Background:
While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting
enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing
brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis
and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s
disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764
and rs4291 are associated with cognitive and functional change in patients with AD, while also taking
APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification.
Methods:
Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers
were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were
estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with
ACEis.
Results:
For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes)
and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of
all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used
ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either
for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of
rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations.
APOE4+ carriers were not responsive to treatment with ACEis.
Conclusion:
ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4-
carriers of specific ACE genotypes.
Potential cost savings to be made by slowing cognitive decline in mild Alzheimer’s disease dementia using a model derived from the UK GERAS observational study