<i>APOE</i>
            alleles predict the rate of cognitive decline in Alzheimer disease

Martins, Carla; Oulhaj, Abderrahim; Jager, Celeste A. de; Williams, Jonathan

doi:10.1212/01.wnl.0000188871.74093.12

Cited by 204 publications

(188 citation statements)

References 54 publications

(89 reference statements)

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“…Further, a meta‐analysis of 1063 APOEε4 carriers and 2983 non‐carriers 32 found no association of APOEε4 with increased cognitive decline at 1 year after surgery (OR 1.15, 95% CI 0.71–1.86). However, APOEε4 has been shown to accelerate cognitive decline in elderly people, whether non‐demented 25 or with Alzheimer's disease 24, regardless of surgery. Thus, elderly cognitively impaired, APOEε4 carriers who experience moderate or major surgery may be in danger of suffering particularly rapid cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

“…Participants were seen at least annually, at many of which visits a Cambridge Cognition Examination (CAMCOG) score (variable termed ‘C’ below) was obtained 23 and details of episodes of surgery since the preceding assessment recorded. Patients were genotyped with regard to the APOEε4 allele, which is known to be associated with a greater risk of cognitive decline 24, 25 and diagnosis of Alzheimer's dementia 26. We sought participants with at least two measures of CAMCOG who had joined the study as controls, or with mild cognitive impairment 27, who had participated in at least 3 years of follow‐up.…”

Section: Methodsmentioning

confidence: 99%

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Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort

et al. 2016

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SummaryConcerns have been raised about the effects on cognition of anaesthesia for surgery, especially in elderly people. We recorded cognitive decline in a cohort of 394 people (198 women) with median (IQR) age at recruitment of 72.6 (66.6–77.8) years, of whom 109 had moderate or major surgery during a median (IQR) follow‐up of 4.1 (2.0–7.6) years. Cognitive decline was more rapid in people who on recruitment were: older, p = 0.0003; male, p = 0.027; had worse cognition, p < 0.0001; or carried the ε4 allele of apoliprotein E (APOEε4), p = 0.008; and after an operation if cognitive impairment was already diagnosed, p = 0.0001. Cognitive decline appears to accelerate after surgery in elderly patients diagnosed with cognitive impairment, but not other elderly patients.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort

et al. 2016

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“…AD begins with subtle changes in synaptic efficacy well before neuronal degeneration is apparent, and loss of synapses likely disrupts hippocampal and cortical circuits, with functional consequences contributing to progressive cognitive impairment [28][29][30]. Even in non-demented middle-aged and elderly human subjects, apoE4 is associated with greater cognitive decline, and the decline shows a gene doseresponse [31][32][33]. A significant association was found between apoE4 and transition from normal to mild cognitive impairment [34], which represents early-stage AD and with high positive predictive value for eventual conversion to AD [35].…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

Zhong

Scearce‐Levie

Ramaswamy

et al. 2008

Alzheimer's & Dementia

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BackgroundApolipoprotein E4 (apoE4), the major genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases, has three structural and biophysical properties that distinguish it from the other isoforms—domain interaction, reduced stability, and lack of cysteine. Assessing their relative contributions to effects of apoE4‐associated pathogenesis in AD is important from a mechanistic and therapeutic perspective, that is not possible using human apoE transgene or knock‐in models.MethodsWe analyzed Arg‐61 apoE mice, a gene‐targeted model that selectively displays domain interaction.ResultsThe mice displayed age‐dependent loss of the synaptic protein synaptophysin in neocortex and hippocampus and had lower levels of the postsynaptic neuroligin‐1. Activation of dentate gyrus granule neurons increased Arc expression 3.5‐fold in wildtype mice but only 2.3‐fold in Arg‐61 mice. The losses of synaptic proteins caused a mild memory deficit in Arg‐61 mice in the water‐maze test. Since synaptic integrity requires efficient glutamate uptake, we measured astrocyte glutamate transporter 1 in the hippocampus. The level was reduced in Arg‐61 mice, suggesting that inefficient glutamate uptake by astrocytes causes chronic excitotoxicity. Consistent with the reduced secretion of Arg‐61 apoE by astrocytes in this model, cholesterol secretion was also reduced 34%. This reduction could also contribute to the synaptic deficits by limiting the availability of cholesterol for neuronal repair.ConclusionsDomain interaction in the absence of other structural characteristics of apoE4 is sufficient to cause synaptic pathology and functional synaptic deficits, potentially associated with astrocyte dysfunction and impaired maintenance of neurons. Therapeutic targeting of domain interaction might blunt effects of apoE4 in neurodegenerative disease.

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“…2,3 The literature is conflicting as to the effect of e4 on rate of cognitive decline; some studies show slower [4][5][6] whereas others faster rates. [7][8][9][10][11] This discrepancy may reflect chance findings because of a lack of power in smaller studies. Studies with over 200 AD subjects have consistently shown a more aggressive course of disease with the e4 allele, 7,8,10 and in the PROSPER trial (a large prospective study in the elderly with 5804 subjects) the e4 allele was associated both with poorer memory performance at baseline and with more rapid cognitive decline.…”

mentioning

confidence: 99%

“…[7][8][9][10][11] This discrepancy may reflect chance findings because of a lack of power in smaller studies. Studies with over 200 AD subjects have consistently shown a more aggressive course of disease with the e4 allele, 7,8,10 and in the PROSPER trial (a large prospective study in the elderly with 5804 subjects) the e4 allele was associated both with poorer memory performance at baseline and with more rapid cognitive decline. 11 Nonetheless, smaller studies have generated some striking findings.…”

mentioning

confidence: 99%