Abstract Introduction: Recent meta-analyses and epidemiological evidence have reported an inverse association between developments of ADRD and Cancer. This study provided biological mechanisms to the hypothesis that ADRD occurs less frequently in older adults previously diagnosed with cancer than those who remain free of cancer diagnosis. Considering these assumptions, here we report the biological mechanisms where the expression of Alzheimer genes APOEε4 and APOEε3 genes, or gene products ApoE4 and ApoE3 protein treatment in glioblastoma and Neuroblastoma cancer cells resulted in suppression of cancer proliferation and metastasis. Materials and Methods: RT-PCR and Western blotting techniques were used to analyze the genes and proteins involved in cancer proliferation and metastasis in the brain tissues from glioblastoma and Alzheimer patients compared with Age Matched Controls. Stable transformants of human neuroblastoma (SY5Y) and glioblastoma cells (T98G) expressing APOEε3 and APOEε4 were used to analyze the expression levels of genes and proteins that facilitates cancer metastasis and Autophagy. Results: Gene and protein levels of MyD88, NFκB, IL6 and IL-8 were highly expressed in both Alzheimer’s and Cancer patients. Calcineurin which is an important phosphatase that promotes cancer cell cycle progression by stabilizing proliferation-driving proteins like CyclinD1 and Estrogen receptor α (ER- α) and mTORC1 which are important for autophagy mechanisms. In contrast, the lower expression of phosphatases is the characteristic feature of Alzheimer’s and Parkinson's diseases which is evidenced by the accumulation of hyper phosphorylated Tau For the formation of Neurofibrillary Tangles in Alzheimer’s and hyper phosphorylated α-synuclein for the Lewy bodies Parkinson's disease. MyD88, NFκB, Calcineurin, IL-6 and IL-8 are significantly elevated in cancer conditions. In vitro studies using Glioblastoma and Neuroblastoma cancerous cells treated with ApoE4 and ApoE3 resulted in the suppression of MyD88, NFκB, Calcineurin, IL6 and IL-8 gene and protein levels that are involved in maintenance of the proliferation and metastatic properties in cancers clearly indicating the anti-cancer properties of Alzheimer gene products. Whereas ApoE2 protein treatment didn’t change these properties. Autophagy is a cellular process that clears cells of metabolic waste thus favoring cancer proliferation and metastasis. Autophagy modifies the tumor microenvironment along with promotion of angiogenesis. Treatment with ApoE4, ApoE3 protein in Glioblastoma and Neuroblastoma cells resulted in the decreased expression of autophagy gens and proteins after 48h treatment. ApoE4, ApoE3 treatments also increased the expression of early and late apoptotic markers like BCL-2 and caspases. Whereas the treatment with ApoE2 protein resulted in the suppression of apoptotic markers thus by increasing autophagy facilitating cancer cell proliferation and metastasis. These results were supported by the increase in neurotoxin markers after treating with ApoE4 and ApoE3 proteins in the cultured cancer cells. Conclusions: These findings refer to a potential neuro-protective effect of biological processes implicated in cancer, or an abrupt neuro-protective effect of cancer chemotherapies as plausible drivers for the observed associations. Citation Format: Jagadeesh Narasimhappagari, Meenakshisundaram Balasubramaniam, Srinivas Ayyadevara, W Sue T Griffin. Inverse relationship between cancer and Alzheimer’s disease: Important interplay between autophagy and apoptosis signaling mechanisms abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB320.
Narasimhappagari et al. (Fri,) studied this question.