Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Iacono, Diego; Feltis, Gloria C

doi:10.18632/aging.101757

Cited by 17 publications

(13 citation statements)

References 288 publications

(268 reference statements)

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“…APOE genotype and single APOE allelic frequencies across TBI+ and TBI– groups did not show differences in comparison to APOE genotype and single APOE allelic frequencies as measured in the general Caucasian population. These APOE findings confirmed then that also in these NACC TBI subjects cohorts (the majority of which were Caucasians), the E3 is the most frequent allele followed by the allele E4 and E2 of the APOE gene ( 38 , 39 ). Nonetheless, when considering pairwise proportion tests with multiple comparisons adjustment for the E4 allelic frequency through the entire TBI+ subjects group only, a difference was detected in TBI+/Impaired vs. TBI+/Dementia group ( p = 0.044), but not between TBI+/Impaired and TBI+/MCI, or between TBI+/MCI and TBI+/Dementia ( Figure 3 ).…”

Section: Resultssupporting

confidence: 82%

“…However, it will take a few years, or even decades, before a consistent amount of detailed longitudinally-collected clinical, cognitive, behavioral, genetic, and neuropathological data from TBI subjects will be available. Consequently, we hypothesized that it would have been worthwhile to explore some possible general demographic, cognitive and genotype-associated aspects on TBI and cognitive decline by cross-sectional analyses using existing databases that contain already a sufficient amount of information on subjects prospectively assessed for cognitive and non-cognitive domains (e.g., motor, behavior), history of TBI, TBI time points, and APOE genotype frequencies (being the allele APOE4 is a well-known genetic risk factor for AD and other dementias) ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

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Traumatic Brain Injury Exposure Lowers Age of Cognitive Decline in AD and Non-AD Conditions

et al. 2021

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We aimed to detect the possible accelerating role of previous traumatic brain injury (TBI) exposures on the onset of later cognitive decline assessed across different brain diseases. We analyzed data from the National Alzheimer's Coordinating Center (NACC), which provide information on history of TBI and longitudinal data on cognitive and non-cognitive domains for each available subject. At the time of this investigation, a total of 609 NACC subjects resulted to have a documented history of TBI. We compared subjects with and without a history of previous TBI (of any type) at the time of their first cognitive decline assessment, and termed them, respectively, TBI+ and TBI– subjects. Three hundred and sixty-one TBI+ subjects (229 male/132 female) and 248 TBI– subjects (156 male/92 female) were available. The analyses included TBI+ and TBI– subjects with a clinical diagnosis of Mild Cognitive Impairment, Alzheimer's disease, Dementia with Lewy bodies, Progressive supranuclear palsy, Corticobasal degeneration, Frontotemporal dementia, Vascular dementia, non-AD Impairment, and Parkinson's disease. The data showed that the mean age of TBI+ subjects was lower than TBI– subjects at the time of their first cognitive decline assessment (71.6 ± 11.2 vs. 74.8 ± 9.5 year; p < 0.001). Moreover, the earlier onset of cognitive decline in TBI+ vs. TBI– subjects was independent of sex, race, attained education, APOE genotype, and importantly, clinical diagnoses. As for specific cognitive aspects, MMSE, Trail Making Test part B and WAIS-R scores did not differ between TBI+ and TBI– subjects, whereas Trail Making Test part A (p = 0.013) and Boston Naming test (p = 0.008) did. In addition, data showed that neuropsychiatric symptoms [based on Neuropsychiatry Inventory (NPI)] were much more frequent in TBI+ vs. TBI– subjects, including AD and non-AD neurodegenerative conditions such as PD. These cross-sectional analyses outcomes from longitudinally-assessed cohorts of TBI+ subjects that is, subjects with TBI exposure before the onset of cognitive decline in the contest of different neurodegenerative disorders and associated pathogenetic mechanisms, are novel, and indicate that a previous TBI exposure may act as a significant “age-lowering” factor on the onset of cognitive decline in either AD and non-AD conditions independently of demographic factors, education, APOE genotype, and current or upcoming clinical conditions.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury Exposure Lowers Age of Cognitive Decline in AD and Non-AD Conditions

et al. 2021

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“…Given this multitude of functions, it is unclear which mechanisms explain the increased AD risk in APOE4 carriers. Patients with an APOE4 allele are typically diagnosed with AD in their 7 th or 8 th decade of life, even though the APOE protein is expressed within the CNS throughout life [13]. This suggests that APOE4 likely contributes to AD risk before cognitive deficits first appear [14, 15].…”

Section: Introductionmentioning

confidence: 99%

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Berger

Cooter

Roesler

et al. 2020

Preprint

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Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objectives: To characterize CSF proteomic changes as a function of APOE4 copy number. Methods: We analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons. Results: In the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (q<0.05 for each). In the second model (controlling for age, sex, and AD clinical status), increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusions: Increasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

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“…Given this multitude of functions, it is unclear which mechanisms explain the increased AD risk in APOE4 carriers. Patients with an APOE4 allele are typically diagnosed with AD in their 7th or 8th decade of life, even though the ApoE protein is expressed within the CNS throughout life [13]. This suggests that APOE4 likely contributes to AD risk before cognitive deficits first appear [14,15].…”

Section: Introductionmentioning

confidence: 99%

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

Berger

Cooter

Roesler

et al. 2021

JAD

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Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

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Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Cited by 17 publications

References 288 publications

Traumatic Brain Injury Exposure Lowers Age of Cognitive Decline in AD and Non-AD Conditions

Traumatic Brain Injury Exposure Lowers Age of Cognitive Decline in AD and Non-AD Conditions

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

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