Association of cancer history with Alzheimer's disease onset and structural brain changes

Abstract

Epidemiological studies show a reciprocal inverse association between cancer and Alzheimer's disease (AD). The common mechanistic theory for this effect posits that cells have an innate tendency toward apoptotic or survival pathways, translating to increased risk for either neurodegeneration or cancer. However, it has been shown that cancer patients experience cognitive dysfunction pre- and post-treatment as well as alterations in cerebral gray matter density (GMD) on MRI. To further investigate these issues, we analyzed the association between cancer history (CA±) and age of AD onset, and the relationship between GMD and CA± status across diagnostic groups in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort study. Data was analyzed from 1609 participants with information on baseline cancer history and AD diagnosis, age of AD onset, and baseline MRI scans. Participants were CA+ (N = 503) and CA− (N = 1106) diagnosed with AD, mild cognitive impairment (MCI), significant memory concerns (SMC), and cognitively normal older adults. As in previous studies, CA+ was inversely associated with AD at baseline (P = 0.025); interestingly, this effect appears to be driven by non-melanoma skin cancer (NMSC), the largest cancer category in this study (P = 0.001). CA+ was also associated with later age of AD onset (P < 0.001), independent of apolipoprotein E (APOE) ε4 allele status, and individuals with two prior cancers had later mean age of AD onset than those with one or no prior cancer (P < 0.001), suggesting an additive effect. Voxel-based morphometric analysis of GMD showed CA+ had lower GMD in the right superior frontal gyrus compared to CA− across diagnostic groups (Pcrit < 0.001, uncorrected); this cluster of lower GMD appeared to be driven by history of invasive cancer types, rather than skin cancer. Thus, while cancer history is associated with a measurable delay in AD onset independent of APOE ε4, the underlying mechanism does not appear to be cancer-related preservation of GMD.

Mild Cognitive Impairment and Dementia Show Contrasting Associations with Risk of Cancer

“…We found that dementia is associated with a decreased risk of cancer, which is in line with findings from previous studies for various cancer types including breast, prostate, colon, and NMSC [1-8, 18]. Various biological mechanisms have been proposed, and the most frequently postulated mechanisms are to do with a genetic predisposition for either promoting or suppressing metabolic survival or apoptotic cellular pathways [10].…”

“…We argued that if the inverse link between dementia and cancer is rooted in biology, this decreased risk would be reflected in persons with MCI as well. One previous study looked into the history of cancer among persons with and without MCI and showed that 31% of the persons with MCI were previously diagnosed with cancer [8]. However, no longitudinal analysis was performed in this group of persons and the risk of cancer after MCI or dementia diagnosis was not investigated.…”

“…Interestingly, several studies have consistently shown an inverse link between the 2 diseases. Patients with dementia have a decreased risk of cancer [1-7], while persons with a history of cancer are affected less often from subsequent dementia [1, 2, 4, 5, 8]. …”

Association of cancer and Alzheimer's disease risk in a national cohort of veterans

“…7 An analysis in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), found a measurable delay in AD onset in cancer survivors that was independent of APOE4 status; individuals diagnosed with multiple cancers had an even longer delay. 15 …”

Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

“…Unfortunately, we could not obtain information on cancer history from each study in order to directly examine the impact of cancer survivorship on our estimation. However, a study based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, one of the studies included in the ADGC of IGAP, suggested that the proportion of subjects with a history of cancer incidence in the study was around 31% (sample size = 1609), and those with AD at baseline were less likely to be cancer survivors than participants with mild cognitive impairment, subjective memory complaints and normal cognition (Nudelman et al 2014). …”