Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by synapse injury and neuronal death in the brain (Hardy and Selkoe 2002). Cancer, also known as malignant tumors, belongs to a group of diseases involving the uncontrolled proliferation of cells (Mohammad et al. 2015). Both AD and cancer are common diseases in the elderly. Epidemiological studies have indicated that cancer survivors have a lower risk for developing AD and vice versa (Driver et al. 2012; White et al. 2013; Frain et al. 2013). A series of studies have also expounded the pathophysiological association between cancer and AD (Tirumalasetti, Han, and Birkett 1991), while a large amount of details remains unknown. Amyloid-beta (Aβ) is the initial factor in AD pathogenesis, which is a normal product of amyloid precursor protein (APP) proteolysis by β- or γ-secretase and can be measured in the brain, cerebrospinal fluid, and blood (Haass et al. 1992; Seubert et al. 1992; Shoji et al. 1992). Aβ in blood originates from both brain and peripheral tissues and is a potential biomarker for AD (DeMattos et al. 2001; DeMattos et al. 2002; Frackowiak et al. 2003; Joachim 1989). Abnormal Aβ deposition is associated with the subsequent aggregation of tau, synaptic dysfunction, neuronal loss, and cognitive impairment (Hardy and Selkoe 2002; Martin-Rehrmann et al. 2005). To investigate the effect of cancer on AD pathophysiology, we examined whether plasma Aβ levels are reduced in patients with cancer, which was associated with reduced risk for AD in epidemiological studies, including esophagus cancer, colorectal cancer, hepatic cancer, and lung cancer.

Materials and Methods

Study Population

In total, 110 cancer patients, including 21 esophagus cancer patients, 23 colorectal cancer patients, 22 hepatic cancer patients, and 44 lung cancer patients, were recruited from Chongqing Daping Hospital from 2014 to 2015, and 70 age- and gender-matched normal controls (NC) without cancer were randomly recruited from the health examination center of the same hospital. Seventy patients with AD were recruited from Chongqing Daping Hospital. The exclusion criteria included (i) a family history of dementia; (ii) cognitive impairment or concomitant neurological disorders potentially affecting cognitive function (e.g., severe Parkinson’s disease); (iii) enduring mental illness (e.g., schizophrenia); and (iv) patients with autoimmune diseases or severe cardiac, pulmonary, hepatic, or renal dysfunctions. Demographic data, including age, gender, and educational level, was collected on admission.

Diagnosis of Cancer and Blood Sampling

All clinical assessments of cancer are diagnosed by specialist physicians depending on reliable pathological examinations, genetic characteristics, image features, and clinical manifestations. Tumor locations are determined by imaging tests and clinical manifestations. Fasting blood was sampled between 07:00 a.m. and 08:00 a.m. to avoid the variation related to possible circadian rhythm effects. All blood samples were centrifuged immediately following blood withdrawal, and then stored at −80 °C until used. An informed consent was obtained from each participant before the acquisition of the blood sample.

Measurements of Aβ and Cytokines in Plasma

Plasma levels of Aβ40 and Aβ42 were determined using human Aβ enzyme-linked immunosorbent assay (ELISA) kits (Covance, USA), which recognize x-40 and x-42 with a standard range of 7.4–250 pg/ml. Plasma levels of pro-inflammatory cytokines, including interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interferon-γ(IFN-γ), anti-inflammatory cytokines interleukin-4 (IL-4), chemokines, and cytokines monocyte chemotactic protein-1 (MCP-1) were measured with relevant ELISA kits (4A Biotech, China). All the above ELISA measurements were performed according to the manufacturer’s instructions. Each sample was measured in duplicate, and the mean value was used for statistical analyses.

Statistical Analysis

The differences in demographic characteristics and plasma Aβ levels between groups were assessed by either a two-independent t tests (Mann–Whitney U test) or a chi-squared test, where appropriate. Partial correlation analysis was used to examine the correlations between Aβ levels and pro-inflammatory cytokines. The data were expressed as the mean ± standard deviation (SD) for numerical variables or as the number (%) for categorical variables. All hypothesis testing was two-sided, and a p value of less than 0.05 was defined as statistically significant. Computations were carried out with SPSS version 19.0 (SPSS, Chicago, IL, USA).

Results

Demographic Characteristics

The demographic characteristics of subjects are shown in Table 1. In this study, 110 cognitively normal cancer patients, 70 patients with AD, and 70 age- and gender-matched NC were enrolled. There were no significant differences in age, gender, education, and comorbidities (such as diabetes mellitus and hypertension) between cancer patients and NC. The main therapies for cancer patients include chemotherapy, radiotherapy, and surgery. The treatment of patients with different cancers is also shown in Table 1.

Table 1 Characteristics of study population
Full size table

Plasma Aβ Levels in Cancer Patients

First, we compared the plasma Aβ levels in all cancer patients and NC. Compared with NC, plasma levels of Aβ40 (94.19 ± 105.60 vs. 60.95 ± 57.68 pg/ml, p = 0.0709), Aβ42 (59.59 ± 79.14 vs. 30.50 ± 33.51 pg/ml, p = 0.0030), and total Aβ (153.78 ± 179.24 vs. 91.45 ± 74.04 pg/ml, p = 0.0635) were higher in all cancer patients but a little lower than the AD group (Fig. 1). Secondly, four types of cancer were analyzed separately with the NC group. We found that plasma Aβ40 (199.84 ± 139.03 vs. 60.95 ± 57.68 pg/ml, p < 0.0001), Aβ42 (142.03 ± 107.79 vs. 30.50 ± 33.51 pg/ml, p < 0.0001), and total Aβ (341.87 ± 242.59 vs. 91.45 ± 74.04 pg/ml, p < 0.0001) levels were significantly increased in hepatic cancer patients (Fig. 1). Increasing plasma Aβ40 (86.99 ± 88.90 vs. 60.95 ± 57.68 pg/ml, p = 0.3745), Aβ42 (45.63 ± 57.83 vs. 30.50 ± 33.51 pg/ml, p = 0.2684), and total Aβ (132.62 ± 151.57 vs. 91.45 ± 74.04 pg/ml, p = 0.3539) levels were found in esophagus cancer patients compared with NC, but the difference was not statistically significant (p > 0.05). In patients with colorectal cancer or lung cancer, no significant difference was found in plasma Aβ40, Aβ42, or total Aβ levels. Compared with AD patients, plasma Aβ40 (199.84 ± 139.03 vs. 100.42 ± 99.62 pg/ml, p < 0.0001), Aβ42 (142.03 ± 107.79 vs. 67.41 ± 60.57 pg/ml, p < 0.0001), and total Aβ (341.87 ± 242.59 vs. 167.83 ± 110.47 pg/ml, p < 0.0001) levels were also significantly higher for liver cancer patients, which were lower for colorectal cancer and lung cancer patients (Fig. 1).

Fig. 1
figure 1

Plasma Aβ40 (a), Aβ42 (b), and total Aβ(c) levels in normal controls (NC) and different types of cancer patients. *p < 0.05, **p < 0.01, ***p < 0.001

Full size image

Effect of Chemotherapy on Aβ Levels

To investigate whether chemotherapy has an effect on Aβ levels, cancer patients were divided into two subgroups according to whether they had received chemotherapy or not. As shown in Fig. 2, no significant difference in plasma Aβ40 or Aβ42 levels was found between the two subgroups of all cancer patients (Fig. 2). Then, we aimed to analyze the plasma Aβ levels in patients with each type of cancer for the two subgroups. However, with the limited sample size, we only conducted the subgroup analysis in lung cancer patients. There are no significant differences in plasma Aβ40 (48.53 ± 39.17 vs. 54.45 ± 54.26 pg/ml, p = 0.8673), Aβ42 (24.79 ± 25.69 vs. 32.78 ± 25.71 pg/ml, p = 0.0878), and total Aβ (73.33 ± 52.89 vs. 87.23 ± 68.47 pg/ml, p = 0.6937) levels between chemotherapy and no chemotherapy subgroups.

Fig. 2
figure 2

There are no significant differences in plasma Aβ40 (a), Aβ42 (b), and total Aβ (c) levels between the chemotherapy group and the no chemotherapy. All four cancers and lung cancer were analyzed; no significant difference was found

Full size image

Effect of pro-Inflammatory, Anti-Inflammatory and Chemokines and Cytokines on Aβ Levels

The plasma pro-inflammatory cytokines IL-1β, IL-6, TNF-α, IFN-γ, anti-inflammatory IL-4, chemokines, and cytokines MCP-1 of cancer patients were measured. Plasma IFN-γ levels were significantly increased in hepatic cancer patients in comparison to NC (27.55 ± 14.64 vs. 17.44 ± 13.10 ng/ml, p = 0.0433) (Fig. 3). In esophagus cancer patients, plasma TNF-α (15.90 ± 11.06 vs. 9.40 ± 12.03 pg/ml, p = 0.0338) levels showed a significant increase. Then, we analyzed the correlation of IFN-γ and TNF-α with Aβ in hepatic cancer and esophagus cancer patients, respectively. However, no significant correlation was found.

Fig. 3
figure 3

Plasma pro-inflammatory, anti-inflammatory, chemokines, and cytokines including IL-1β (a), TNF-α (b), IL-6(c), IFN-γ(d), IL-4(e), and MCP-1(f) in patients with different cancers and normal controls. Plasma IFN-γ levels are significantly increased in hepatic cancer patients. In esophagus cancer patients, plasma TNF-α showed significant increase, while IL-6 is significantly decreased. *p < 0.05

Full size image

Discussion

In the present study, a significant increase of plasma Aβ levels in cancer patients, particularly in patients with hepatic cancer, were found. Possible influential factors of Aβ levels in cancer patients, including inflammation and chemotherapy, were also analyzed. However, neither the inflammatory cytokines nor the chemotherapy history could explain the elevation of plasma Aβ levels in cancer patients.

Increasing epidemiological investigations shows an inverse association between cancer and AD. In a Framingham Heart Study of 1278 participants, cancer survivors had a 33% lower risk for developing AD, especially in survivors of smoking-related cancers (Driver et al. 2012). Some special types of cancer have been separately researched. For instance, it was reported that nonmelanoma skin cancer was associated with reduced risk of AD (White et al. 2013). Interestingly, prostate cancer and melanoma were associated with an increased risk for AD (Frain et al. 2013).

To date, the potential mechanism of the impact of cancer on AD still remains unknown. These two diseases are characterized by opposite cell development directions in which cells die in AD but proliferate in cancer. Current studies mainly focus on the opposite directions from gene to organ levels. A DNA repair protein tied to breast cancer, BRCA1, could be depleted by the pathological accumulation of Aβ (Suberbielle et al. 2015). Pin 1, an intracellular signaling molecule, could facilitate the tangle and plaque pathologies when deleted and promotes oncogenesis when overexpressed (Driver et al. 2015; Lu 2010). The revelation of some common microRNAs (miRNAs) acting in both cancer and AD, including the miR-9 family, the miR-29 family, and the miR-34 family, indicates that common miRNA pathways regulating differentiation, proliferation, and the death of cells may be another link between cancer and AD (Saito and Saito 2012).

Aβ is the most important pathogenic factor in AD. Aβ could induce apoptosis, which would accelerate AD but fight against cancer (Thinnes 2012a). However, in another study, Aβ was reported to accelerate the development of tumors potentially due to its pro-inflammatory effect (Serrano et al. 2010). Epidemiological studies have shown that several types of cancer, such as lung cancer, esophagus cancer, colorectal cancer, and liver cancer, are associated with reduced risk of AD. Taken together, we speculated that cancer might protect people against AD via decreasing Aβ levels. However, contrary to our speculation, Aβ levels were found to increase in cancer patients, especially in hepatic cancer patients. It is possible that the proliferation of the cancer cells is useless for Aβ metabolism; our results seem to support the latter hypothesis. Previous studies indicate that liver plays an important role in peripheral Aβ excretion and catabolism (Ghiso et al. 2004; Tamaki et al. 2006; Hone et al. 2003; Xiang et al. 2015). Liver cancer is the late stage of liver lesion formation and is always accompanied with liver function damage. The elevated plasma Aβ levels in hepatic cancer patients might be due to the impairment of Aβ clearance ability in the liver.

Aβ is mainly produced and deposited in the center nervous system (Hardy and Selkoe 2002). Chemotherapy may damage the permeability of the blood–brain barrier (BBB) and increase the efflux of Aβ from the brain (Thinnes 2012b). Therefore, we tried to investigate the effect of chemotherapy on plasma Aβ levels. However, no significant difference in Aβ levels between chemotherapy and no chemotherapy subgroups was found. Inflammation plays an important role in both AD and cancer pathogenesis, and the relationship between inflammatory cytokines and Aβ levels are frequently concerned (Rubio-Perez and Morillas-Ruiz 2012; Dursun et al. 2015; Belkhelfa et al. 2014; Murgas et al. 2012). No significant correlations of Aβ levels with inflammatory cytokines were detected, although plasma IFN-γ level was significantly elevated in hepatic cancer patients. These results indicate that the elevation of Aβ levels in cancer patients is independent of chemotherapy and inflammation.

There are two major limitations in our study. First, as we could not collect CSF from our cohort, we tried to use plasma Aβ to reflect the AD pathogenesis. But it was suggested that plasma Aβ might reflect peripheral Aβ production more than they reflect AD brain pathology (Olsson et al. 2016). Consistently, plasma Aβ40/42 ratio did not differ between AD and NC (2.03 ± 2.26 vs. 2.28 ± 1.73, p = 0.4411) in our study cohort, suggesting that plasma Aβ would not be an ideal biomarker for AD. Second, only four types of cancer were selected for our research. Additional types of cancer are required to validate the results.

In conclusion, plasma Aβ levels increased in cancer patients, particularly in patients with hepatic cancer. The impairment of Aβ clearance ability in the liver may be responsible for the elevated plasma Aβ levels. However, it is still unknown about the impact of cancer on central Aβ. Opposite results of plasma Aβ levels in cancer patients also imply that reduction of plasma Aβ may not be sufficient for AD therapy. A recent study about the anti-cancer drug PD-1 immune checkpoint blockade suggested that the immunological response induced by PD-1 immune checkpoint blockade could accelerate clearance of cerebral Aβ plaques and improve cognitive performance in an AD mouse model (Baruch et al. 2016). The immune activation of macrophages by anti-cancer drugs is practical for the clearance of central Aβ, which needs further confirmation in clinical studies. Further verification of the association between AD and cancer is also needed in the future.