Cancer–Alzheimer inverse comorbidity from epidemiology to protein self-assembly
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, Stanford University
- 2Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio
Abstract
Cancer and Alzheimer’s disease (AD) are common age-associated disorders characterized by contrasting cellular outcomes, yet epidemiological studies repeatedly report an apparent, modest bidirectional inverse association between cancer and dementia, including AD. This Mini Review examines the extent to which this pattern reflects biological antagonism versus competing mortality, diagnostic bias, survivor selection, and treatment exposure. Breast and prostate cancers are considered as endocrine models because estrogen- and androgen-receptor signaling supports tumor growth while also regulating neuronal metabolism, mitochondrial function, vascular homeostasis, and inflammation. Population studies show heterogeneous neurological associations for breast cancer hormone-modulating therapy and prostate cancer androgen-deprivation therapy, emphasizing the need to distinguish tumor biology from systemic endocrine treatment. Mechanistically, cancer and AD engage overlapping metabolic pathways, including insulin/IGF–PI3K–AKT, mTOR, and AMPK; cell-fate programs involving cell-cycle control and senescence; and proteostatic systems involving molecular chaperones and autophagy–lysosomal function. These networks produce divergent outcomes: proliferative and proteotoxic adaptation in tumors versus energetic failure, impaired proteostasis, and neuronal degeneration in AD. Protein self-assembly provides an additional, context-dependent connection: amyloidogenic proteins can modify cancer-cell fitness, while recent preclinical evidence identifies a tumor-derived cystatin C–TREM2 pathway that enhances cerebral Aβ clearance. Whether these mechanisms contribute to human cancer–AD inverse comorbidity remains unproven. The observed cancer–AD inverse comorbidity therefore likely reflects interacting epidemiological, endocrine, metabolic, proteostatic, and protein-assembly mechanisms rather than a single causal pathway. Treatment-aware longitudinal studies incorporating AD biomarkers and physiologically relevant models are needed to distinguish genuine biological antagonism from observational bias.
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BibTeX
@article{zhang2026canceralzheimer,
title = {{Cancer–Alzheimer inverse comorbidity from epidemiology to protein self-assembly}},
author = {Yanxian Zhang and Lijin Wang and Jialun Wei and Nazmul Shuzan and Jie Zheng},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1992522},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1992522/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cancer–Alzheimer inverse comorbidity from epidemiology to protein self-assembly
AU - Yanxian Zhang
AU - Lijin Wang
AU - Jialun Wei
AU - Nazmul Shuzan
AU - Jie Zheng
PY - 2026
DA - 2026/10/19
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1992522
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1992522/full
AB - Cancer and Alzheimer’s disease (AD) are common age-associated disorders characterized by contrasting cellular outcomes, yet epidemiological studies repeatedly report an apparent, modest bidirectional inverse association between cancer and dementia, including AD. This Mini Review examines the extent to which this pattern reflects biological antagonism versus competing mortality, diagnostic bias, survivor selection, and treatment exposure. Breast and prostate cancers are considered as endocrine models because estrogen- and androgen-receptor signaling supports tumor growth while also regulating neuronal metabolism, mitochondrial function, vascular homeostasis, and inflammation. Population studies show heterogeneous neurological associations for breast cancer hormone-modulating therapy and prostate cancer androgen-deprivation therapy, emphasizing the need to distinguish tumor biology from systemic endocrine treatment. Mechanistically, cancer and AD engage overlapping metabolic pathways, including insulin/IGF–PI3K–AKT, mTOR, and AMPK; cell-fate programs involving cell-cycle control and senescence; and proteostatic systems involving molecular chaperones and autophagy–lysosomal function. These networks produce divergent outcomes: proliferative and proteotoxic adaptation in tumors versus energetic failure, impaired proteostasis, and neuronal degeneration in AD. Protein self-assembly provides an additional, context-dependent connection: amyloidogenic proteins can modify cancer-cell fitness, while recent preclinical evidence identifies a tumor-derived cystatin C–TREM2 pathway that enhances cerebral Aβ clearance. Whether these mechanisms contribute to human cancer–AD inverse comorbidity remains unproven. The observed cancer–AD inverse comorbidity therefore likely reflects interacting epidemiological, endocrine, metabolic, proteostatic, and protein-assembly mechanisms rather than a single causal pathway. Treatment-aware longitudinal studies incorporating AD biomarkers and physiologically relevant models are needed to distinguish genuine biological antagonism from observational bias.
SN - 1664-2392
ER -