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Background Apolipoprotein E epsilon 4 ( APOE -ε4) carrier status is an established risk factor for Alzheimer’s disease (AD) dementia. It has also been linked with sleep disturbance in healthy older adults and increased insomnia risk. This association may be driven by the effect of  APOE -ε4 on AD pathological change, itself associated with sleep abnormalities. To assess this relationship, we have evaluated post-mortem neuropathological findings in patients with and without cognitive impairment and AD pathology, who had extensive clinical assessment within 12 months of death. Methods This retrospective cohort study used UK Brain Banks Network data. Eligible subjects were aged over 50, with pre-mortem neuropsychiatry inventory scores of sleep disturbance (NPI-K), neurocognitive testing and functional cognitive status assessment (Clinical Dementia Rating scale). Neuropathological data included Thal phase, Braak stage and CERAD scores (measures of Aβ plaque distribution, tangle distribution and neuritic plaque density, respectively) combined to form the National Institute on Aging Alzheimer’s Association (NIA-AA) ABC score reflecting AD neuropathology. Participants with other significant intracerebral pathology or pathological features of non-AD dementia were excluded. Multivariate linear regression was performed with NPIK Global Score (NPIK frequency score multiplied by severity score) as the dependent variable and  APOE -ε4 heterozygosity or homozygosity as independent variables. Covariates included age, gender,  APOE -ε2 status and ABC NPI measures reflecting depression and anxiety. Further models stratified by ABC score and functional cognitive status were also produced. Results Seven hundred twenty-eight records were identified. Two hundred two participants were included in the final analysis: mean (SD) age 84.0 (9.2) and MMSE 14.0 (11.8). Mean sleep disturbance scores were highest in ε4 homozygosity ( n =11), 4.55 (5.4); intermediate in ε4 heterozygosity ( n =95), 2.03 (4.0); and lowest in non-ε4 carriers ( n =96), 1.36 (3.3). Within the full sample, controlling for pathological status, age, gender, depression, anxiety and CDR-SOB status,  APOE -ε4 homozygosity was associated with sleep disturbance ( β  2.53,  p =0.034).  APOE- ε4 heterozygosity was similarly associated in individuals without dementia ( β  1.21,  p =0.048). Conclusion These findings lend weight to the hypothesis that  APOE -ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets.

APOE ε4, Alzheimer’s disease neuropathology and sleep disturbance, in individuals with and without dementia