Abstract
Background and Purpose- APOE-ε4 genotype is a risk factor for sporadic Alzheimer disease and reduced recovery from brain injury. Since data on APOE genotype and dementia associated with transient ischemic attack/stroke are sparse, we determined the associations in a longitudinal population-based cohort. Methods- All patients with transient ischemic attack or stroke (2002-2012) in a defined population of 92 728 OxVASC (Oxford Vascular Study) had follow-up to 5-years. Pre-event and incident postevent dementia were ascertained through direct patient assessment and follow-up, supplemented by review of hospital/primary care records. Associations between pre- and post-event dementia and APOE genotype (ε4/ε4-homozygous and ε4/ε3-heterozygous versus ε3/ε3) were examined using logistic regression and Cox regression models, respectively, adjusted for age, sex, education, cerebrovascular burden (stroke severity, prior stroke, white matter disease), diabetes mellitus, and dysphasia. Results- Among 1767 genotyped patients (mean/SD age, 73.0/13.0 years, 901 [51%] male, 602 [34%] transient ischemic attack), 1058 (59.9%) were APOE-ε3/ε3, 403 (22.8%) were ε4/ε3 and 30 (1.7%) were ε4-homozygous. Homozygosity was associated with both pre-event (adjusted odds ratio, 5.81 [95% CI, 1.93-17.48]; P=0.002) and postevent dementia (adjusted hazard ratio, 3.64 [95% CI, 1.90-7.00]; P<0.0001). Association with postevent dementia was maintained after further adjustment for baseline cognitive impairment (hazard ratio, 2.41 [95% CI, 1.19-4.89]; P=0.01). There were no associations overall between ε4/ε3 and pre-event dementia (adjusted odds ratio, 1.47 [95% CI, 0.88-2.45]; P=0.14) or postevent dementia (hazard ratio, 1.11 [95% CI, 0.84-1.48]; P=0.47). Conclusions- In patients with transient ischemic attack and stroke, APOE-ε4 homozygosity was associated with both pre- and post-event dementia. Associations were independent of cerebrovascular burden and may be mediated through increased neurodegenerative pathology or vulnerability to injury.
Highlights
Background and PurposeAPOE-ε4 genotype is a risk factor for sporadic Alzheimer disease and reduced recovery from brain injury
APOE is a lipoprotein produced in several organs including the brain with 3 major isoforms (APOE 2, 3, and 4) encoded by 3 different alleles located on chromosome 19: APOE-ε4, APOE-ε3, and APOE-ε2.1,2 Allelic frequencies in whites are 15% for APOE-ε4 and 8% for APOE-ε2 with the remainder being APOE-ε3.1,3 The 3 isoforms differ by single amino acid residues resulting in structural and functional differences.[1]
The APOE4 isoform has neuropathological effects on neurons, the blood-brain barrier, and blood vessels resulting in various clinical manifestations including worse outcomes after brain injury.[2,4,5,6,7]
Summary
All patients with transient ischemic attack or stroke (2002–2012) in a defined population of 92 728 OxVASC (Oxford Vascular Study) had follow-up to 5-years. Pre-event and incident postevent dementia were ascertained through direct patient assessment and follow-up, supplemented by review of hospital/primary care records. Ascertainment of all TIA and ischemic or hemorrhagic stroke events, including in those with early deaths and TIA/stroke occurring in nonhospitalized/nonreferred patients, was achieved by multiple methods and has been shown to be near-complete,[31] and to minimize selection biases in determining dementia risk.[25] Informed consent (or assent from relatives) was obtained for study interview and follow-up, including ongoing review of all primary care/hospital records and death certificates. Patients who were moribund/unlikely to survive were considered not eligible for genotyping
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