The Greater Sensitivity of Elderly APOE ε4 Carriers to Anticholinergic Medications is Independent of Cerebrovascular Disease Risk

Abstract

Background Recent studies found use of anticholinergic medications to be associated with greater performance decrements in older persons who carry an ε4 allele of the apolipoprotein E (APOE) gene than in those carrying only ε2 or ε3 alleles. Objectives The present study examined whether the apparently greater behavioral toxicity of anticholinergic drugs in ε4 carriers may result from an increased risk of cerebrovascular disease, which is more common in ε4 carriers. Methods Cross-sectional data were available from 240 normal elderly [pe1]community volunteers who had participated in 2 different studies of the cognitive and motor effects of normal aging. As part of these studies, information was gathered on subjects' use of anticholinergic medications (based on an inventory of medications taken within 24 hours of testing), risk of cerebrovascular disease (Framingham Stroke Risk Profile), and APOE genotype. Performance data were also available from measures of general cognitive status (Mini-Mental State Examination), executive function (Trail Making Test), mood (Geriatric Depression Scale), sleep (Pittsburgh Sleep Quality Index), and walking speed. Logistic and linear regression models were used to examine how outcomes differed between genotypes and drug use, independent of the risk of cerebrovascular disease. Results In persons with a non-ε4 genotype, anticholinergic medication use did not significantly affect any of the behavioral measures. By contrast, among ε4 carriers, those taking anticholinergic drugs performed significantly worse than did those not taking such drugs on tests of general cognitive status, executive function, mood, and sleep. Adjusting for participants' stroke risk had a minimal effect on these results. Conclusions Anticholinergic medication use was associated with poorer performance on measures of cognition, sleep, and mood only in older persons who carried 1 or more ε4 alleles of the APOE gene; this effect did not appear to be the result of an increased risk of cerebrovascular disease.

Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep

“…However the precise relationship between APOE genotype, sleep, and AD is unclear. Several studies suggest that the ε4 allele may potentiate sleep disturbance 11–13,15,36 . Others suggest that sleep disruption and APOE genotype may interact to worsen cognitive function 13,16,17 .…”

Sex and ApoE Genotype Differences in Treatment Response to Two Doses of Intranasal Insulin in Adults with Mild Cognitive Impairment or Alzheimer's Disease

“…There is growing evidence that ApoE ε4 carriers are different than non-carriers in how they respond to treatments such as exercise [40], insulin-sensitizing drugs [41], and many other health-related interventions [42]. However, many studies examining the ApoE ε4 gene do not examine sex as a potential modifier, but instead sex is only utilized as a control variable.…”

Association of Brain Amyloid-β With Slow Gait in Elderly Individuals Without Dementia

“…We included an interaction term in the models to examine whether the association between PiB SUVR and gait speed was different in APOE ε4 carriers and non-carriers, based on our observations in other setting. 36 However, recognizing that interaction terms have low statistical power, we a priori planned an exploratory analysis stratified by APOE ε4 carrier status. Finally, we performed an another exploratory analysis of regional association between PiB SUVR and gait speed initially adjusting for all covariates including cognition and then with further adjusting for APOE ε4 status.…”