scholarly journals APOE genotype regulates pathology and disease progression in synucleinopathy

2020 ◽  
Vol 12 (529) ◽  
pp. eaay3069 ◽  
Author(s):  
Albert A. Davis ◽  
Casey E. Inman ◽  
Zachary M. Wargel ◽  
Umber Dube ◽  
Brittany M. Freeberg ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Transgenic Mice ◽  
Cognitive Decline ◽  
Apolipoprotein E ◽  
Motor Performance ◽  
Apoe Genotype ◽  
Amyloid Β ◽  
Tau Pathology ◽  
Increased Risk ◽  
Over Time

Apolipoprotein E (APOE) ε4 genotype is associated with increased risk of dementia in Parkinson’s disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. APOE ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether APOE genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on Apoe knockout (A53T/EKO) or human APOE knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other APOE genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, APOE ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that APOE genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that APOE ε4 exacerbates pathology, and suggest that APOE ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.

scholarly journals Blocking the apolipoprotein E/Amyloid β interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid β and tau pathology

2013 ◽  
Vol 128 (4) ◽  
pp. 577-591 ◽  
Author(s):  
Shan Liu ◽  
Ariel Breitbart ◽  
Yanjie Sun ◽  
Pankaj D. Mehta ◽  
Allal Boutajangout ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Apolipoprotein E ◽  
Amyloid Β ◽  
Tau Pathology

scholarly journals Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP × Tau Transgenic Mice

2007 ◽  
Vol 171 (6) ◽  
pp. 2012-2020 ◽  
Author(s):  
Tristan Bolmont ◽  
Florence Clavaguera ◽  
Melanie Meyer-Luehmann ◽  
Martin C. Herzig ◽  
Rebecca Radde ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Β ◽  
Brain Extract ◽  
Tau Pathology ◽  
Intracerebral Infusion

The Role of Apolipoprotein E ε4 in Early and Late Mild Cognitive Impairment

2021 ◽  
Vol 84 (6) ◽  
pp. 472-480
Author(s):  
Yulin Luo ◽  
Li Tan ◽  
Joseph Therriault ◽  
Hua Zhang ◽  
Ying Gao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Apolipoprotein E ◽  
Amyloid Β ◽  
Disease Assessment ◽  
Tau Pathology ◽  
Ε4 Allele ◽  
State Examination

<b><i>Background:</i></b> Apolipoprotein E (<i>APOE</i>) ε4 is highly associated with mild cognitive impairment (MCI). However, the specific influence of <i>APOE</i> ε4 status on tau pathology and cognitive decline in early MCI (EMCI) and late MCI (LMCI) is poorly understood. Our goal was to evaluate the association of <i>APOE</i> ε4 with cerebrospinal fluid (CSF) tau levels and cognition in EMCI and LMCI patients in the Alzheimer’s Disease Neuroimaging Initiative database, and whether this association was mediated by amyloid-β (Aβ). <b><i>Methods:</i></b> Participants were 269 cognitively normal (CN), 262 EMCI, and 344 LMCI patients. They underwent CSF Aβ42 and tau detection, <i>APOE</i> ε4 genotyping, Mini-Mental State Examination, (MMSE), and Alzheimer’s disease assessment scale (ADAS)-cog assessments. Linear regressions were used to examine the relation of <i>APOE</i> ε4 and CSF tau levels and cognitive scores in persons with and without Aβ deposition (Aβ+ and Aβ−). <b><i>Results:</i></b> The prevalence of <i>APOE</i> ε4 is higher in EMCI and LMCI than in CN (<i>p</i> &#x3c; 0.001 for both), and in LMCI than in EMCI (<i>p</i> = 0.001). <i>APOE</i> ε4 allele was significantly higher in Aβ+ subjects than in Aβ− subjects (<i>p</i> &#x3c; 0.001). Subjects who had a lower CSF Aβ42 level and were <i>APOE</i> ε4-positive experienced higher levels of CSF tau and cognitive scores in EMCI and/or LMCI. <b><i>Conclusions:</i></b> An <i>APOE</i> ε4 allele is associated with increased CSF tau and worse cognition in both EMCI and LMCI, and this association may be mediated by Aβ. We conclude that <i>APOE</i> ε4 may be an important mediator of tau pathology and cognition in the early stages of AD.

scholarly journals Recurrent delirium over 12 months predicts dementia: results of the Delirium and Cognitive Impact in Dementia (DECIDE) study

2020 ◽  
Author(s):  
Sarah J Richardson ◽  
Daniel H J Davis ◽  
Blossom C M Stephan ◽  
Louise Robinson ◽  
Carol Brayne ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Decline ◽  
Hospital Admissions ◽  
Outcome Data ◽  
Illness Severity ◽  
Cognitive Outcomes ◽  
Dementia Diagnosis ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Abstract Background Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established. Methods For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity. Results Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (−1.8 Mini-Mental State Examination points [95% CI –3.5 to –0.2]) and an increased risk of new dementia diagnosis at follow up (OR 8.8 [95% CI 1.9–41.4]). More than one episode and more days with delirium (&gt;5 days) were associated with worse cognitive outcomes. Conclusions Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia.

scholarly journals Apolipoprotein E genotype and MRI-detected brain alterations pertaining to neurodegeneration: A systematic review

2021 ◽  
Author(s):  
Albert Dayor Piersson ◽  
Mazlyfarina Mohamad ◽  
Subapriya Suppiah ◽  
Nor Fadilah Rajab
Keyword(s):  
Systematic Review ◽  
Apolipoprotein E ◽  
Temporal Lobe ◽  
Late Onset ◽  
Apoe Genotype ◽  
Posterior Cingulate Cortex ◽  
Parahippocampal Gyrus ◽  
Carrier Status ◽  
Apoe Ε4 ◽  
Increased Risk

AbstractIntroductionThe effect of apolipoprotein E (APOE) genotype, particularly APOE ε4, the main genetic risk factor for late-onset Alzheimer’s disease (LOAD), has been widely explored in neuroimaging studies pertaining to older adults. The goal of this systematic review was to review the literature on the relationship between carriage of the APOE ε4 allele and grey matter (GM) changes across various age groups and its influence on neurodegeneration as evidenced by structural magnetic resonance imaging (MRI).MethodsA search of the electronic databases Pubmed, Scopus, Ovid and Cochrane was carried out till March 2020. Only studies published in English were included. Risk of bias of each study was assessed using the modified Newcastle-Ottawa Scale.ResultsA total of 115 articles met the inclusion criteria. Methodological quality varied from poor to good. There is moderate evidence of reduced GM volume in the middle frontal gyrus, precuneus, hippocampus, hippocampal subfields, amygdala, parahippocampal gyrus, middle temporal lobe, whole temporal lobe, temporal pole, and posterior cingulate cortex in APOE ε4 carriers.ConclusionThe present data supports the utility of the hippocampal GM volume to evaluate early structural neurodegenerative changes that occurs in APOE ε4 positive elderly individuals who are at increased risk of developing LOAD. Furthermore, the evidence supports serial measurements and comparison of hippocampal volume based on age group, to track the progression of neurodegeneration in APOE ε4 carriers. Additional longitudinal studies are necessary to confirm whether the combination of MRI-detected hippocampal atrophy with APOE ε4 carrier status, can better predict the development of LOAD in cognitively normal individuals.

scholarly journals A Systematic Review of Longitudinal Associations Between Reaction Time Intraindividual Variability and Age-Related Cognitive Decline or Impairment, Dementia, and Mortality

2017 ◽  
Vol 23 (5) ◽  
pp. 431-445 ◽  
Author(s):  
Becky I. Haynes ◽  
Sarah Bauermeister ◽  
David Bunce
Keyword(s):  
Systematic Review ◽  
Reaction Time ◽  
Cognitive Decline ◽  
Cognitive Task ◽  
Adverse Outcomes ◽  
Intraindividual Variability ◽  
Age Related ◽  
Increased Risk ◽  
Normal Ageing ◽  
Over Time

AbstractObjectives: Intraindividual variability (IIV) in reaction time refers to the trial-to-trial fluctuations in responding across a given cognitive task. Cross-sectional research suggests that IIV increases with normal and neuropathological ageing and it may serve as a marker of neurobiological integrity. This raises the possibility that IIV may also predict future cognitive decline and, indeed, neuropathology. Therefore, we conducted a systematic review to address these issues. Methods: A search of electronic databases Embase, Medline, PsycINFO, and Web of Science was completed on May 17, 2016 that identified longitudinal investigations of IIV in middle-aged or older adults. Results: A total of 688 studies were initially identified of which 22 met the inclusion criteria. Nine included longitudinal IIV measures and 17 predicted subsequent outcome (cognitive decline or impairment, dementia, mortality) from baseline IIV. The results suggested IIV increased over time, particularly in participants aged over 75 years. Greater baseline IIV was consistently associated with increased risk of adverse outcomes including cognitive decline or impairment, and mortality. Conclusions: Increased IIV over time is associated with normal ageing. However, further increases in IIV over and above those found in normal ageing may be a risk factor for future cognitive impairment or mortality. Measures of IIV may, therefore, have considerable potential as a supplement to existing clinical assessment to aid identification of individuals at risk of adverse outcomes such as dementia or death. (JINS, 2017, 23, 431–445)

scholarly journals Is there a connection among atrial fibrillation, anticoagulant treatment, and dementia?

2020 ◽  
Vol 22 (Supplement_E) ◽  
pp. E79-E81
Author(s):  
Claudio Ferri ◽  
Rita Del Pinto
Keyword(s):  
Atrial Fibrillation ◽  
Cognitive Decline ◽  
Oral Anticoagulation ◽  
Cost Containment ◽  
The Elderly ◽  
Common Mechanism ◽  
Anticoagulant Treatment ◽  
Increased Risk ◽  
High Prevalence ◽  
Over Time

Abstract It is well-known that atrial fibrillation carries an increased risk of stroke and dementia. The connecting pathogenic common mechanism is the thromboembolic state provided by atrial fibrillation, which is responsible for the acute cerebral events, as well as more saddle anatomic lesions, which accumulating over time, could lead to a progressive cognitive decline. It is plausible, instinctively, that oral anticoagulation could decrease this risk, although the possibility of micro-haemorrhages, which cannot be ignored, could make anticoagulation in this contest even dangerous. In this regard, whether there are firm, well established, evidences documenting a significant reduction in stroke occurrence with anticoagulant treatment in atrial fibrillation, the same level of evidences are not supporting the treatment in preventing dementia. Bringing some more clarity to this issue could have some considerable advantages, also in term of healthcare cost containment, considering the high prevalence of atrial fibrillation and dementia in the elderly.

scholarly journals The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia

2019 ◽  
Vol 12 ◽  
pp. 117864691988563
Author(s):  
Arne Olav Ervik ◽  
Stein-Erik Hafstad Solvang ◽  
Jan Erik Nordrehaug ◽  
Per Magne Ueland ◽  
Øivind Midttun ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Apolipoprotein E ◽  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
Picolinic Acid ◽  
Apoe Genotype ◽  
Synaptic Function ◽  
P Value ◽  
Gene Variant ◽  
Serum Concentrations

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele ( P-value of the interactions < .05). Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.

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