Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer's disease
Abstract
Background Many factors could be responsible for the different response to treatment with the cholinesterase inhibitors (ChEIs) donepezil and rivastigmine in Alzheimer's disease (AD) patients. Sex and the variants of the estrogen receptor α (ESR1) gene are reported to modulate AD susceptibility or the course of the disease. The aim of the present study was to verify whether patient's sex and ESR1 genotype could influence the response to ChEI treatment, as there is evidence that estrogens affect cholinergic system functioning. Methods Two ESR1 intronic polymorphisms (PvuII, rs2234693; XbaI, rs9340799) were examined in 184 AD patients: 157 were receiving treatment with donepezil or rivastigmine and 27 were receiving no treatment. Cognitive status was assessed using the mini mental state examination at four time points (1, 3, 9, and 15 months into therapy). Results Among the patients under treatment with either ChEI, the women responded more markedly than the men. As compared with the untreated patients, the effects of treatment were statistically significant for both donepezil and rivastigmine. A significant effect of ESR1 genotypes was observed for the donepezil-treated patients, among which those carrying at least one copy of P and X alleles showed a significantly lower cognitive decline than the noncarriers. Conclusions The present data seem to confirm a sex-related influence on treatment, as the women seemed to be more sensitive to therapy and to have experienced less cogni…
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Previously, drug responses for donepezil were shown to be modulated by the sex hormone estrogen receptor alpha (ESR1) genotype.
“Previously, drug responses for donepezil were shown to be modulated by the sex hormone estrogen receptor alpha (ESR1) genotype [64].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [64]
Cites
The cholinergic hypothesis of Alzheimer’s disease: A review of progress
Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.66.2.137 · Cited by 2,198 · cited 1× · see citing works
“Because a cholinergic deficit is an early and consistent feature of AD, cholinesterase inhibitors (ChEIs) are currently used in symptomatic treatment of the disease (Giacobini, 1994; Francis et al., 1999).”
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Sex differences in Alzheimer's disease and other dementias
Mazure, C. M., & Swendsen, J. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00067-3 · Cited by 350 · see citing works
Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders
Pinares-Garcia, P., Stratikopoulos, M., Zagato, A., Loke, H., & Lee, J. (2018) · Brain Sciences · doi:10.3390/brainsci8080154 · Cited by 200 · see citing works
Reimagining cholinergic therapy for Alzheimer’s disease
Giacobini, E., Cuello, A. C., & Fisher, A. (2022) · Brain · doi:10.1093/brain/awac096 · Cited by 187 · see citing works
Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine
Eid, A., Mhatre, I., & Richardson, J. R. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.03.005 · Cited by 164 · see citing works
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Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease
Ray, B., Maloney, B., Sambamurti, K., Karnati, H. K., Nelson, P. T., Greig, N. H., & Lahiri, D. K. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0709-x · Cited by 91 · see citing works
Sex-specific DNA methylation differences in Alzheimer’s disease pathology
Zhang, L., Young, J. I., Gomez, L., Silva, T. C., Schmidt, M. A., Cai, J., Chen, X., Martin, E. R., & Wang, L. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01177-8 · Cited by 58 · see citing works
“Previously, drug responses for donepezil were shown to be modulated by the sex hormone estrogen receptor alpha (ESR1) genotype [64].”
BackgroundCommon variants of human TERT and TERC genes and susceptibility to sporadic Alzheimers disease
Scarabino, D., Broggio, E., Gambina, G., Pelliccia, F., & Corbo, R. M. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2016.12.017 · Cited by 36 · see citing works
Self-citation
- Authors
- Scacchi, R., Gambina, G., Broggio, E., & Corbo, R. M.
- Affiliations
- Institute of Molecular Biology and Pathology (IT)
- University of Verona (IT)
- Corresponding author
- Scacchi, Renato
- Venue
- International Journal of Geriatric Psychiatry
- Publisher
- Wiley
- Published
- 2013-10-22
- Volume
- 29
- Issue
- 6
- Pages
- 610-615
- ISSN
- 0885-6230 (ISSN-L)
- 1099-1166
- OpenAlex
- W1949622308
- Cited by
- 58
- References
- 1
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 1
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Geriatric Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, donepezil, rivastigmine, cholinesterase inhibitors, estrogen receptor alpha, ESR1 polymorphisms, sex differences, treatment response, cognitive decline, genetic susceptibility, interindividual variability
- MeSH terms
- Rivastigmine, Donepezil, Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Cholinesterase Inhibitors, Female, Gene Frequency, Genotype, Humans, Indans, Male, Middle Aged, Brief Psychiatric Rating Scale, Piperidines, Sex Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Estrogen Receptor alpha, Phenylcarbamates
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