Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Populations
2.2. Outcome, Exposure, and Risk Factors
2.3. Statistical Analysis
3. Results
3.1. Overall Sample Characteristics
3.2. Pain and AD Risk
3.3. Patterns of Pain Rating
3.4. Racial and Tumor Site Variation in AD Risk
4. Discussion
4.1. Pain as a Protective Factor for AD in Patients with Cancer
4.2. Hypothesis on Cancer-AD Association
4.3. Other Risk Factors for AD in Patients with Cancer
4.4. Study Strengths
4.5. Study Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Majd, S.; Power, J.; Majd, Z. Alzheimer’s Disease and Cancer: When Two Monsters Cannot Be Together. Front. Neurosci. 2019, 13, 155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lanni, C.; Masi, M.; Racchi, M.; Govoni, S. Cancer and Alzheimer’s disease inverse relationship: An age-associated diverging derailment of shared pathways. Mol. Psychiatry 2021, 26, 280–295. [Google Scholar] [CrossRef] [PubMed]
- Snyder, H.M.; Ahles, T.; Calderwood, S.; Carrillo, M.C.; Chen, H.; Chang, C.H.; Craft, S.; De Jager, P.; Driver, J.A.; Fillit, H.; et al. Exploring the nexus of Alzheimer’s disease and related dementias with cancer and cancer therapies: A convening of the Alzheimer’s Association & Alzheimer’s Drug Discovery Foundation. Alzheimers Dement. 2017, 13, 267–273. [Google Scholar] [CrossRef] [Green Version]
- Mezencev, R.; Chernoff, Y.O. Risk of Alzheimer’s Disease in Cancer Patients: Analysis of Mortality Data from the US SEER Population-Based Registries. Cancers 2020, 12, 796. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Driver, J.A.; Beiser, A.; Au, R.; Kreger, B.E.; Splansky, G.L.; Kurth, T.; Kiel, D.P.; Lu, K.P.; Seshadri, S.; Wolf, P.A. Inverse association between cancer and Alzheimer’s disease: Results from the Framingham Heart Study. BMJ 2012, 344, e1442. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seddighi, S.; Houck, A.L.; Rowe, J.B.; Pharoah, P.D.P. Evidence of a Causal Association between Cancer and Alzheimer’s Disease: A Mendelian Randomization Analysis. Sci. Rep. 2019, 9, 13548. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hanson, H.A.; Horn, K.P.; Rasmussen, K.M.; Hoffman, J.M.; Smith, K.R. Is Cancer Protective for Subsequent Alzheimer’s Disease Risk? Evidence From the Utah Population Database. J. Gerontol. B Psychol. Sci. Soc. Sci. 2017, 72, 1032–1043. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Realmuto, S.; Cinturino, A.; Arnao, V.; Mazzola, M.A.; Cupidi, C.; Aridon, P.; Ragonese, P.; Savettieri, G.; D’Amelio, M. Tumor diagnosis preceding Alzheimer’s disease onset: Is there a link between cancer and Alzheimer’s disease? J. Alzheimers Dis. 2012, 31, 177–182. [Google Scholar] [CrossRef]
- Ren, R.J.; Huang, Q.; Xu, G.; Gu, K.; Dammer, E.B.; Wang, C.F.; Xie, X.Y.; Chen, W.; Shao, Z.Y.; Chen, S.D.; et al. Association between Alzheimer’s disease and risk of cancer: A retrospective cohort study in Shanghai, China. Alzheimers Dement. 2022, 18, 924–933. [Google Scholar] [CrossRef]
- Lee, J.E.; Kim, D.; Lee, J.H. Association between Alzheimer’s Disease and Cancer Risk in South Korea: An 11-year Nationwide Population-Based Study. Dement. Neurocogn. Disord. 2018, 17, 137–147. [Google Scholar] [CrossRef]
- Freedman, D.M.; Wu, J.; Chen, H.; Kuncl, R.W.; Enewold, L.R.; Engels, E.A.; Freedman, N.D.; Pfeiffer, R.M. Associations between cancer and Alzheimer’s disease in a U.S. Medicare population. Cancer Med. 2016, 5, 2965–2976. [Google Scholar] [CrossRef]
- Musicco, M.; Adorni, F.; Di Santo, S.; Prinelli, F.; Pettenati, C.; Caltagirone, C.; Palmer, K.; Russo, A. Inverse occurrence of cancer and Alzheimer disease: A population-based incidence study. Neurology 2013, 81, 322–328. [Google Scholar] [CrossRef] [PubMed]
- Frain, L.; Swanson, D.; Cho, K.; Gagnon, D.; Lu, K.P.; Betensky, R.A.; Driver, J. Association of cancer and Alzheimer’s disease risk in a national cohort of veterans. Alzheimers Dement. 2017, 13, 1364–1370. [Google Scholar] [CrossRef] [PubMed]
- Du, X.L.; Song, L.; Schulz, P.E.; Xu, H.; Chan, W. Risk of Developing Alzheimer’s Disease and Related Dementias in Association with Cardiovascular Disease, Stroke, Hypertension, and Diabetes in a Large Cohort of Women with Breast Cancer and with up to 26 Years of Follow-Up. J. Alzheimers Dis. 2022, 87, 415–432. [Google Scholar] [CrossRef] [PubMed]
- Zabłocka, A.; Kazana, W.; Sochocka, M.; Stańczykiewicz, B.; Janusz, M.; Leszek, J.; Orzechowska, B. Inverse Correlation between Alzheimer’s Disease and Cancer: Short Overview. Mol. Neurobiol. 2021, 58, 6335–6349. [Google Scholar] [CrossRef] [PubMed]
- Nagaraj, S.; Zoltowska, K.M.; Laskowska-Kaszub, K.; Wojda, U. microRNA diagnostic panel for Alzheimer’s disease and epigenetic trade-off between neurodegeneration and cancer. Ageing Res. Rev. 2019, 49, 125–143. [Google Scholar] [CrossRef]
- Wang, K.; Liu, H. Association between widespread pain and dementia, Alzheimer’s disease and stroke: A cohort study from the Framingham Heart Study. Reg. Anesth. Pain Med. 2021, 46, 879–885. [Google Scholar] [CrossRef]
- Khalid, S.; Sambamoorthi, U.; Innes, K.E. Non-Cancer Chronic Pain Conditions and Risk for Incident Alzheimer’s Disease and Related Dementias in Community-Dwelling Older Adults: A Population-Based Retrospective Cohort Study of United States Medicare Beneficiaries, 2001–2013. Int. J. Environ. Res. Public Health 2020, 17, 5454. [Google Scholar] [CrossRef]
- Innes, K.E.; Sambamoorthi, U. The Association of Osteoarthritis and Related Pain Burden to Incident Alzheimer’s Disease and Related Dementias: A Retrospective Cohort Study of U.S. Medicare Beneficiaries. J. Alzheimers Dis. 2020, 75, 789–805. [Google Scholar] [CrossRef]
- Khalid, S.; Sambamoorthi, U.; Umer, A.; Lilly, C.L.; Gross, D.K.; Innes, K.E. Increased Odds of Incident Alzheimer’s Disease and Related Dementias in Presence of Common Non-Cancer Chronic Pain Conditions in Appalachian Older Adults. J. Aging Health 2022, 34, 158–172. [Google Scholar] [CrossRef]
- Ganguli, M. A reduced risk of Alzheimer’s disease in those who survive cancer. BMJ 2012, 344, e1662. [Google Scholar] [CrossRef] [PubMed]
- Ording, A.G.; Horváth-Puhó, E.; Veres, K.; Glymour, M.M.; Rørth, M.; Sørensen, H.T.; Henderson, V.W. Cancer and risk of Alzheimer’s disease: Small association in a nationwide cohort study. Alzheimers Dement. 2020, 16, 953–964. [Google Scholar] [CrossRef] [PubMed]
- Bowles, E.J.A.; Walker, R.L.; Anderson, M.L.; Dublin, S.; Crane, P.K.; Larson, E.B. Risk of Alzheimer’s disease or dementia following a cancer diagnosis. PLoS ONE 2017, 12, e0179857. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Du, X.L.; Song, L.; Schulz, P.E.; Xu, H.; Chan, W. Associations Between Vascular Diseases and Alzheimer’s Disease or Related Dementias in a Large Cohort of Men and Women with Colorectal Cancer. J. Alzheimers Dis. 2022, 90, 211–231. [Google Scholar] [CrossRef] [PubMed]
- van den Beuken-van Everdingen, M.H.; Hochstenbach, L.M.; Joosten, E.A.; Tjan-Heijnen, V.C.; Janssen, D.J. Update on Prevalence of Pain in Patients with Cancer: Systematic Review and Meta-Analysis. J. Pain Symptom Manag. 2016, 51, 1070–1090. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- van den Beuken-van Everdingen, M.H.; de Rijke, J.M.; Kessels, A.G.; Schouten, H.C.; van Kleef, M.; Patijn, J. Prevalence of pain in patients with cancer: A systematic review of the past 40 years. Ann. Oncol. 2007, 18, 1437–1449. [Google Scholar] [CrossRef] [PubMed]
- Kong, W.; Mou, X.; Deng, J.; Di, B.; Zhong, R.; Wang, S.; Yang, Y.; Zeng, W. Differences of immune disorders between Alzheimer’s disease and breast cancer based on transcriptional regulation. PLoS ONE 2017, 12, e0180337. [Google Scholar] [CrossRef] [Green Version]
- Cao, S.; Fisher, D.W.; Yu, T.; Dong, H. The link between chronic pain and Alzheimer’s disease. J. Neuroinflammation 2019, 16, 204. [Google Scholar] [CrossRef] [Green Version]
- Ospina-Romero, M.; Glymour, M.M.; Hayes-Larson, E.; Mayeda, E.R.; Graff, R.E.; Brenowitz, W.D.; Ackley, S.F.; Witte, J.S.; Kobayashi, L.C. Association Between Alzheimer Disease and Cancer with Evaluation of Study Biases: A Systematic Review and Meta-analysis. JAMA Netw. Open 2020, 3, e2025515. [Google Scholar] [CrossRef]
- Sacks, D.; Baxter, B.; Campbell, B.C.V.; Carpenter, J.S.; Cognard, C.; Dippel, D.; Eesa, M.; Fischer, U.; Hausegger, K.; Hirsch, J.A.; et al. Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int. J. Stroke 2018, 13, 612–632. [Google Scholar] [CrossRef]
- Martinez-Sanchez, N.; Sweeney, O.; Sidarta-Oliveira, D.; Caron, A.; Stanley, S.A.; Domingos, A.I. The sympathetic nervous system in the 21st century: Neuroimmune interactions in metabolic homeostasis and obesity. Neuron 2022, 110, 3597–3626. [Google Scholar] [CrossRef] [PubMed]
- Egerman, R.S.; Andersen, R.N.; Manejwala, F.M.; Sibai, B.M. Neuropeptide Y and nitrite levels in preeclamptic and normotensive gravid women. Am. J. Obstet. Gynecol. 1999, 181, 921–923. [Google Scholar] [CrossRef] [PubMed]
- Masters, C.L. Major risk factors for Alzheimer’s disease: Age and genetics. Lancet Neurol. 2020, 19, 475–476. [Google Scholar] [CrossRef] [PubMed]
- Nianogo, R.A.; Rosenwohl-Mack, A.; Yaffe, K.; Carrasco, A.; Hoffmann, C.M.; Barnes, D.E. Risk Factors Associated with Alzheimer Disease and Related Dementias by Sex and Race and Ethnicity in the US. JAMA Neurol. 2022, 79, 584–591. [Google Scholar] [CrossRef]
- Akushevich, I.; Yashkin, A.P.; Kravchenko, J.; Kertai, M.D. Chemotherapy and the Risk of Alzheimer’s Disease in Colorectal Cancer Survivors: Evidence From the Medicare System. JCO Oncol. Pract. 2021, 17, e1649–e1659. [Google Scholar] [CrossRef]
- Butterfield, D.A. The 2013 SFRBM discovery award: Selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Radic. Biol. Med. 2014, 74, 157–174. [Google Scholar] [CrossRef] [Green Version]
- Okereke, O.I.; Meadows, M.E. More Evidence of an Inverse Association Between Cancer and Alzheimer Disease. JAMA Netw. Open 2019, 2, e196167. [Google Scholar] [CrossRef]
- Nudelman, K.N.; Risacher, S.L.; West, J.D.; McDonald, B.C.; Gao, S.; Saykin, A.J. Association of cancer history with Alzheimer’s disease onset and structural brain changes. Front. Physiol. 2014, 5, 423. [Google Scholar] [CrossRef]
Variable | Case Group, No. (%) (n = 25,512) | Control Group, No. (%) (n = 127,560) | p-Value |
---|---|---|---|
Age at cancer diagnosis, mean (SD), y | 71.92 (9.76) | 71.72 (9.80) | 0.003 a |
Sex | <0.001 b | ||
Male | 8842 (34.7) | 61,649 (48.3) | |
Female | 16,670 (65.3) | 65,911 (51.7) | |
Race | <0.001 b | ||
White | 23,355 (91.5) | 106,957 (83.8) | |
Asian/Pacific Islander | 1217 (4.8) | 13,254 (10.4) | |
Black | 891 (3.5) | 7223 (5.7) | |
American Indian/Alaska Native | 49 (0.2) | 126 (0.1) | |
Pain rating c | <0.001 b | ||
I | 2118 (8.3) | 8169 (6.4) | |
II | 23,394 (91.7) | 119,391 (93.6) | |
Total number of in situ/malignant tumors | 1.17 (0.45) | 1.20 (0.50) | <0.001 a |
Total number of benign/borderline tumors | 0.40 × 10−2 (0.07) | 0.18 × 10−2 (0.04) | <0.001 a |
Cancer site | <0.001 b | ||
Bone and Joint | 10 (0) | 65 (0.1) | |
Breast | 8390 (32.9) | 30,030 (23.5) | |
Digestive | 5037 (19.7) | 30,987 (24.3) | |
Endocrine | 243 (1) | 1154 (0.9) | |
Hematological | 279 (1.1) | 1924 (1.5) | |
Kaposi Sarcoma | 17 (0.1) | 181 (0.1) | |
Mesothelioma | 2 (0) | 15 (0) | |
Miscellaneous | 3 (0) | 7 (0) | |
Respiratory | 525 (2.1) | 6870 (5.4) | |
Skin and Soft Tissue | 1428 (5.6) | 5557 (4.4) | |
Urogenital | 9578 (37.5) | 50,770 (39.8) | |
Radiation therapy | 0.61 b | ||
Yes | 6507 (25.5) | 32,341 (25.4) | |
No | 19,005 (74.5) | 95,219 (74.6) | |
Cancer-directed surgery | <0.001 b | ||
Yes | 23,269 (91.2) | 112,996 (88.6) | |
No | 2243 (8.8) | 14,564 (11.4) | |
Chemotherapy | 0.003 b | ||
Yes | 1854 (7.3) | 8613 (6.8) | |
No/Unknown | 23,658 (92.7) | 11,8947 (93.2) | |
Survival years after the first tumor diagnosis | 15.62 (8.86) | 11.71 (8,16) | <0.001 a |
Variable | OR (95% CI) a | p-Value | Adjusted OR b (95%CI) | p-Value |
---|---|---|---|---|
Age at cancer diagnosis, mean, y | 1.055 (1.053–1.057) | <0.001 | 1.055 (1.053–1.057) | <0.001 |
Sex | ||||
Male | 1 [Reference] | 1 [Reference] | ||
Female | 1.315 (1.269–1.362) | <0.001 | 1.315 (1.269–1.362) | <0.001 |
Race | ||||
White | 1 [Reference] | 1 [Reference] | ||
Asian/Pacific Islander | 0.408 (0.384–0.434) | <0.001 | 0.408 (0.384–0.434) | <0.001 |
Black | 0.670 (0.623–0.721) | <0.001 | 0.670 (0.623–0.721) | <0.001 |
American Indian/Alaska Native | 2.179 (1.545–3.075) | <0.001 | 2.179 (1.545–3.075) | <0.001 |
Pain rating | ||||
I | 1 [Reference] | 1 [Reference] | ||
II | 0.849 (0.805–0.896) | <0.001 | 0.849 (0.805–0.896) | <0.001 |
Total number of in situ/malignant tumors | 0.764 (0.740–0.788) | <0.001 | 0.764 (0.740–0.788) | <0.001 |
Total number of benign/borderline tumors | 1.987 (1.573–2.509) | <0.001 | 1.987 (1.573–2.509) | <0.001 |
Cancer site | ||||
Bone and Joint | 0.829 (0.416–1.652) | 0.59 | 0.829 (0.416–1.652) | 0.59 |
Breast | 1.090 (1.047–1.136) | <0.001 | 1.090 (1.047–1.136) | <0.001 |
Digestive | 0.784 (0.753–0.816) | <0.001 | 0.784 (0.753–0.816) | <0.001 |
Endocrine | 1.040 (0.897–1.204) | 0.61 | 1.040 (0.897–1.204) | 0.61 |
Hematological | 0.683 (0.597–0.781) | <0.001 | 0.683 (0.597–0.781) | <0.001 |
Kaposi Sarcoma | 0.435 (0.263–0.722) | 0.001 | 0.435 (0.263–0.722) | 0.001 |
Mesothelioma | 0.769 (0.170–3.474) | 0.73 | 0.769 (0.170–3.474) | 0.73 |
Miscellaneous | 2.133 (0.484–9.402) | 0.32 | 2.133 (0.484–9.402) | 0.32 |
Respiratory | 0.533 (0.486–0.586) | <0.001 | 0.533 (0.486–0.586) | p < 0.001 |
Skin and Soft Tissue | 1.190 (1.114–1.272) | <0.001 | 1.190 (1.114–1.272) | <0.001 |
Urogenital | 1 [Reference] | 1 [Reference] | ||
Cancer-directed surgery | ||||
Yes | 0.902 (0.857–0.951) | <0.001 | 0.902 (0.857–0.951) | <0.001 |
No | 1 [Reference] | 1 [Reference] | ||
Chemotherapy | ||||
Yes | 1.450 (1.370–1.534) | <0.001 | 1.450 (1.370–1.534) | <0.001 |
No | 1 [Reference] | 1 [Reference] | ||
Survival years after the first tumor diagnosis | 1.096 (1.093–1.098) | <0.001 | 1.096 (1.093–1.098) | <0.001 |
Variable | Case Group (n = 25,512) | Control Group (n = 127,560) | ||||
---|---|---|---|---|---|---|
I, No. (%) (n = 2118) | II, No. (%) (n = 23,394) | p-Value | I, No. (%) (n = 8169) | II, No. (%) (n = 11,939) | p-Value | |
Age at cancer diagnosis, mean (SD), y | 71.21 (10.11) | 71.98 (9.73) | 0.001 | 71.45 (10.06) | 71.74 (9.78) | 0.01 b |
Sex | <0.001 | <0.001 c | ||||
Male | 349 (16.5) | 8493 (36.3) | 2545 (31.2) | 59,104 (49.5) | ||
Female | 1769 (83.5) | 14,901 (63.7) | 5624 (68.8) | 60,287 (50.5) | ||
Race | 0.24 | 0.72 c | ||||
White | 1950 (92.1) | 21,405 (91.5) | 6834 (83.7) | 100,123 (83.9) | ||
Asian/Pacific Islander | 86 (4.1) | 1131 (4.8) | 871 (10.7) | 12,383 (10.4) | ||
Black | 80 (3.8) | 811 (3.5) | 454 (5.6) | 6769 (5.7) | ||
American Indian/Alaska Native | 2 (0.1) | 47 (0.2) | 10 (0.1) | 116 (0.1) | ||
Total number of in situ/malignant tumors | 1.22 (0.49) | 1.17 (0.45) | <0.001 | 1.29 (0.59) | 1.20 (0.49) | <0.001 b |
Total number of benign/borderline tumors | 0 | 0 | 0.70 | 0 (0.05) | 0 (0.04) | 0.26 b |
Cancer site | <0.001 | <0.001 c | ||||
Bone and Joint | 0 (0) | 10 (0) | 0 (0) | 65 (0.1) | ||
Breast | 1172 (55.3) | 8390 (32.9) | 3428 (42) | 26,602 (22.3) | ||
Digestive | 372 (17.6) | 5037 (19.7) | 2636 (32.3) | 28,351 (23.7) | ||
Endocrine | 0 (0) | 243 (1) | 1 (0) | 1153 (1) | ||
Hematological | 0 (0) | 279 (1.1) | 0 (0) | 1924 (1.6) | ||
Kaposi Sarcoma | 0 (0) | 17 (0.1) | 0 (0) | 181 (0.2) | ||
Mesothelioma | 0 (0) | 2 (0) | 0 (0) | 15 (0) | ||
Miscellaneous | 0 (0) | 3 (0) | 0 (0) | 7 (0) | ||
Respiratory | 1 (0) | 525 (2.1) | 12 (0.1) | 6858 (5.7) | ||
Skin and Soft Tissue | 390 (18.4) | 1428 (5.6) | 1317 (16.1) | 4240 (3.6) | ||
Urogenital | 183 (8.6) | 9578 (37.5) | 775 (9.5) | 49,995 (41.9) | ||
Radiation therapy | <0.001 | <0.001 c | ||||
Yes | 311 (14.7) | 6196 (26.5) | 904 (11.1) | 31,437 (26.3) | ||
No | 1807 (85.3) | 17,198 (73.5) | 7265 (88.9) | 87,954 (73.7) | ||
Cancer-directed surgery | <0.001 | <0.001 c | ||||
Yes | 2115 (99.9) | 21,154 (90.4) | 8136 (99.6) | 104,860 (87.8) | ||
No | 3 (0.1) | 2240 (9.6) | 33 (0.4) | 14,531 (12.2) | ||
Chemotherapy | <0.001 | <0.001 c | ||||
Yes | 6 (0.3) | 1848 (7.9) | 28 (0.3) | 8585 (7.2) | ||
No/Unknown | 2112 (99.7) | 21,546 (92.1) | 8141 (99.7) | 110,806 (92.8) | ||
Survival years after the first tumor diagnosis | 16.54 (8.81) | 15.54 (8.86) | <0.001 | 12.61 (8.55) | 11.65 (8.13) | <0.001 b |
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Xia, S.; Yu, X.; Chen, G. Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer. Cancers 2023, 15, 248. https://doi.org/10.3390/cancers15010248
Xia S, Yu X, Chen G. Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer. Cancers. 2023; 15(1):248. https://doi.org/10.3390/cancers15010248
Chicago/Turabian StyleXia, Siqi, Xiaobo Yu, and Gao Chen. 2023. "Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer" Cancers 15, no. 1: 248. https://doi.org/10.3390/cancers15010248
APA StyleXia, S., Yu, X., & Chen, G. (2023). Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer. Cancers, 15(1), 248. https://doi.org/10.3390/cancers15010248