Different Exposures to Risk Factors Do Not Explain the Inverse Relationship of Occurrence Between Cancer and Neurodegenerative Diseases An Italian Nested Case-control Study Federica Prinelli, PhD,* Fulvio Adorni, MSc,* Maria Lea Correa Leite, MD,* Carla Pettenati, MD,w Antonio Russo, MD,z Simona Di Santo, MSc,y and Massimo Musicco, MD* Abstract: Several studies reported that cancer is less frequent in persons with Alzheimer’s and Parkinson’s Diseases (AD/PD) and vice-versa. We evaluated whether a different distribution of known nongenetic risk factors for cancer and AD/PD, might explain their inverse relationship of occurrence. We nested 2 case-control studies in a subsample of a large cohort of 1,000,000 resident in Lombardy Region in Italy (n = 1515), followed-up for cancer and AD/PD occurrence since 1991 until 2012. Conditional logistic regression was performed to determine the odds ratios (OR) and 95% confidence intervals (CI) of AD/PD in subjects with and without cancer and the risk of cancer in those with and without AD/PD. A total of 54 incident cases of AD/PD and 347 cancer cases were matched with 216 and 667 controls, respectively. After controlling for low education, obesity, history of hypertension, diabetes, dyslipidemia, physical activity, smoking habit, alcohol consumption, and dietary habit, cancer was found inversely associated with the risk of AD/PD (OR, 0.66; 95% CI, 0.32-1.38), and the risk of cancer in AD/PD was similarly reduced (OR, 0.42; 95% CI, 0.20-0.91). Different exposures to nongenetic risk factors of both diseases do not explain their competitive relationship of occurrence. Key Words: Alzheimer’s Disease, Parkinson’s Disease, cancer, risk factors, administrative health registries (Alzheimer Dis Assoc Disord 2017;00:000–000) N eurodegenerative disorders, particularly Alzheimer’s Disease (AD) (the most common form of dementia) and Parkinson’s Disease (PD), are the third leading cause of death in the elderly following cancer and vascular dis- eases. 1 Several previous studies reported that the risk of cancer is reduced in people with neurodegenerative dis- eases, 2–13 and vice-versa. 2–6,10,11,14 This finding might be explained by factors, possibly genetically based, that com- petitively could predispose to cancer or to AD/PD. 15 However, the negative association between the 2 diseases might be explained by different exposures to specific risk factors of persons with AD/PD or cancer in comparison to the general population. AD incidence was found increased in subjects with vascular risk factors 16–19 and poor adherence to the Medi- terranean Diet (MeDi). 20 In contrast, AD incidence was reported reduced in people who are highly educated and employed in cognitively stimulating activities, 21 and in those who are physically active. 22 Conversely, results on the direction of the association between smoking and AD are still conflicting. 23,24 Studies on PD reported a protective role of tobacco, physical exercise 25,26 and high adherence to the MeDi 27 whereas the role of vascular risk factors is more controversial. 28,29 Diabetes, smoking, overweight, low physical activity, and adherence to the MeDi are also positively associated with cancer occurrence. 30–32 In our previous cohort study on approximately 1,000,000 subjects aged 60 years and older in Northern Italy, we eval- uated the incidence of cancer in persons with AD and the incidence of AD in subjects with cancer by analyzing admin- istrative data. When compared with the general population of the same age and sex, the risk of AD among individuals with cancer was reduced by 35% [relative risk (RR), 0.65, 95% confidence interval (CI), 0.56-0.76] and the risk of cancer among those with AD was decreased by 43% (RR, 0.57; 95% CI, 0.49-0.67). 5 The potential sources of bias because of under- diagnosis and life expectancy reduction in persons with AD or cancer were addressed by performing the analysis before and after the diagnosis of each disease, and stratifying by survivors and nonsurvivors. The main limitation was the lack of avail- able information on clinical and lifestyle determinants of Received for publication January 30, 2017; accepted May 4, 2017. From the *Epidemiology Unit, Institute of Biomedical Technologies— National Research Council, Segrate; wAlzheimer Unit, Salvini Hospital, Passirana of Rho, Rho; zEpidemiologic Unit, Agency for Health Protection of the Metropolitan Area of Milan, Milan; and yDepartment of Neuroscience, University of Tor Vergata’ University of Rome, Rome, Italy. F.P., F.A., S.G.D.S., C.P., M.L.C.L., A.R., MM.: made a substantial contribution to the conception and design of the work, and inter- pretation of data. F.P.: acquisition of data, statistical analysis and draft of the article. F.A. and M.L.C.L.: acquisition of data, and statistical analysis of the data. A.R.: acquisition of data. M.M.: revising critically the manuscript for important intellectual content. All authors read and approved the final version of the manuscript to be published. AD indicates Alzheimer’s Diseases; AD/PD, Alzheimer’s or Parkin- son’s Diseases; ATC, anatomic therapeutic chemicals classification; BMI, body mass index; FFQ, food frequency questionnaire; ICD-9 and ICD-10, International Classification of Diseases, Ninth and Tenth Revision coding system; MeDi, Mediterranean Diet; OR (95% CI), odds ratio (95% confidence intervals); PD, Parkinson’s Diseases. The authors declare no conflicts of interest. Reprints: Federica Prinelli, PhD, Epidemiology Unit, Institute of Biomedical Technologies—National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Milan, Italy (e-mail: federica.prinelli@itb.cnr.it). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved. ORIGINAL ARTICLE Alzheimer Dis Assoc Disord  Volume 00, Number 00, ’’ 2017 www.alzheimerjournal.com | 1 Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.