Dataset Information

Impact of APOE ?4 genotype on initial cognitive symptoms differs for Alzheimer's and Lewy body neuropathology.

ABSTRACT:

Background

APOE ?4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ?4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ?4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP).

Methods

A retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer's Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score???1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ?4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups.

Results

One thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ?4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7-2.14, p?=?0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47-0.96, p?=?0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ?4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02-110.62, p?ConclusionsThe odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ?4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ?4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ?4 carriers. This supports the hypothesis that APOE ?4 differentially impacts initial cognitive symptoms together with underlying neuropathology.

SUBMITTER: Pillai JA

PROVIDER: S-EPMC7825215 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Impact of APOE ε4 genotype on initial cognitive symptoms differs for Alzheimer's and Lewy body neuropathology.

Pillai Jagan A JA Bena James J Bonner-Jackson Aaron A Leverenz James B JB

Alzheimer's research & therapy 20210123 1

<h4>Background</h4>APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP).<h4>Methods</h4>A retrospective cohort study of 2288 participants with neuropatho ...[more]

PMID: 33485373

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Project description:BackgroundApolipoprotein 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.MethodsThis 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.ResultsSeven 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).ConclusionThese 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.