The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

Hunsberger, Holly C.; Pinky, Priyanka D.; Smith, Warren E.; Suppiramaniam, Vishnu; Reed, Miranda N.

doi:10.1042/ns20180203

Cited by 45 publications

(30 citation statements)

References 146 publications

(160 reference statements)

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“…Other than cerebrovascular disorders, we were able to confirm several well‐known risk factors of AD‐related pathology, including APOE ε4 genotype, positive family history of dementia, and age. Specifically, based on the prevalence of APOE ε4 carriers per ATN stage, we can confirm that APOE ε4 seems to be a major driver of AD pathology, in line with current evidence 51 …”

Section: Discussionsupporting

confidence: 88%

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Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort

Ingala

Boer

Masselink

et al. 2021

Alzheimer's & Dementia

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Background We classified non‐demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. Materials and methods From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut‐offs of 1000 pg/mL for amyloid beta (Aß)1‐42 and 27 pg/mL for p‐tau181 were validated using Gaussian mixture models. Given strong correlation of p‐tau and t‐tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age‐adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. Results Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A–T–N–, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non‐Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T–N– compared to A–T–N– (P < 0.001). Discussion In non‐demented individuals along the AD continuum, p‐tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

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Section: Discussionsupporting

confidence: 88%

“…Specifically, based on the prevalence of APOE ε4 carriers per ATN stage, we can confirm that APOE ε4 seems to be a major driver of AD pathology, in line with current evidence. 51 …”

Section: Discussionmentioning

confidence: 99%

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort

Ingala

Boer

Masselink

et al. 2021

Alzheimer's & Dementia

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“…In addition to AD, abnormal cholesterol metabolism in the brain also causes many neurological diseases, like Parkinson's disease, Huntington's disease, and lateral amyotrophic lateral sclerosis (Jin et al, 2019). Diabetes, dyslipidemia or stroke increase the risk of AD (Hunsberger et al, 2019). We used PCO as a natural antioxidant with hypocholesterolemic, anti-aging, and hypoglycemic properties (Elseweidy et al, 2016;Nam et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotective Effects of Policosanol on Learning and Memory Impairment in a Male Rat Model of Alzheimer's Disease

Safari

Mirazi

Ahmadi

et al. 2021

Preprint

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Alzheimer's disease (AD) as a neurodegenerative disease is recognized with progressive cognitive function failure, which is determined by beta-amyloid (Aβ) accumulation in extracellular space and hyperphosphorylation of intracellular Tau protein. Aβ stimulates some kinds of active oxygen and causes oxidative stresses and apoptosis. Policosanol (PCO) is a reducing lipid complement, which has antioxidant and anti-inflammatory activities. In the current research, the PCO effects on learning and memory impairment were investigated in a rat model of AD. Healthy adult male Wistar rats (230–250g) were divided randomly into 7 groups (n=6-7): Control, Sham (5 µL of phosphate-buffered saline, intracerebroventricular (ICV) microinjection), AD model (5 µL, ICV injection of Aβ), acacia gum (50 mg/kg, 8 weeks, gavage), PCO (50 mg/kg, 8 weeks, gavage), AD + acacia gum (50 mg/kg, 8 weeks, gavage), and AD + PCO (50 mg/kg, 8 weeks, gavage). Passive avoidance learning (PAL) and memory were assessed by shuttle box, cognitive memory by novel object recognition (NOR), and spatial memory by the Morris water maze (MWM) test. The oxidant and antioxidant parameters were examined at the end of the experiments. According to our results, ICV injection of Aβ caused reduced cognitive memory in NOR, spatial memory in MWM, and passive avoidance in PAL tests. PCO caused a recovery in cognitive memory, spatial memory, and PAL memory. Aβ plaques increased in the AD group, while PCO decreased it. Aβ increased total oxidant status and decreased total antioxidant capacity, whereas PCO reversed these parameters. Our results demonstrated that PCO has neuroprotective effects and can protect learning and memory impairments via its hypolipidemic and antioxidant effects.

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“…Three genes are known to cause FAD: Amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2), with PS1 mutations accounting for most of early onset FAD [41]. Additionally, the ε4 allele of apolipoprotein E (APOE4) is a known genetic risk factor, which increases the likelihood to develop LOAD, with homozygous APOE4 carriers being nearly 15 times more likely to develop the disease [42].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s Disease, and Breast and Prostate Cancer Research: Translational Failures and the Importance to Monitor Outputs and Impact of Funded Research

Herrmann

Bernasconi

McCarthy

et al. 2020

Animals

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Dementia and cancer are becoming increasingly prevalent in Western countries. In the last two decades, research focused on Alzheimer’s disease (AD) and cancer, in particular, breast cancer (BC) and prostate cancer (PC), has been substantially funded both in Europe and worldwide. While scientific research outcomes have contributed to increase our understanding of the disease etiopathology, still the prevalence of these chronic degenerative conditions remains very high across the globe. By definition, no model is perfect. In particular, animal models of AD, BC, and PC have been and still are traditionally used in basic/fundamental, translational, and preclinical research to study human disease mechanisms, identify new therapeutic targets, and develop new drugs. However, animals do not adequately model some essential features of human disease; therefore, they are often unable to pave the way to the development of drugs effective in human patients. The rise of new technological tools and models in life science, and the increasing need for multidisciplinary approaches have encouraged many interdisciplinary research initiatives. With considerable funds being invested in biomedical research, it is becoming pivotal to define and apply indicators to monitor the contribution to innovation and impact of funded research. Here, we discuss some of the issues underlying translational failure in AD, BC, and PC research, and describe how indicators could be applied to retrospectively measure outputs and impact of funded biomedical research.

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The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions

Cited by 45 publications

References 146 publications

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort

Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort

The Neuroprotective Effects of Policosanol on Learning and Memory Impairment in a Male Rat Model of Alzheimer's Disease

Alzheimer’s Disease, and Breast and Prostate Cancer Research: Translational Failures and the Importance to Monitor Outputs and Impact of Funded Research

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