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An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ?4 allele.

ABSTRACT: OBJECTIVE:Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (A?-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF A?-42 compared to patients with normal levels. METHODS:The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF A?-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF A? at baseline, PD participants with normal CSF A?, and both groups combined). Having at least one copy of the APOE ?4 allele, time, and the interaction of APOE ?4 and time were predictor variables for cognitive change, adjusting for age, gender and education. RESULTS:423 de novo PD participants were followed up to 5?years with annual cognitive assessments. 103 participants had low baseline CSF A?-42 (39 APOE ?4+, 64 APOE ?4-). Compared to participants with normal CSF A?-42, those with low CSF A?-42 declined faster on most cognitive tests. Within the low CSF A?-42 group, APOE ?4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p?=?.005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p?=?.002; 5-year standardized change of 0.72). DISCUSSION:PD patients with low CSF A?-42 and APOE ?4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF A?-42 and APOE ?4 might interact to promote early cognitive changes in PD patients.

SUBMITTER: Shahid M

PROVIDER: S-EPMC6588475 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele.

Shahid Marian M Kim Jeehyun J Leaver Katherine K Hendershott Taylor T Zhu Delphine D Cholerton Brenna B Henderson Victor W VW Tian Lu L Poston Kathleen L KL

Neurobiology of disease 20190228

<h4>Objective</h4>Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aβ-42 compared to patients with normal levels.<h4>Methods</h4>The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aβ-42 dete ...[more]

PMID: 30826425

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Project description:BackgroundSubjective cognitive decline (SCD) is characterized by self-reported cognitive deficits without measurable cognitive impairment. It has been suggested that individuals with SCD exhibited brain structural alterations in widespread cortical thinning or gray matter loss in the medial temporal and frontotemporal regions. Apolipoprotein E (APOE) ε4 allele is thought to be a genetic marker associated with risk of SCD. Neuropsychiatric symptoms may provide insight in detecting higher-risk elders for early Alzheimer's disease as well. Therefore, we aim to explore the characteristics of brain morphology in SCD and to determine whether it is influenced by APOE ε4 as well as neuropsychiatric symptoms in SCD.MethodsA total of 138 cognitively normal older individuals from the SILCODE cohort underwent a clinical interview, neuropsychological assessments, a blood test, and MRI. A two-sample t-test was used to examine the cortex volume and bilateral cortical surface area alterations between SCD (n = 65) and controls (n = 73). A general linear model analysis was used to test for both main and interaction effects of clinical phenotype (SCD vs. controls) and APOE on global and regional cortex volume and bilateral cortical surface area and thickness. A multiple linear regression analysis was conducted to determine the effects of the APOE genotype on the relationships between morphometric features and neuropsychiatric symptoms in SCD.ResultsCompared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area. SCD APOE ε4 carriers showed additive reduction in the right cortical surface area. The evaluation scores of anxiety symptoms were negatively associated with the right cortical surface area in SCD APOE 4 non-carriers.ConclusionsIndividuals with SCD had an altered cortical surface area, and APOE genotype and anxiety symptoms are modified factors on the cortical surface area decrease in SCD.Trial registrationClinicalTrials.gov (Identifier: NCT03370744 ). Registered 15 March 2017.

Project description:BackgroundThe apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer's disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility.Methods and findingsThis rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018).ConclusionsContrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.

Dataset Information

An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ?4 allele.

Publications

An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele.

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