reduced risk of dementia, while those initiating TZD or insulin had no difference in risk.

"These results provide preliminary evidence that the benefits of insulin sensitizers may extend beyond glycemic control to neurocognitive health," said Whitmer. "Research in animals suggests that metformin may contribute to the creation of new brain cells and enhance spatial memory."

Trials are currently under way to evaluate metformin as a potential therapy for dementia and mild cognitive impairment, which is thought to be, in some cases, a precursor to Alzheimer's disease.

Older age at retirement is associated with reduced risk of dementia

Some research has suggested that intellectual stimulation and mental engagement throughout life may be protective against Alzheimer's disease and other dementias. In an analysis of health and insurance records of more than 429,000 self-employed workers in France, reported at AAIC 2013, Carole Dufouil, Ph.D., director of research in neuroepidemiology at INSERM (Institut National de la santé et de la recherché médicale) at the Bordeaux School of Public Health, and colleagues found that retirement at older age is associated with a reduced risk of dementia.

The researchers linked health and pension databases of self-employed workers who were living and retired as of December 31, 2010. Workers had been retired on average for more than 12 years. Prevalence of dementia in this group was 2.65 percent.

Analyses showed that the risk of being diagnosed with dementia was lower for each year of working longer (i.e., higher age at retirement) (hazard ratio of dementia was 0.968 (95 percent Confidence Interval = [0.962-0.973]). Even after excluding workers who had dementia diagnosed within the 5 years following retirement, the results remained unchanged and highly significant (p< 0.0001).

"Our data show strong evidence of a significant decrease in the risk of developing dementia associated with older age at retirement, in line with the ‘use it or lose it' hypothesis," said Dufouil. "The patterns were even stronger when we focused on more recent birth cohorts."

"Professional activity may be an important determinant of intellectual stimulation and mental engagement, which are thought to be potentially protective against dementia," observed Dufouil. "As countries around the world respond to the aging of their populations, our results highlight the importance of maintaining high levels of cognitive and social stimulation throughout work and retired life, and they emphasize the need for policies to help older individuals achieve cognitive and social engagement.

The study was also coordinated by the International Longevity Center-France (Head: Prof. Françoise Forette).

Socioeconomic disparities may explain higher Alzheimer's risk among African Americans

Alzheimer's disease and other dementias have been shown to be higher among older blacks in the United States than older whites; however, risk factors that might account for this difference have not been extensively studied.

Note: According to the Alzheimer's Association 2013 Alzheimer's Disease Facts and Figures report, older African-Americans are about twice as likely to have Alzheimer's and other dementias as older whites, and Hispanics are about one and one-half times as likely to have Alzheimer's and other dementias as older whites.

Kristine Yaffe, M.D., of the University of California, San Francisco and the San Francisco VA Medical Center, and colleagues sought to determine if differences in dementia rates by race existed among a cohort of community dwelling elders and whether any differences observed could be explained by socioeconomic status (SES) indicators (income, financial adequacy, education and literacy) and health-related factors.

The scientists evaluated dementia risk among 3,075 black and white elders (mean age 74.1 years) participating in the ongoing prospective Health, Aging and Body Composition Study who were free of dementia at baseline.

During 12 years of follow-up, 18.7 percent of participants were determined to have developed dementia, based on prescribed medications, hospital records and cognitive decline. In this population, African-Americans were 1.5 times more likely to develop dementia than whites (21.9 percent vs. 16.4 percent). However, after adjusting for socioeconomic factors including education level, literacy, income and financial adequacy, the researchers found that the difference in risk was no longer statistically significant.

"Our findings suggest that differences in socioeconomic factors may, in large part, explain racial and ethnic disparities in dementia rates," said Yaffe. "Future studies that investigate these disparities should take a broad range of socioeconomic factors into account."

Yaffe suggested that more studies are needed "to explore the potential benefits of improving socioeconomic risk factors as a way of reducing dementia rates."

(Disclosure: Dr. Yaffe is co-chair of the AAIC 2013 Program Committee.)

About AAIC

The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association

The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.

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Proposal ID: 38545
Topic: Public Health and Psychosocial
Subtopic: Epidemiology of risk factors of Alzheimer's disease
Presentation: Poster session, Tuesday, July 16, 2013, 11:45 a.m. ET

A Reduced Risk of Alzheimer's Disease is Associated with the Majority of Cancers in a National Cohort of Veterans

Presenting author: Laura Frain, Laura Frain*1, David Swanson2, Rebecca Betensky2, Kelly Cho3, David Gagnon4, Neil Kowall3, Kun Ping Lu5, J. Michael Gaziano4, Jane Driver3 1GRECC, VA Boston Healthcare System, Boston, Massachusetts, United States; 2Harvard School of Public Health, Boston, Massachusetts, United States; 3VA Boston Healthcare System, Boston, Massachusetts, United States; 4VA Boston Healthcare System, Jamaica Plain, Massachusetts, United States; 5Beth Israel Deaconness Medical Center, Boston, Massachusetts, United States.

Background: Increasing evidence suggests an inverse relationship between cancer and Alzheimer's disease (AD); whether the association differs between cancer types or is modulated by cancer treatment is unknown. The objective of this study was to evaluate the relation between a history of 14 different cancers, cancer treatment and subsequent AD in the national Veterans Administration Healthcare System (VAHCS) database.

Methods: We assembled a retrospective cohort of 3,499,378 veterans seen in the VAHCS between 1996-2011 who were = age 65 and free of dementia at baseline. We used ICD-9 codes to define dementia and cancer. We used Cox regression to estimate hazard ratios and 95 percent confidence intervals (HR, 95 percent CI) for the risk of AD in veterans with and without specific cancer types. All models were adjusted for cancer treatment and multiple comorbidities.

Results: 82,028 veterans were diagnosed with AD during a median follow-up of 5.65 years. AD was less frequent in veterans with a history of cancer (24 percent) than without (76 percent). The majority of cancers had an inverse relationship with AD. The lower risk was greatest among survivors of lung (HR 0.75, 95 percent CI 0.69-0.81), leukemia (HR 0.77, 95 percent CI 0.68-0.87), myeloma (HR 0.73, 95 percent CI 0.60-0.90), esophageal (HR 0.66, 95 percent CI 0.51-0.86), pancreas (HR 0.56, 95 percent CI 0.39-0.80), and liver (HR 0.49, 95 percent CI 0.31-0.75) cancer. Notable exceptions included prostate cancer (HR 1.12, 95 percent CI 1.09 -1.15) and melanoma (HR 1.14, 95 percent CI 1.05-1.25). In contrast, all cancers were associated with a substantially increased risk of stroke when we used this as an alternative outcome (HR 1.27-1.70). Regardless of cancer type, receiving chemotherapy and/or radiation substantially reduced AD risk by 17-23 percent. In the subset of patients with cancer, chemotherapy but not radiation conferred a lower risk of AD (HR 0.55-0.80) for all cancers except prostate.

Conclusions: We found that the majority of cancers have an inverse relationship with AD even after adjustment for treatment. Reception of chemotherapy was associated with a reduced risk for subsequent AD in nearly all cancers. These findings were not primarily due to mortality bias. Additional research is needed to determine if these findings have therapeutic implications for AD.

History of Cancer and Risk of Subsequent AD

Cancer type

HR and 95% CI for AD*

Any cancer (n=771,285) 1.03 (1.01-1.05)
Smoking (n=174,632) 0.87 (0.83-0.90)
Non-smoking (n=414,499) 1.05 (1.03-1.08)
Prostate (n=251,616) 1.12 (1.09-1.15)
Lung (n=79,818) 0.75 (0.69-0.81)
Colorectal (n=55,600) 0.99 (0.93-1.05)
Bladder (n=42,842) 1.01 (0.95-1.08)
Head + neck (n=40,837) 0.85 (0.78-0.92)
Head + neck (n=40,837) 0.80 (0.71-0.90)
Melanoma (n=20,095) 1.14 (1.05-1.25)
Leukemia (n=20,049) 0.77 (0.68-0.87)
Renal (n=15,849) 0.78 (0.68-0.90)
Myeloma (n=8,994) 0.73 (0.60-0.90)
Esophagus (n=8,983)
0.66 (0.51-0.86)
Pancreas (n=7,076) 0.56 (0.39-0.80)
Liver (n=5,915) 0.49 (0.31-0.75)
Stomach (n=5,738) 0.80 (0.62-1.02)

Model adjusted for: cancer treatment, number of visits in year prior to baseline, high cholesterol, hypertension, obesity, CAD, DM, stroke

Proposal ID: 39348
Topic: Public Health and Psychosocial
Subtopic: Epidemiology; Prevention, primary or secondary
Presentation: Oral session, Sunday, July 14, 2013

Anti-Hyperglycemic Therapy and Risk of Dementia: A New User Cohort Study

Presenting author: Rachel Whitmer, Rachel Whitmer*1, Charles Quesenberry Jr2, Jessica Allison2, Andy Karter1 1Kaiser Permanente Division of Research, Oakland, California, United States; 2Kaiser Permanente, Oakland, California, United States

Background: Even though those with type 2 diabetes (T2DM) have double the risk of dementia there's a paucity of work examining the association between diabetes treatment and risk of dementia. This is important in light of ongoing clinical trials evaluating insulin sensitizers as a potential treatment for mild cognitive impairment and Alzheimer's disease. Our objective was to evaluate the impact of initiating new diabetes therapies on time-to-incident dementia in a new user cohort study of patients with T2DMs to adjust for confounding by indication.

Methods: We studied a cohort of 14,891 T2DM patients aged 55+ in the Kaiser Permanente Diabetes Registry who initiated any diabetes pharmacotherapy between October 1999 and November 2001. Only patients initiating single new therapies ("new users") were included to reduce confounding and create mutually exclusive exposure groups. We constructed Cox proportional hazards models to evaluate the impact of initiating new diabetes therapies on time to dementia defined by medical record diagnoses made in visits to primary care, memory clinics and neurology from 1/1/2002-12/31/2007. Models were adjusted for age, race, education and diabetes duration.

Results: 1487 (9.9 percent) patients were diagnosed with dementia in the 5 year follow-up period. Of these 1487 patients 55 percent initiated Metformin, 25 percent Sulfonylurea, 14 percent Thiazolidinediones (TZDs), and 6 percent insulin. With sulfonylureas as the reference group those initiating metformin had a 20 percent reduced risk of dementia (Hazards Ratio {HR},=0.79, 95 percent Confidence Interval {CI}, .65, .95), while those initiating TZD or insulin had no difference in risk. In comparison to those initiating metformin, those initiating SU had a 24 percent increased risk (HR=1.24, 95 percent CI 1.1,1.4), TZDs an 18 percent increased risk (HR=1.18, 95 percent CI 1.1, 1.4) and insulin a 28 percent increased risk (HR=1.28, 1.1,1.6). Findings were similar when models additionally adjusted for glycosylated hemoglobin.

Conclusions: In diabetic patients those initiating metformin had a five year reduced risk of dementia in comparison to patients initiating other therapies. Animal models suggest metformin may contribute to neurogenesis and trials are evaluating metformin as a potential therapeutic for mild cognitive impairment. These results are preliminary evidence that benefits of insulin sensitizers may extend beyond glycemic control to neurocognitive health.

Proposal ID: 38966
Topic: Public Health and Psychosocial
Subtopic: Epidemiology of risk factors of Alzheimer's disease
Presentation: Oral session, Monday, July 15, 2013, 4 p.m. ET

Older age at retirement is associated with decreased risk of dementia. Analysis of a healthcare insurance database of self-employed workers

Presenting author: Carole Dufouil, Carole Dufouil*1, Edwige Pereira2, Geneviève Chêne3, M. Maria Glymour4, annick alpérovitch5, Elodie Saubusse6, Mathilde Risse-Fleury7, Brigitte Heuls7, Jean-Claude Salord8, Marie-Anne Brieu8, Francoise Forette8 1INSERM U708 & CIC-EC7, Bordeaux, France; 2INSERM U708, Bordeaux, France; 3INSERM U897, Bordeaux, France; 4Harvard School of Public Health, Boston, Massachusetts, United States; 5INSERM U708, Paris, France; 6RSI Aquitaine, Bruges, France; 7RSI, Saint-Denis, France; 8ILC France, Paris, France.

Background: Intellectual stimulation and mental engagement throughout life might be protective against dementia. We investigated whether age at retirement influences dementia risk among self-employed workers in France.

Methods: We linked health and pension databases including self-employed workers who were living and retired as of Dec. 31, 2010. Dementia cases were defined based either on ICD-10th diagnosis or on claim for one of the medication against dementia (donepezil, galantamine, rivastigmine). Data were analyzed using Cox proportional hazard model where age at dementia diagnosis or age at censoring (Dec. 31, 2010) was the dependent variable and age of retirement was the independent variable. Hazard ratios were computed adjusting for gender, marital status, occupational category, type of retirement, pension amount, diagnosis of hypertension, diabetes. Sensitivity analyses to assess potential reverse causation and differential cohort or temporal diagnosis biases were undertaken.

Results: Among the 429,803 retired self-employed workers alive on Dec. 31, 2010, prevalence of dementia was 2.65 percent. Workers had been retired on average for more than 12 years. Multivariable analyses showed that the hazard ratio (HR) of dementia was 0.968 (95 percent Confidence Interval= [0.962-0.973]) per each extra year of age at retirement. After excluding workers who had dementia diagnosed within the 5 years following retirement, the results remained unchanged and highly significant (p<0.0001). Results were also similar in further analyses stratified by age categories or year of dementia diagnosis.

Conclusions: Professional activity may be an important determinant of mental exercise and social integration. Our data show strong evidence of a significant decrease in the risk of developing dementia associated with older age at retirement, in line with the "use it or lose it" hypothesis. This health perspective should be taken into consideration when the age of cessation of professional activity is discussed. Our results thus highlight the importance of maintaining high levels of cognitive and social stimulation throughout work and retiree life and emphasize the need for interventions and policies to help older individuals achieve such cognitive and social engagement.

Proposal ID: 37195
Topic: Public Health and Psychosocial
Subtopic: Epidemiology of risk factors of other dementias
Presentation: Oral session, Monday, July 15, 2013, 4 p.m. ET

Do Socioeconomic Disparities Explain Higher Dementia Incidence among Black Older Adults?

Presenting author: Kristine Yaffe, Kristine Yaffe*1, Cherie Falvey2, Tamara Harris3, Anne Newman4, Suzanne Satterfield5, Annemarie Koster6, Hilsa Ayonayon1, Eleanor Simonsick6, 1University of California San Francisco, San Francisco, California, United States; 2UCSF, San Francisco, California, United States; 3NIH, Bethesda, Maryland, United States; 4University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States; 5University of Tennessee, Memphis, Tennessee, United States; 6National Institute on Aging, Bethesda, Maryland, United States.

Background: Dementia rates in the United States have been shown to be higher among black than white elders. Whether this increased incidence reflects greater risk factors among black than white elders has not been extensively evaluated. We sought to determine if black-white differences in dementia rates existed among a cohort of community dwelling elders and whether differences observed could be explained by socioeconomic status (SES) indicators (income, financial adequacy, education and literacy) and health-related factors.

Methods: We evaluated dementia risk among 3,075 black and white elders (mean age 74.1 years; 41.7 percent black; 51.5 percent female) participating in the prospective Health Aging and Body Composition study and who were free from dementia at baseline. Dementia was determined over a 12-year follow-up by prescribed dementia medications, hospital records and decline in global cognition. To examine the influence of SES and health related factors on dementia rates, we conducted a series of Cox-proportional hazard models in which these variables were sequentially added to the base model in covariate blocks.

Results: Over follow-up, 575 (18.7 percent) participants developed dementia. Black participants had a greater risk of developing dementia than white participants (21.9 percent vs. 16.4 percent, P<.0001; unadjusted hazard ratio [HR] 1.57; 95 percent confidence interval [CI], 1.33, 1.84). The HR lessened somewhat after adjustment for demographics, APOE e4, comorbidities, and lifestyle factors (1.40; 95 percent CI: 1.17, 1.68) but was greatly reduced and no longer statistically significant when SES was added to the model (HR: 1.17, 95 percent CI: 0.95-1.45). Additional adjustment for baseline 3MS score attenuated the effect size slightly.

Conclusions: Results suggest that differences in risk factors, especially SES, may contribute to the higher dementia rates observed among black compared to white elders. Strategies aimed at reducing these disparities may favorably impact dementia incidence.

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Make history at AAIC 2013 • Boston, MA • July 13-18, 2013