A growing body of epidemiological evidence points to an inverse relationship between cancer and Alzheimer’s disease (AD): individuals with a cancer diagnosis appear to have a lower subsequent risk of developing AD, and patients with AD seem less likely to develop cancer. This pattern is observed across diverse populations and persists for several cancer types, most strikingly for hormone-dependent cancers such as breast, prostate, endometrial, ovarian, and thyroid cancer. Yet the biological basis of this paradox remains incompletely understood.

Several non-mutually exclusive explanations have been proposed, including survival bias and competing risks, shared but oppositely regulated molecular pathways (cell-cycle control, apoptosis, DNA repair, mitochondrial bioenergetics, autophagy, oxidative stress, proteostasis), and antagonistic pleiotropy in genes such as TP53, PIN1, WNT, PTEN, and APOE. A particularly underexplored axis is the endocrine dimension: sex steroids, growth-factor signaling, the HPA axis, thyroid hormones, and adipokines exert powerful effects on both tumor biology and brain aging, and the long-term endocrine consequences of cancer therapies (tamoxifen, aromatase inhibitors, GnRH agonists, androgen-deprivation therapy) may reshape AD risk decades after treatment.

Disentangling these explanations requires the integration of molecular and endocrine biology with epidemiology across the life course. Hormone-driven cancers and AD share several signaling nodes, including estrogen-receptor activity in the brain, IGF-1 / insulin pathway regulation, HPA-axis activity and glucocorticoid signaling, and thyroid hormone action, that can plausibly produce opposite effects in proliferating tumors and in post-mitotic neurons. Endocrine therapies represent long, well-documented exposures that lend themselves to pharmacoepidemiological and Mendelian-randomization approaches, while life-course data link early hormonal exposures, reproductive history, menopause timing, obesity, and metabolic health to both cancer and dementia risk decades later. A clearer mechanistic and epidemiological understanding could open opportunities for repurposing endocrine and oncology drugs for neurodegenerative prevention and for identifying shared biomarkers and therapeutic targets at the cancer–brain interface.

This Research Topic aims to provide a timely and integrative overview of the cancer–AD inverse association, with a particular focus on endocrine mechanisms and life-course epidemiology. We bring together original research, reviews, and perspectives that connect epidemiological evidence with molecular, hormonal, and pharmacological insights, and that test or critically appraise emerging theories underpinning this paradox.

We welcome original research, reviews, mini-reviews, systematic reviews, and perspectives addressing, but not limited to:

• Epidemiological evidence of inverse comorbidity between cancer (overall and by hormone-dependent site) and AD or related dementias

• Life-course epidemiology of hormonal, reproductive, and metabolic exposures (menarche, parity, menopause timing, hormonal contraception, obesity, metabolic syndrome) in relation to joint cancer and dementia risk

• Methodological approaches to address survival bias, competing risks, immortal-time bias, and confounding in cancer–AD studies, including Mendelian randomization and target-trial emulation

• Endocrine mechanisms shared by hormone-driven cancers and AD: estrogen-receptor signaling in the brain, androgen action, IGF-1 / insulin pathway, HPA-axis and glucocorticoid signaling, thyroid hormone action, adipokines and metabolic hormones

• Shared molecular pathways acting in opposite directions in cancer and AD (cell cycle, apoptosis, autophagy, mitochondrial bioenergetics, oxidative stress, DNA-damage response, proteostasis)

• Genetic and genomic evidence: pleiotropic loci, TP53, PIN1, WNT, PTEN, APOE, polygenic risk scores, hormone-pathway gene variants

• Long-term effects of endocrine and other cancer therapies (tamoxifen, aromatase inhibitors, SERMs, GnRH agonists, androgen-deprivation therapy, chemotherapy, radiotherapy, immunotherapy) on AD risk and brain aging

• Repurposing of endocrine and oncology drugs for neurodegenerative prevention or treatment

• Multi-omics integration (transcriptomics, proteomics, metabolomics, epigenomics) of shared and divergent cancer–AD signatures, with emphasis on endocrine and metabolic axes

• Sex differences, aging biology, immunosenescence, and inflammation as common ground between hormone-driven cancers and AD

• Shared biomarkers and biomarker-based stratification for joint cancer–dementia risk prediction across the life course

• Critical appraisals and new theoretical frameworks for the cancer–AD paradox, integrating endocrine and epidemiological perspectives

Are you interested in contributing a manuscript to this Research Topic?

Inverse Comorbidity of Cancer and Alzheimer’s Disease: A Molecular Epidemiological Perspective