Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Zdanys, Kristina; Kleiman, Timothy G; MacAvoy, Martha G.; Black, Benjamin; Rightmer, Tracy; Grey, Monique; Garman, Katherine S.; Tampi, Rajesh R.; Gelernter, Joel; Dyck, Christopher H. van

doi:10.1038/sj.npp.1301148

Cited by 40 publications

(30 citation statements)

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“…Neuropathology and neuropathological 'spreading' of Alzheimer's disease Alzheimer's disease is characterized by neocortical atrophy, selective neuronal loss, cytoskeletal disruption, loss of synaptic contacts (resulting in altered cortico-cortical connectivity), deposition and aggregation of amyloid as senile plaques with amyloid angiopathy and neuritic changes that include the formation of neurofibrillary tangles [16][17][18][19]. Generally, the magnitude of these defects mirrors the temporal sequence of declining cognitive status in the Alzheimer patient [18][19][20].…”

Section: Discussionmentioning

confidence: 99%

“…Visual processing deficits in Alzheimer's disease Hallucinations and related deficits in visual processing associated with late-stage Alzheimer's disease are thought to be due, in part, to compromised primary visual circuitry distal to the retina, and the interpretation of primary visual signals in the higher association areas of the neocortex [16,23,24]. The individual contributions of the primary visual circuitry and neocortical visual signal processing and interpretation in Alzheimer's disease have been difficult to assess.…”

Section: Daxxmentioning

confidence: 99%

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Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer's disease

et al. 2007

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Alzheimer's disease is associated with progressively dysfunctional gene expression in the limbic system of the brain. The thalamus and primary visual cortex are thought to be initially spared of Alzheimer-type changes that ravage the association neocortex. In this study, using DNA arrays and Western immunoassay, gene expression patterns were examined in the thalamus and primary visual cortex of moderate-stage and late-stage Alzheimer's disease and age-matched controls using a set of proinflammatory genes known to be upregulated in the temporal lobe neocortex and hippocampus of moderate-stage Alzheimer's disease. The data indicate that, in late-stage Alzheimer's disease, proinflammatory and proapoptotic gene expression spreads into the primary visual sensory cortex. This upregulation of pathological gene expression could be, in part, responsible for the visual disturbances associated with end-stages of the Alzheimer process.

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Section: Discussionmentioning

confidence: 99%

Section: Daxxmentioning

confidence: 99%

Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer's disease

et al. 2007

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“…Patients with schizophrenia who carry this gene have less severe positive symptoms . However, patients with Alzheimer's disease who carry this allele are more likely to suffer hallucinations and delusions (Zdanys et al, 2007). Apolipoprotein E4 is involved in lipid metabolism; however, data on its neural interactions are emerging, for example, ApoE4 modulates NMDA receptor function via effects on insulin-degrading enzymes and protein kinase A (Sheng et al, 2008), which is indicative of a potential role of cyclic AMP signaling in the psychotomimetic effects of ketamine.…”

Section: Genetic Effectsmentioning

confidence: 99%

Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

Corlett

Honey

Krystal

et al. 2010

Neuropsychopharmacol

207

173

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Modulating glutamatergic neurotransmission induces alterations in conscious experience that mimic the symptoms of early psychotic illness. We review studies that use intravenous administration of ketamine, focusing on interindividual variability in the profundity of the ketamine experience. We will consider this individual variability within a hypothetical model of brain and cognitive function centered upon learning and inference. Within this model, the brains, neural systems, and even single neurons specify expectations about their inputs and responding to violations of those expectations with new learning that renders future inputs more predictable. We argue that ketamine temporarily deranges this ability by perturbing both the ways in which prior expectations are specified and the ways in which expectancy violations are signaled. We suggest that the former effect is predominantly mediated by NMDA blockade and the latter by augmented and inappropriate feedforward glutamatergic signaling. We suggest that the observed interindividual variability emerges from individual differences in neural circuits that normally underpin the learning and inference processes described. The exact source for that variability is uncertain, although it is likely to arise not only from genetic variation but also from subjects' previous experiences and prior learning. Furthermore, we argue that chronic, unlike acute, NMDA blockade alters the specification of expectancies more profoundly and permanently. Scrutinizing individual differences in the effects of acute and chronic ketamine administration in the context of the Bayesian brain model may generate new insights about the symptoms of psychosis; their underlying cognitive processes and neurocircuitry.

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“…Similarly, while both cognitive impairment and aggression accompany AD, they are not necessarily temporally colocalized and may but do not necessarily respond to identical treatments [59][60][61][62]. These behavioral manifestations in mice are directly relevant since AD can be accompanied by psychosis and agitation [63], and ApoE4 can also potentiate psychotic symptoms in humans [64]. These findings suggest that aggression, but not cognition, may be one instance in which the presence of the E4 (and E3) genotype, rather than the absence of ApoE function (i.e., ApoE-/-mice) may be the contributing factor [65].…”

Section: Nutritional Deficiency Potentiates the Impact Of Deficiency mentioning

confidence: 99%

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

Chan

Shea

2010

JAD

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Abstract. The presence of one or more copies of the E4 allele of apolipoprotein E (ApoE) is strongly associated with of Alzheimer's disease (AD). The impact of E4 on neurodegeneration is potentiated by dietary oxidative challenge. Our prior studies in transgenic mice demonstrate that, in the face of dietary oxidative challenge, E3 does not provide any further protection than E4 or lack of murine ApoE for aggression, oxidative damage, presenilin-1 expression, and γ-secretase activity, and provides only partial reduction in phospho-tau levels. Extrapolation of these findings to the human condition leads us to hypothesize that the E3 allele may not provide sufficient neuroprotection under conditions of dietary compromise and/or oxidative challenge. Epidemiological evidence is consistent with this possibility. The E3 allele is approximately half as effective compared to E2 at buffering the impact of a single E4 allele. In addition, the risk of AD increases linearly for the genotypes E2/2, E2/3, and E3/3. It has been proposed that that clinical manifestation of AD may in some cases require the convergence of 2 or more risk factors. We hypothesize that the combined impact of dietary oxidative stress and either the ApoE3 or E4 genotype represents one such condition.Keywords: Alzheimer's disease, apolipoprotein E, diet, nutritional deficiency, oxidative stresss APOE, OXIDATIVE DAMAGE, AND ALZHEIMER'S DISEASEA major risk factor for Alzheimer's disease (AD) is the presence of the E4 allele of apolipoprotein E (ApoE), which accounts for up to 50% of the cases of AD [1][2][3][4][5]. Considerable effort has been devoted to determining the nature and extent of risk imparted by ApoE4 and what might be done to lessen this risk [6]. Oxidative damage represents an early and perhaps pivotal factor contributing to age-related decline in cogni- * Correspondence to: Thomas B. Shea, Center for Cellular Neurobiology and Neurodegeneration Research, UMassLowell, Lowell, Massachusetts 01854, USA. Tel.: +1 978 934 2881; Fax: +1 978 934 3044; E-mail: Thomas Shea@uml.edu. tive performance including that associated with AD [7][8][9][10][11][12]. Oxidative damage and ApoE4 are inter-related, as the extent of brain oxidative damage in AD is correlated with the presence of E4 [13][14][15][16]. ApoE mediates transport and clearance of lipids, including those subjected to oxidative damage. In doing so, ApoE prevents a cascade of neuronal oxidative damage by quenching downstream products of lipid oxidation, preventing secondary glutamate excitotoxicity and sequestering oxidative metals such as iron [4,17,18,20]. However, ApoE4 is thought to be less effective at this latter function [21].While over 20 other genes are suspected of being related to AD [22], deficiency in ApoE function has a particularly far-reaching impact in that it not only impairs overall brain metabolism and may impair compensato-

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Apolipoprotein E ɛ4 Allele Increases Risk for Psychotic Symptoms in Alzheimer's Disease

Cited by 40 publications

References 53 publications

Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer's disease

Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer's disease

Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

Apolipoprotein E3 as a Risk Factor for Alzheimer's Disease Under Conditions of Nutritional Imbalance

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