P4‐675: Cholinesterase Inhibitors Have a Disease Modifying Effect in Ad Relative to Chrfam7a Genotype, Suggesting an A7nachr Dependent Mechanism
Year: 2019
Type: article
Abstract: Cholinergic neuronal loss is the hallmark of AD related neurodegeneration and three of the four FDA approved drugs increase cholinergic tone. a7NAChR is hypothesized to account for this selective neuronal vulnerability. Preclinical promise of a7NAChR agonists failed to translate into humans. GWAS studies reported an association between CHRFAM7A, a human specific fusion gene, and AD. We hypothesized that incorporation of CHRFAM7A into the a7NAChR pentamer accounts for the translational gap in a7NAChR targeting, and more broadly for cholinergic therapies. Exposure to ChEI is used as a proof of principal study. In this paradigm the effect of non-selective agonists (ChEI) of the a7NAChR is measured in the context of a7NAChR specific readout (CHRFAM7A genotype). Double blind pharmacogenetic study. The Texas Alzheimer Research and Care Consortium (TARCC) was a longitudinal multicenter cohort study of Probable AD diagnosed by NINCDS-ADRDA criteria. The cohort underwent yearly cognitive assessments (MMSE, primary outcome measure) and AD drug exposure is ascertained. Inclusion criteria for this sub-study were mild-moderate AD (MMSE 10-26), at least 2 assessments 1 year apart, and absence of other brain or systemic disease that could account for the cognitive impairment. CHRFAM7A genotyping was performed by TaqMan assay for copy number and by capillary sequencing for the 2bp deletion to decipher orientation. We performed a general linear model using age, sex, APOE4, CHRFAM7A (carrier/non-carrier), drug at baseline visit (ChEI or ChEI+memantine) and interaction terms APOE*visit, CHRFAM7A*visit and visit*drug. 261 CHRFAM7A carriers (harbors direct orientation functional gene; 75.5%) and 85 non-carriers (24.5%) met inclusion criteria. Baseline MMSE was similar (20.95+/−3.98 and 21.78+/-3.92). CHRFAM7A non-carriers had a benefit from ChEI over the 7-year observation period (p=0.0048) irrespective of monotherapy or combination with memanatine. APOE4 had no effect.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980718094