Cancer linked to Alzheimer disease but not vascular dementia

We thank Drs Kinnunen, Tavares et al., and Burke for their interest in our report [1] of an inverse association between AD and cancer. We are also intrigued by the hypotheses involving host defense peptides [5] and the mitogenic properties of acetylcholine [6] to explain this association.

We did not request data about cholinesterase inhibitor drug use among Cardiovascular Health Study participants. Therefore, we are unable to address the proposal by Tevares et al. that exposure to these drugs in AD patients could influence cancer occurrence.

We agree with Dr. Burke that specific cancer subtypes may be increased in AD as suggested by similar studies in PD [2]. In Dr. Burke's epidemiologic necropsy study [9], they eliminated those with a cancer diagnoses during life from their sample, which may have led to selection bias for asymptomatic or mildly symptomatic cancers.

Our incident cancer cases were severe enough during life to require inpatient hospitalization, which also has limitations [1]. If the underlying biological prevalence of cancer is similar for those with and without AD, but cancer is underdiagnosed during life among individuals with AD, then exclusion of cancer cases diagnosed during life should result in a higher prevalence of undiagnosed cancer among autopsied AD cases. Therefore, it is puzzling that Dr. Burke et al. [9] found a higher prevalence for pancreatic cancer and not for other cancer subtypes.

The findings of Dr. Burke et al. are not supported by other autopsy series examining the association of cancer and AD [11,12]. Although the presence of dementia may result in cancer being underdiagnosed among individuals with AD, there was no relationship of cancer incidence for individuals with vascular dementia who would be underdiagnosed for cancer for the same reason. This suggests that the association of AD and cancer relates to mechanisms involved in neurodegeneration rather than to underdiagnosis due to presence of dementia.

Further investigation is needed before concluding that there is a clear association between cancer and AD, but we are gratified that others are interested in this possibility.

Disclosures: See original article for full disclosure list.

Roe et al. further confirm the negative correlations between the incidences of cancer and Alzheimer— but not vascular—dementia. [1] Parkinson disease (PD) also seems to 'protect' patients from some cancers. [2] Roe et al. and editorialists Bennett and Leuergans [3] discuss possible links in the signalling systems involved in these pathologies. While specific oncogenes are vital to this issue, other possibilities should be considered.

First, there is consensus that host defense peptides (HDP)— including antimicrobial peptides—eradicate cancer cells, targeting negatively charged phospholipids on the outer surface of bacteria and tumor cells. [4,5] Recent evidence suggests that HDP also targets oxidized lipids. [5]

Second, cancer and several neurodegenerative diseases are associated with increased oxidative stress, the latter causing the formation of oxidatively-modified lipids on the outer membrane surface of the affected cells. This results in neural cells becoming vulnerable to cytotoxicity by amyloid forming peptides such as Abeta peptide in Alzheimer disease (AD).

Third, the cytotoxic peptides involved in neurodegenerative diseases such as AD and PD seem to share the same mechanism of toxicity with HDP: membrane permeabilization caused by lipid-induced peptide oligomers. [5]

Augmented cell death due to oxidative stress in some neurodegenerative diseases and cancer caused by cytotoxic amyloid forming peptides and HDP (5) complies with the apparent protective effect of AD and PD from cancer. (1,2) In addition, these mechanisms would also promote cancer by antioxidants, suppressing apoptosis as we recently discussed in a review on membrane induced amyloid formation. [5]

References

1. Roe, CM, Fitzpatrick AL, Xiong C, et al. Cancer linked to Alzheimer's disease but not to vascular dementia. Neurology 2010; 74: 106-112.

2. Inzelberg R, Jankovic A. Are Parkinson disease patients protected from some but not all cancers? Neurology 2007;69:1542-1550.

3. Bennett DA, Leuergans S. Is there a link between cancer and Alzheimer disease? Neurology 2010;74:100-101.

4. Hoskin DW, Ramamoorthy A. Studies on anticancer activities of antimicrobial peptides. Biochim Biophys Acta 2008;1778: 357-375.

5. Kinnunen, PKJ. Amyloid formation on lipid membrane surfaces. The Open Biology Journal 2009;2:163-175.

Disclosure: Dr. Kinnunen is a shareholder in Kibron Inc. and serves as the Chairman of its Board of Directors. Dr. Kinnunen receives research funding from The Academy of Finland and Sigrid Juselius Foundation as well as European Union Framework 6 and 7 projects Nanoear and Sonodrugs, respectively.

Roe et al. elegantly describe a longitudinal association between AD and a reduced risk for cancer and the inverse association between a history of cancer and a reduced risk of AD. [1]

Since acetylcholine (ACh) is considered a mitogen, these associations may imply that the degeneration of ACh-secreting cells plays a protective role on cancer onset as this neurotransmitter would be less available to stimulate cell proliferation. Alternatively, normal cells and various tumors are known to secrete ACh to promote proliferation and survival. [6] Excessive activation of ACh Receptors (AChR), which leads to carcinogenesis, was recently detected in various types of cancer.

For example, major expression of alpha7nAChRs is related to the activation of the Rb–Raf-1/phospho-ERK/phospho-p90RSK pathway, playing an important role in lung cancer growth and tumor progression. [7] Furthermore, downregulation of nicotinic AChRs is associated with enhancement of anti-proliferative effects of drugs. [8] Roe et al.'s findings may be partially explained by hyper- and hypocholinergic tones simultaneously affecting AChRs on the brain and cancer target tissues. [1]

Compared to AD, cholinergic deficit is less intense in vascular dementia. In other dementias with severe cholinergic deficiency, such as Lewy body dementia, a similar mechanism is possible and a reduced risk for cancer would be expected.

We would like to know about treatments with cholinesterase inhibitors in the AD patients included in Roe et al.'s study. A hallmark of the current concept of AD, cholinergic deficiency, is also the basis for its symptomatic treatment, in which the enzyme responsible for ACh degradation, acetylcholinesterase, is inhibited by drugs, such as donepezil, rivastigmine, and galantamine. Amply used in AD, these drugs extend the duration of ACh activity because its degradation is decreased.

There are no data to determine if extended exposure to ACh could affect cancer incidence among cholinesterase-inhibitor treated AD patients compared to non-treated AD patients. We recommend that cholinesterase inhibitors are used with caution in patients where there is an increased risk for carcinogenesis associated with nAChR hyperactivation until further investigations are completed.

References

6. Schuller HM. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nat Rev Cancer 2009;9:195-205.

7. Paleari L, Catassi A, Ciarlo M, Cavalieri Z, Bruzzo C, Servent D, Cesario A, Chessa L, Cilli M, Piccardi F, Granone P, Russo P. Role of alpha7-nicotinic acetylcholine receptor in human non-small cell lung cancer proliferation. Cell Prolif 2008;41:936-959.

8. Shih YL, Liu HC, Chen CS, et al. Combination Treatment with Luteolin and Quercetin Enhances Antiproliferative Effects in Nicotine-Treated MDA-MB- 231 Cells by Down-regulating Nicotinic Acetylcholine Receptors. J Agric Food Chem 2010;58:235-241.

Disclosure: Dr. Tavares serves as a member of the editorial board of the Revista de Psiquiatria Clínica, São Paulo; receives royalties from the publication of the book "Compêndio de Neuropsiquiatria Geriátrica", Editora Guanabara Koogan, Rio de Janeiro; and received funding for a trip from Novartis. Drs. de Melo and Sternberg report no disclosures.

Regarding the occurrence of cancer in AD [1], we examined all histopathology reports of complete autopsies of patients 50-100 years old at Saint Louis University Group Hospitals from 1983-1988 for diagnoses of AD and cancer. [9]

Control patients had no histopathological evidence of AD. Of the 900 patient reports reviewed, 19.7% of AD and 29.3% of non-AD controls had a pre-mortem diagnosis of cancer. These cases were eliminated from the complete analysis to control for clinical selection bias that results when previously diagnosed cases are included [10], leaving 71 AD and 575 control cases for further analysis.

Sixteen organs were examined for evidence of cancer. We found no statistical difference in total, lung, or prostate cancer between AD and control patients. There was a 6.7-fold increased prevalence of pancreatic cancer in AD patients compared to controls. Controlling for multiple comparisons using Bonferroni's correction, the odds ratio for pancreatic cancer was significantly (p<0.001) different between AD patients and controls.

We conclude that some of the apparent pre-mortem reduced risk of cancer in AD [1] is due to the difficulty in making a diagnosis of cancer in AD patients versus controls. Specific cancer subtypes may be increased in AD.

References

9. Burke WJ, McLaughlin JR, Chung HD, et al. Occurrence of cancer in Alzheimer and elderly control patients: an epidemiologic necropsy study. Alzheimer Disease and Related Disorders 1994; 8:22-28.

10. McFarlane MJ, Feinstein AR, Wells CK, Chan CK. The epidemiologic necropsy. JAMA 1987; 258:331-338.

Disclosure: The author reports no disclosures.