Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aß) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aß25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aß25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aß25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aß25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aß25-35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aß on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.

Transcriptional risk scores in Alzheimer's disease: From pathology to cognition.

INTRODUCTION: Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS. METHODS: We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS). RESULTS: Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850. DISCUSSION: Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker. HIGHLIGHTS: Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.

Cellular cholesterol homeostasis and Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid-ß (Aß) peptides (especially Aß1-42) and neurofibrillary tangles, composed of hyperphosphorylated tau and accompanied by chronic neuroinflammation. Aß peptides are derived from the amyloid precursor protein (APP). The oligomeric form of Aß peptides is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques. ApoE is the major apolipoprotein of the lipoprotein(s) present in the CNS. ApoE has three alleles, of which the Apoe4 allele constitutes the major risk factor for late-onset AD. Here we describe the complex relationship between ApoE4, oligomeric Aß peptides, and cholesterol homeostasis. The review consists of four parts: 1) key elements involved in cellular cholesterol metabolism and regulation; 2) key elements involved in intracellular cholesterol trafficking; 3) links between ApoE4, Aß peptides, and disturbance of cholesterol homeostasis in the CNS; 4) potential lipid-based therapeutic targets to treat AD. At the end, we recommend several research topics that we believe would help in better understanding the connection between cholesterol and AD for further investigations.

Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease.

Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer's disease (AD). At this regard no evidence still exists in vivo. In this study we explored the relationships between CSF pressure and AD pathology, as measured with CSF core biomarkers. We enrolled 16 patients with probable AD and 21 controls, collecting demographics, clinical data, CSF opening pressure and CSF levels of beta-amyloid-42 fragment (Aß42), total-tau (t-tau), phosphorylated-tau-181 (p-tau), albumin and albumin ratio. Differences between the groups were calculated with non-parametric tests, while correlations among all parameters were separately calculated with Spearman's test in each group. The groups significantly differed in biomarkers' concentration with lower Aß42, and higher t-tau and p-tau in AD patients. Moreover, CSF pressure was significantly lower in AD group (11.0 ± 2.8 vs. 13.3 ± 3.0 mmHg, p < 0.05) and directly correlated with Aß42 levels (R = 0.512; p < 0.05), but not with other biomarkers or parameters. No significant correlations emerged for biomarkers in control group. AD patients exhibit low CSF pressure whose values are directly and selectively related to CSF Aß42 levels. This interesting correlation may confirm in vivo the association between CSF dynamic and beta-amyloid metabolism occurring in AD.

ß-amyloidopathy in the Pathogenesis of Age-Related Macular Degeneration in Correlation with Neurodegenerative Diseases.

Involvement of new biotechnology and genetic engineering methods to the study of the aging organism allowed to select a group of neurodegenerative diseases (NDD) which have a similar mechanism of pathogenesis including pathological processes of protein aggregation and its deposition in the structures of nerve tissue. The development of eye and brain from one embryonic germ layer, community of ethiopathogenetic and morphological manifestations of age-related macular degeneration (AMD) and Alzheimer's disease (AD), a common pathway of ß-amyloid precursor protein (APP) are associated with the pathological aggregation of fibrillar ß-amyloid (Aß) protein and the development of ß-amyloidopathy in structural elements of the eye and the brain. The review demonstrates the keynote of AMD and AD pathogenesis is ß-amyloidopathy that is a manifestation of proteinopathy leading to cytotoxicity, neurodegeneration and the development of pathological apoptosis activated by the formation of intracellular Aß. This view on the problem predetermines the development of new strategies for the creating of ophthalmogeriatric and neuroprotective drugs affecting the pathogenesis and including all stages of Aß formation and pathological aggregation.

Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid ß peptide.

Accumulation of beta-amyloid (Aß) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aß-overexpressing transgenic mice indicates that increased brain Aß levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Aß 1-42 peptide. Whole cell current clamp recordings were compared between Aß-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aß treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra-threshold stimuli. However, Aß 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aß at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aß oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients.

Brain cellular senescence in mouse models of Alzheimer's disease.

The accumulation of senescent cells contributes to aging pathologies, including neurodegenerative diseases, and its selective removal improves physiological and cognitive function in wild-type mice as well as in Alzheimer's disease (AD) models. AD models recapitulate some, but not all components of disease and do so at different rates. Whether brain cellular senescence is recapitulated in some or all AD models and whether the emergence of cellular senescence in AD mouse models occurs before or after the expected onset of AD-like cognitive deficits in these models are not yet known. The goal of this study was to identify mouse models of AD and AD-related dementias that develop measurable markers of cellular senescence in brain and thus may be useful to study the role of cellular senescence in these conditions. We measured the levels of cellular senescence markers in the brains of P301S(PS19), P301L, hTau, and 3xTg-AD mice that model amyloidopathy and/or tauopathy in AD and related dementias and in wild-type, age-matched control mice for each strain. Expression of cellular senescence markers in brains of transgenic P301L and 3xTg-AD mice was largely indistinguishable from that in WT control age-matched mice. In contrast, markers of cellular senescence were differentially increased in brains of transgenic hTau and P301S(PS19) mice as compared to WT control mice before the onset of AD-like cognitive deficits. Taken together, our data suggest that P301S(PS19) and hTau mice may be useful models for the study of brain cellular senescence in tauopathies including, but not limited to, AD.

The Role of Vitamin D in Alzheimer's Disease: A Transcriptional Regulator of Amyloidopathy and Gliopathy.

Alzheimer's disease (AD) is characterized by amyloid-beta (Aß) accumulation and cognitive mental decline. Epidemiological studies have suggested an association between low serum vitamin D levels and an increased risk of AD. Vitamin D regulates gene expression via the vitamin D receptor, a nuclear ligand-dependent transcription factor. However, the molecular mechanism underlying the pathogenic and therapeutic effects of vitamin D on AD is not fully understood yet. To better understand how vitamin D regulates the expression of genes related to AD pathology, first, we induced vitamin D deficiency in 5xFAD mice by providing a vitamin-D-deficient diet and observed the changes in the mRNA level of genes related to Aß processing, which resulted in an increase in the Aß load in the brain. The vitamin D-deficient diet also suppressed the expression of genes for microglial Aß phagocytosis. Interestingly, vitamin D deficiency in the early stage of AD resulted in earlier memory impairment. In addition, we administered vitamin D intraperitoneally to 5xFAD mice with a normal diet and found lower Aß levels with the suppressed expression of genes for Aß generation and observed improved memory function, which may be potentially associated with reduced MAO-B expression. These findings strongly suggest the role of vitamin D as a crucial disease-modifying factor that may modulate the amyloid pathology with regard to reducing AD symptoms.

Analysis of Age-Dependent Alterations in Excitability Properties of CA1 Pyramidal Neurons in an APPPS1 Model of Alzheimer's Disease.

Age-dependent accumulation of amyloid-ß, provoking increasing brain amyloidopathy, triggers abnormal patterns of neuron activity and circuit synchronization in Alzheimer's disease (AD) as observed in human AD patients and AD mouse models. Recent studies on AD mouse models, mimicking this age-dependent amyloidopathy, identified alterations in CA1 neuron excitability. However, these models generally also overexpress mutated amyloid precursor protein (APP) and presenilin 1 (PS1) and there is a lack of a clear correlation of neuronal excitability alterations with progressive amyloidopathy. The active development of computational models of AD points out the need of collecting such experimental data to build a reliable disease model exhibiting AD-like disease progression. We therefore used the feature extraction tool of the Human Brain Project (HBP) Brain Simulation Platform to systematically analyze the excitability profile of CA1 pyramidal neuron in the APPPS1 mouse model. We identified specific features of neuron excitability that best correlate either with over-expression of mutated APP and PS1 or increasing Aß amyloidopathy. Notably, we report strong alterations in membrane time constant and action potential width and weak alterations in firing behavior. Also, using a CA1 pyramidal neuron model, we evidence amyloidopathy-dependent alterations in I h . Finally, cluster analysis of these recordings showed that we could reliably assign a trace to its correct group, opening the door to a more refined, less variable analysis of AD-affected neurons. This inter-disciplinary analysis, bringing together experimentalists and modelers, helps to further unravel the neuronal mechanisms most affected by AD and to build a biologically plausible computational model of the AD brain.

Linking Oxidative Stress and Proteinopathy in Alzheimer's Disease.

Proteinopathy and excessive production of reactive oxygen species (ROS), which are the principal features observed in the Alzheimer's disease (AD) brain, contribute to neuronal toxicity. ß-amyloid and tau are the primary proteins responsible for the proteinopathy (amyloidopathy and tauopathy, respectively) in AD, which depends on ROS production; these aggregates can also generate ROS. These mechanisms work in concert and reinforce each other to drive the pathology observed in the aging brain, which primarily involves oxidative stress (OS). This, in turn, triggers neurodegeneration due to the subsequent loss of synapses and neurons. Understanding these interactions may thus aid in the identification of potential neuroprotective therapies that could be clinically useful. Here, we review the role of ß-amyloid and tau in the activation of ROS production. We then further discuss how free radicals can influence structural changes in key toxic intermediates and describe the putative mechanisms by which OS and oligomers cause neuronal death.

Plasma Amyloid-ß Oligomerization Tendency Predicts Amyloid PET Positivity.

PURPOSE: Among other emerging amyloid-targeting blood-based biomarkers, Multimer Detection System-Oligomeric Amyloid-ß (MDS-OAß) measures dynamic changes in concentration of oligomeric amyloid-ß (OAß), which is considered the main pathogenic culprit of Alzheimer's disease (AD), in plasma after spiking with synthetic amyloid-ß (Aß). We aimed to investigate the predictability of MDS-OAß on amyloid positron emission tomography (PET) positivity. PATIENTS AND METHODS: A total of 96 subjects who visited Seoul National University Bundang Hospital for medical check-up complaining of cognitive decline and had undergone extensive medical assessment were recruited. Amyloid statuses were dichotomized into positive or negative based on visual assessment of amyloid PET. Plasma OAß concentration was measured by MDS-OAß. In the previous validation study, 0.78ng/mL was established as the cut-off value and the plasma OAß concentration higher than or equal to the cut-off value was defined as MDS-OAß positive. RESULTS: MDS-OAß positivity could discriminate amyloid PET positivity with the AUC value of 0.855 (95% CI 0.776-0.933). Adding MDS-OAß positivity to prediction models including age, MMSE score, and APOE ε4 status improved performance up to the AUC value of 0.926 (95% CI 0.871-0.980). CONCLUSION: The Aß oligomerization tendency in plasma could predict amyloid PET positivity with high performance, and, when it is combined with age, MMSE score, and APOE ε4 status, predictability was improved substantially. This suggests the potential of MDS-OAß as a useful initial stage test in the clinical and research fields of AD.

Parkinsonian gait in aging: A feature of Alzheimer's pathology?

INTRODUCTION: Central neurological gait abnormalities (CNGA; i.e. frontal or parkinsonian) are frequently associated with neurodegenerative conditions in older adults, but their pathophysiological substrates remain poorly described. This cross-sectional study aims to assess the association between cerebrospinal fluid (CSF) Alzheimer's biomarkers and CNGA. METHODS: CSF biomarkers (phosphor-tau, total tau and Aß1-42) were measured in 52 patients with CNGA (77.33 ± 6.09 years; 28.8% female). Gait phenotypes were evaluated by two diagnosis-blinded assessors and classified as frontal gait, parkinsonian gait or other gait abnormalities. RESULTS: Parkinsonian gait was significantly associated with a decreased CSF Aß42 even after adjusting on age, gender, comorbidities and white matter changes (ß: -0.32; 95% CI: [-340.6; -22.9]; p value: 0.026). Phosphor-tau and total tau were not associated with any other CNGA (i.e. frontal gait and other gait abnormalities). DISCUSSION: Parkinsonian gait represents a gait phenotype of Alzheimer's pathology in patients with CNGA.

Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer's disease.

Recently, increased neuronal activity in nucleus reuniens (Re) has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether altered intrinsic electrophysiological properties could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons display hyperpolarized membrane potentials in J20 mice without changes to the incidence or frequency of spontaneous action potentials. Re neurons recorded from J20 mice did not exhibit increased action potential generation in response to depolarizing current stimuli but an increased propensity to rebound burst following hyperpolarizing current stimuli. Increased rebound firing did not appear to result from alterations to T-type Ca2+ channels. Finally, in J20 mice, there was an ~8% reduction in spike width, similar to what has been reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to hippocampal-thalmo-cortical hyperexcitability observed under pathological beta-amyloid load.

Brain-Derived Neurotrophic Factor (BDNF) Preserves the Functional Integrity of Neural Networks in the ß-Amyloidopathy Model in vitro.

Alzheimer's disease (AD) is a widespread chronic neurodegenerative pathology characterized by synaptic dysfunction, partial neuronal death, cognitive decline and memory impairments. The major hallmarks of AD are extracellular senile amyloid plaques formed by various types of amyloid proteins (Aß) and the formation and accumulation of intracellular neurofibrillary tangles. However, there is a lack of relevant experimental models for studying changes in neural network activity, the features of intercellular signaling or the effects of drugs on the functional activity of nervous cells during AD development. In this work, we examined two experimental models of amyloidopathy using primary hippocampal cultures. The first model involves the embryonic brains of 5xFAD mice; the second uses chronic application of amyloid beta 1-42 (Aß1-42). The model based on primary hippocampal cells obtained from 5xFAD mice demonstrated changes in spontaneous network calcium activity characterized by a decrease in the number of cells exhibiting Ca2+ activity, a decrease in the number of Ca2+ oscillations and an increase in the duration of Ca2+ events from day 21 of culture development in vitro. Chronic application of Aß1-42 resulted in the rapid establishment of significant neurodegenerative changes in primary hippocampal cultures, leading to marked impairments in neural network calcium activity and increased cell death. Using this model and multielectrode arrays, we studied the influence of amyloidopathy on spontaneous bioelectrical neural network activity in primary hippocampal cultures. It was shown that chronic Aß application decreased the number of network bursts and spikes in a burst. The spatial structure of neural networks was also disturbed that characterized by reduction in both the number of key network elements (hubs) and connections between network elements. Moreover, application of brain-derived neurotrophic factor (BDNF) recombinant protein and BDNF hyperexpression by an adeno-associated virus vector partially prevented these amyloidopathy-induced neurodegenerative phenomena. BDNF maintained cell viability and spontaneous bioelectrical and calcium network activity in primary hippocampal cultures.

Parkinsonism is a Phenotypical Signature of Amyloidopathy in Patients with Gait Disorders.

BACKGROUND: Central neurological gait abnormalities (CNGA) are frequently associated with parkinsonism in older adults. However, the neuropathological substrates and the clinical impact of parkinsonism have been not described in CNGA. OBJECTIVE: This cross-sectional study aims to compare the CSF total tau, Aß1-42, and phosphorylated tau levels in non-Parkinson's disease (PD) patients with CNGA with and without parkinsonism and to study the clinical impact of parkinsonism on gait and cognition. METHODS: CSF biomarkers were measured by ELISA in 49 non-PD patients with CNGA (77.7±6.6 years; 32.7% women). Gait was quantified with an optoelectronic system and cognition with a comprehensive neuropsychological assessment. Parkinsonism was defined by presence of bradykinesia and at least one of the following signs among muscular rigidity, rest tremor, or postural instability. RESULTS: Parkinsonism was identified in 14 CNGA patients (28.6% ). CSF Aß1-42 level was decreased in CNGA patients with parkinsonism (ß: - 189.4; 95% CI [- 352.3; - 26.6]; p = 0.024) even after adjusting for age, gender, comorbidities, and total white matter burden; while CSF total tau and phosphorylated tau levels were similar between CNGA patients with and without parkinsonism. CNGA patients with parkinsonism presented decreased attentional and executive performances but similar gait parameters than those without parkinsonism. CONCLUSION: Parkinsonism represents a phenotype related with amyloidopathy-decreased CSF Aß1-42 level-in non-PD patients with CNGA. This phenotype is clinically associated with impaired cognition, but similar quantitative gait parameters in comparison to CNGA patients without parkinsonism.

Alzheimer's Disease and the Routine Clinical Use of CSF Biomarkers.

Amyloid based hypothesis led to develop biomarkers oriented diagnosis of neurodegenerative dementias. Among them biomarkers for AD, the most diffuse form of dementia, are currently the unique available for scientific and diagnostic purposes. CSF biomarkers like Amyloid beta 42, total tau and phosphorylated tau levels can be easily evaluated in individuals suffering from cognitive decline, to diagnose or exclude AD type dementia, since early stages. Moreover, their analysis gave the opportunity to better understand cognitive decline patho-physiology during aging. Experience from their use and analysis however showed a high degree of variability due to the great heterogeneity of AD on one hand, the presence of isolated CSF biomarker changes that are not to be considered of AD type and deserve a clinico-pathological classification on the other. Aim of this review is to offer the knowledge about CSF biomarker's use in clinics.

Altered intrinsic excitability of hippocampal CA1 pyramidal neurons in aged PDAPP mice.

Amyloidopathy involves the accumulation of insoluble amyloid ß (Aß) species in the brain's parenchyma and is a key histopathological hallmark of Alzheimer's disease (AD). Work on transgenic mice that overexpress Aß suggests that elevated Aß levels in the brain are associated with aberrant epileptiform activity and increased intrinsic excitability (IE) of CA1 hippocampal neurons. In this study we examined if similar changes could be observed in hippocampal CA1 pyramidal neurons from aged PDAPP mice (20-23 month old, Indiana mutation: V717F on APP gene) compared to their age-matched wild-type littermate controls. Whole-cell current clamp recordings revealed that sub-threshold intrinsic properties, such as input resistance, resting membrane potential and hyperpolarization activated "sag" were unaffected, but capacitance was significantly decreased in the transgenic animals. No differences between genotypes were observed in the overall number of action potentials (AP) elicited by 500 ms supra-threshold current stimuli. PDAPP neurons, however, exhibited higher instantaneous firing frequencies after accommodation in response to high intensity current injections. The AP waveform was narrower and shorter in amplitude in PDAPP mice: these changes, according to our in silico model of a CA1/3 pyramidal neuron, depended on the respective increase and reduction of K(+) and Na(+) voltage-gated channels maximal conductances. Finally, the after-hyperpolarization, seen after the first AP evoked by a +300 pA current injection and after 50 Hz AP bursts, was more pronounced in PDAPP mice. These data show that Aß-overexpression in aged mice altered the capacitance, the neuronal firing and the AP waveform of CA1 pyramidal neurons. Some of these findings are consistent with previous work on younger PDAPP; they also show important differences that can be potentially ascribed to the interaction between amyloidopathy and ageing. Such a change of IE properties over time underlies that the increased incidence of seizure observed in AD patients might rely on different mechanistic pathways during progression of the disease.

Advances in the treatment of visual hallucinations in neurodegenerative diseases.

Treatment of visual hallucinations in neurodegenerative disorders is not well advanced. The complexity of underlying mechanisms presents a number of potential avenues for developing treatments, but also suggests that any single one may be of limited efficacy. Reducing medication, with the careful introduction of antidementia medication if needed, is the mainstay of current management. Antipsychotic medication leads to excessive morbidity and mortality and should only be used in cases of high distress that do not otherwise respond. Education, reduction of risk factors and psychological treatments have limited evidence of efficacy, but are unlikely to cause harm.

Anesthetic effects in Alzheimer transgenic mouse models.

Research has improved the diagnosis of Alzheimer's disease, and at earlier stages, but effective therapy continues to be elusive. Current effort is focused on delay. Environmental factors are thought to interact with genetics to modulate the progression of the disease, and one such environmental factor is exposure to general anesthetics. The possibility that some anesthetic effects have long-term consequences is of general interest and concern. The difficulty of studying a chronic, age-related disease in humans combined with the fact that anesthetics are rarely given without surgery, has led to a focus on animal models. Transgenic mouse models have been developed to mimic the hallmarks of Alzheimer's disease, including amyloid beta accumulation (plaque), neurofibrillary tangles, and cognitive dysfunction. While none of the models recapitulate the human disease with high fidelity, they allow a first look at anesthetic-Alzheimer interactions in a reasonable time frame. In studies found to date, none have concluded that anesthetics alone cause a significant change in cognitive decline, but rather an acceleration in Alzheimer neuropathology. Further studies are required to define the best anesthetic paradigm for our elderly population to mitigate changes in neuropathology and potentially cognition.