Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer’s disease.

Many factors could be responsible of the different response to treatment with cholinesterase inhibitors (ChEIs) donepezil and rivastigmine among late-onset sporadic Alzheimer’s disease (AD) patients. Sex and the variants of the estrogen receptor α (ESR1) gene are reported to modulate the susceptibility to AD or the course of the disease. Aim of the present study was to verify whether the two above factors could influence the response to ChEIs treatment, as there is evidence that estrogens affect cholinergic system functioning. Two ESR1 intronic polymorphisms (PvuII, or rs2234693; XbaI, or rs9340799) were examined in 184 AD patients. 157 were treated with donepezil or rivastigmine and were compared with no treated subjects. The cognitive status was quantified using the the Mini Mental State Examination. Females responded markedly to treatment with ChEIs, and the effects were statistically significant for donepezil and at borderline significance for rivastigmine. A significant effect of ESR1 genotypes was observed for treatment with donepezil, as treated patients carrying at least one copy of P and X alleles showed a significantly lower cognitive decline than non-carriers. Present data seem to confirm the role of sex in Alzheimer’s disease, as women seem to be more sensitive to treatment and found to have benefits with regard to cognitive decline. ESR1 may be another gene contributing to to inter-individual variability in response to ChEIs.