Human APP Research Articles

Apolipoprotein E4 exacerbates ethanol-induced neurotoxicity through augmentation of oxidative stress and apoptosis in N2a-APP cells.

Neuronal loss is a prominent phenomenon in Alzheimer's disease (AD) and alcohol-induced brain damage. Alcohol abuse is associated with an increased risk of AD, regardless of the type of alcoholic beverage. Furthermore, the detrimental effect of excessive alcohol consumption on the risk of AD is exacerbated among people carrying apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for AD. However, how APOE ε4 and alcohol abuse synergistically enhance the possibility of AD is unclear. Here we show that in N2a cells stably expressing human APP695 (N2a-APP), high-concentration ethanol-induced neurotoxicity was significantly augmented in the presence of apoE4 protein, compared with apoE3 protein. Early and late apoptotic cells were apparently more in cells treated with the combination of apoE4 and ethanol, compared with that of apoE3 and ethanol. Inhibition of apoptosis using a pan-caspase inhibitor z-vad resulted in abolishment of the apoE isoform-specific effect on high-concentration ethanol-induced neurotoxicity. Moreover, compared with apoE3, apoE4 augmented ethanol-induced cellular oxidative stress, and pre-incubation with a reactive oxygen species (ROS) scavenger NAC abrogated the specific effect of apoE4 on ethanol-induced neurotoxicity. Taken together, our results for the first time demonstrate that apoE4 and high-concentration ethanol synergistically enhance neurotoxicity through elevating cellular oxidative stress and increasing neuronal apoptosis, and support the notion that avoiding excessive alcohol consumption can help to prevent AD especially in APOE ε4 carriers.

The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease

Background: Transgenic animal models are a widely used and powerful tool to investigate human disease and develop therapeutic interventions. Making a transgenic mouse involves random integration of exogenous DNA into the host genome that can have the effect of disrupting endogenous gene expression. The J20 mouse model of Alzheimer's disease (AD) is a transgenic overexpresser of human APP with familial AD mutations and has been extensively utilised in preclinical studies and our aim was to determine the genomic location of the J20 transgene insertion. Methods: We used a combination of breeding strategy and Targeted Locus Amplification with deep sequencing to identify the insertion site of the J20 transgene array. To assess RNA and protein expression of Zbtb20, we used qRT-PCR and Western Blotting. Results: We demonstrate that the J20 transgene construct has inserted within the genetic locus of endogenous mouse gene Zbtb20 on chromosome 16 in an array , disrupting expression of mRNA from this gene in adult hippocampal tissue. Preliminary data suggests that ZBTB20 protein levels remain unchanged in this tissue, however further study is necessary. We note that the endogenous mouse App gene also lies on chromosome 16, although 42 Mb from the Zbtb20 locus. Conclusions: These data will be useful for future studies utilising this popular model of AD, particularly those investigating gene interactions between the J20 APP transgene and other genes present on Mmu16 in the mouse.

Berberine modulates amyloid-β peptide generation by activating AMP-activated protein kinase

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by memory deficits and cognitive decline. Excessive amyloid-β (Aβ) peptide aggregates and forms soluble oligomers and insoluble cerebral amyloid plaques, which is widely thought to be the underlying pathogenic mechanism of AD. Therefore, effective regulation of Aβ metabolism is an important aspect of preventing and improving AD. Berberine, which is the main active component of the traditional medicinal herb Coptidis rhizoma, has a positive effect on reducing Aβ levels. However, the exact mechanism involved is unclear and requires more investigation. In the present study, we examined the role of berberine in the activation of AMP-activated protein kinase (AMPK) in neuroblastoma cells and primary cultured neurons and sought to characterize the role of AMPK in the metabolism of Aβ. The results indicate that berberine reduces Aβ generation and decreases the expression of β-site APP cleaving enzyme-1 (BACE1) via activating AMPK in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a/APP695sw), N2a cells, and primary cultured cortical neurons. Therefore, berberine reduced the accumulation of Aβ, which likely contributes to its memory enhancing effect in patients with AD.

GULP1/CED-6 ameliorates amyloid-β toxicity in a Drosophila model of Alzheimer's disease.

Amyloidogenic processing of APP by β- and γ-secretases leads to the generation of amyloid-β peptide (Aβ), and the accumulation of Aβ in senile plaques is a hallmark of Alzheimer’s disease (AD). Understanding the mechanisms of APP processing is therefore paramount. Increasing evidence suggests that APP intracellular domain (AICD) interacting proteins influence APP processing. In this study, we characterized the overexpression of AICD interactor GULP1 in a Drosophila AD model expressing human BACE and APP695. Transgenic GULP1 significantly lowered the levels of both Aβ1-40 and Aβ1-42 without decreasing the BACE and APP695 levels. Overexpression of GULP1 also reduced APP/BACE-mediated retinal degeneration, rescued motor dysfunction and extended longevity of the flies. Our results indicate that GULP1 regulate APP processing and reduce neurotoxicity in a Drosophila AD model.

The pathological roles of NDRG2 in Alzheimer's disease, a study using animal models and APPwt-overexpressed cells.

To investigate the roles of N-myc downstream-regulated gene 2 (NDRG2) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease (AD). In this study, we confirmed the upregulation of NDRG2 in the brains of aging and AD animal models. To explore the role of NDRG2 in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N-SH cells (SK-N-SH APPwt). By silencing and overexpressing gene of NDRG2, we demonstrated that NDRG2-mediated increase in Aβ1-42 was through the pathways of BACE1 and GGA3. NGRG2 improved tau phosphorylation via enhanced activity of CDK5 and decreased Pin1, but it was not affected by GSK3β pathway. NDRG2 might also induce cell apoptosis through the extrinsic (caspase 8) apoptotic pathway by interaction with STAT3. Our study confirmed the upregulation of NDRG2 in AD animal models and demonstrated its important roles in AD pathology. NDRG2 might be a potential target for studying and treatment of AD.

Effects of phenothiazine-structured compounds on APP processing in Alzheimer's disease cellular model

The excess accumulation of amyloid-β (Aβ) peptides derived from the sequential cleavage of amyloid precursor protein (APP) by secretases, is one of the toxic key events leading to neuronal loss in Alzheimer's disease (AD). Studies have shown that cholinergic activity may also be involved in the regulation of APP metabolism. In the current study, we have investigated the roles of toluidine blue O (TBO) and thionine (TH), newly recognized phenothiazine-derived cholinesterase inhibitors, on the metabolism of APP in Chinese hamster ovary cells stably expressing human APP751 and presenilin 1 (PS70 cells). We assessed the effects of both compounds on the levels of Aβ, soluble APP-α (sAPPα), intracellular APP and β-site APP-cleaving enzyme 1 (BACE1). After treatment of PS70 cells with TBO or TH without any side effect on cell viability, the levels of secreted Aβ40, Aβ42 and sAPPα were assayed by specific sandwich ELISAs while APP and BACE1 in cell lysates were analyzed using Western blot. The secreted Aβ40, Aβ42 and sAPPα in TBO- and TH-treated cells were found to be reduced in a dose-dependent manner compared to vehicle-treated cells. Results suggest that TH mitigated the Aβ pathology by lowering APP levels whereas reduced Aβ caused by TBO treatment seems to be the outcome of both less substrate availability and amyloidogenic APP processing. Taken together, our results represent the first report demonstrating that TBO and TH can affect amyloid metabolism in vitro.

Acquisition and reversal of visual discrimination learning in APPSwDI/Nos2−/− (CVN) mice

Studies of cognitive behavior in rodent models of Alzheimer’s disease (AD) are the mainstay of academic and industrial efforts to find effective treatments for this disorder. However, in the majority of such studies, the nature of rodent behavioral tests is considerably different from the setting associated with cognitive assessments of individuals with AD. The recently developed touchscreen technique provides a more translational way of rodent cognitive testing because the stimulus (images in different locations on the screen) and reaction (touch) are similar to those employed in human test routines, such as the Cambridge Neuropsychological Test Automated Battery. Here, we used Visual Discrimination and Reversal of Visual Discrimination touchscreen tasks to assess cognitive performance of APPSwDI/Nos2−/− (CVN) mice, which express mutated human APP and have a homozygous deletion of the Nos2 gene. We revealed that CVN mice made more first-time errors and received more correction trials than WT mice across both discrimination and reversal phases, although mutation effect size was larger during the latter phase. These results indicate sensitivity of touchscreen-based measurements to AD-relevant mutations in CVN mice and warrant future touchscreen experiments aimed at evaluating other cognitive and motivational phenotypes in this AD mouse model.

Amelioration of amyloid-\u03b2-induced deficits by DcR3 in an Alzheimer\u2019s disease model

BackgroundMicroglia mediate amyloid-beta peptide (Aβ)-induced neuroinflammation, which is one of the key events in the pathogenesis of Alzheimer’s disease (AD). Decoy receptor 3 (DcR3)/TNFRSF6B is a pleiotropic immunomodulator that promotes macrophage differentiation toward the M2 anti-inflammatory phenotype. Based on its role as an immunosupressor, we examined whether DcR3 could alleviate neuroinflammation and AD-like deficits in the central nervous system.MethodWe crossed human APP transgenic mice (line J20) with human DcR3 transgenic mice to generate wild-type, APP, DcR3, and APP/DcR3 mice for pathological analysis. The Morris water maze, fear conditioning test, open-field, and elevated-plus maze were used to access their cognitive behavioral changes. Furthermore, the pathological and immune profiles were examined by immunostaining, ELISA, Q-PCR, and IP. In vitro assays were designed to examine DcR3-mediated innate cytokine profile alteration and the potential protective mechanism.ResultsWe reported that DcR3 ameliorates hippocampus-dependent memory deficits and reduces amyloid plaque deposition in APP transgenic mouse. The protective mechanism of DcR3 mediates through interacting with heparan sulfate proteoglycans and activating IL-4+YM1+ M2a-like microglia that reduces Aβ-induced proinflammatory cytokines and promotes phagocytosis ability of microglia.ConclusionThe neuroprotective effect of DcR3 is mediated via modulating microglia activation into anti-inflammatory M2a phenotype, and upregulating DcR3 expression in the brain may be a potential therapeutic approach for AD.

MJustice: Preliminary Development of a Mobile App for Medical-Forensic Documentation of Sexual Violence in Low-Resource Environments and Conflict Zones.

Digital health development and use has been expansive and operationalized in a variety of settings and modalities around the world, including in low- and middle-income countries. Mobile applications have been developed for a variety of health professionals and frontline health workers including physicians, midwives, nurses, and community health workers. However, there are no published studies on the development and use of digital health related to human rights fieldwork and to our knowledge no mobile health platforms exist specifically for use by frontline health workers to forensically and clinically document sexual violence. We describe a participatory development and user design process with Congolese end-users of a novel human rights app for clinicians intended to standardize the documentation of sexual violence evidence for forensic and legal purposes, called MediCapt. The app, yet to be launched and still in the future proofing phase, has included several development phases: (1) initial needs assessment conducted in 2011, (2) prototype development and field-testing in 2014 with 8 Congolese physicians, (3) prototype refinement and field-testing in 2015 with 9 clinicians. Feedback from the first field-testing phase was incorporated into the design of the second prototype; key features that were added to MediCapt include the ability for users to take photographs and draw on a pictogram to include as part of the evidence package, as well as the ability to print a form with the completed data. Questionnaires and key-informant interviews during the second and third field-testing phases revealed overall positive attitudes about MediCapt, but multiple perceived and actual barriers to implementation were identified, from personal behaviors, such as individual clinicians' comfort with new technology, to more systemic and infrastructure factors, such as strong cultural preferences for print documentation of evidence and limited Internet connectivity. Next phases of development include consideration of patients' acceptance of this technology, how it actually fits in the clinical workflow, and testing of how to transfer the collected evidence to law enforcement and legal authorities. Ultimately, we plan on conducting a robust evaluation to assess effectiveness of the app on medical, legal, and human rights outcomes. We believe our experience of collecting data that will potentially serve as legal evidence broadens the traditional scope of digital health and crosses a wide range of fields including medical, technological, legal, and ethical, and thus propose refining and defining this unique field of exploration as mobile justice, or mJustice.

Investigations into Retinal Pathology in the Early Stages of a Mouse Model of Alzheimer's Disease.

There is increasing recognition that visual performance is impaired in early stages of Alzheimer’s disease (AD); however, no consensus exists as to the mechanisms underlying this visual dysfunction, in particular regarding the timing, nature, and extent of retinal versus cortical pathology. If retinal pathology presents sufficiently early, it offers great potential as a source of novel biomarkers for disease diagnosis. The current project utilized an array of immunochemical and molecular tools to perform a characterization of retinal pathology in the early stages of disease progression using a well-validated mouse model of AD (APPSWE/PS1ΔE9). Analytical endpoints included examination of aberrant amyloid and tau in the retina, quantification of any neuronal degeneration, delineation of cellular stress responses of neurons and particularly glial cells, and investigation of oxidative stress. Brain, eyes, and optic nerves were taken from transgenic and wild-type mice of 3 to 12 months of age and processed for immunohistochemistry, qPCR, or western immunoblotting. The results revealed robust expression of the human APP transgene in the retinas of transgenic mice, but a lack of identifiable retinal pathology during the period when amyloid deposits were dramatically escalating in the brain. We were unable to demonstrate the presence of amyloid plaques, dystrophic neurites, neuronal loss, macro- or micro-gliosis, aberrant cell cycle re-entry, oxidative stress, tau hyperphosphorylation, or upregulations of proinflammatory cytokines or stress signaling molecules in the retina. The overall results do not support the hypothesis that detectable retinal pathology occurs concurrently with escalating amyloid deposition in the brains of APPSWE/PS1ΔE9 mice.

Development of a Reporter System for In Vivo Monitoring of γ-Secretase Activity in Drosophila.

The γ-secretase complex represents an evolutionarily conserved family of transmembrane aspartyl proteases that cleave numerous type-I membrane proteins, including the β-amyloid precursor protein (APP) and the receptor Notch. All known rare mutations in APP and the γ-secretase catalytic component, presenilin, which lead to increased amyloid βpeptide production, are responsible for early-onset familial Alzheimer’s disease. β-amyloid protein precursor-like (APPL) is the Drosophila ortholog of human APP. Here, we created Notch- and APPL-based Drosophila reporter systems for in vivo monitoring of γ-secretase activity. Ectopic expression of the Notch- and APPL-based chimeric reporters in wings results in vein truncation phenotypes. Reporter-mediated vein truncation phenotypes are enhanced by the Notch gain-of-function allele and suppressed by RNAi-mediated knockdown of presenilin. Furthermore, we find that apoptosis partly contributes to the vein truncation phenotypes of the APPL-based reporter, but not to the vein truncation phenotypes of the Notch-based reporter. Taken together, these results suggest that both in vivo reporter systems provide a powerful genetic tool to identify genes that modulate γ-secretase activity and/or APPL metabolism.

Vulnerability of primary neurons derived from Tg2576 Alzheimer mice to oxygen and glucose deprivation: role of intraneuronal amyloid-β accumulation and astrocytes.

ABSTRACTMicrovascular dysfunction is considered an integral part of Alzheimer disease (AD) pathogenesis, but the possible relationship between amyloid pathology, microvascular dysfunction and cell death is still unclear. In order to investigate the influence of intraneuronal amyloid-β (Aβ) accumulation on vulnerability to hypoxia, we isolated primary cortical neurons from Tg2576 (carrying the amyloid precursor protein APPSwe mutation) and wild-type fetal mice. We first demonstrated that neurons isolated from Tg2576 newborn mice show an increase in VEGFa mRNA expression and a decrease in the expression of the two VEGF receptors, Flt1 and Kdr, compared with wild-type cells. Moreover, APPSwe primary neurons displayed higher spontaneous and glutamate-induced cell death. We then deprived the cultures of oxygen and glucose (OGD) as an in vitro model of hypoxia. After OGD, APPSwe neurons display higher levels of cell death in terms of percentage of pyknotic/fragmented nuclei and mitochondrial depolarization, accompanied by an increase in the intraneuronal Aβ content. To explore the influence of intraneuronal Aβ peptide accumulation, we used the γ-secretase inhibitor LY450139, which showed that the reduction of the intracellular amyloid fully protects APPSwe neurons from OGD-induced degeneration. Conditioned medium from OGD-exposed APPSwe or wild-type astrocytes protected APPswe neurons but not wild-type neurons, during OGD. In conclusion, the presence of the mutated human APP gene, leading to the intracellular accumulation of APP and Aβ fragments, worsens OGD toxicity. Protection of APPSwe neurons can be obtained either using a γ-secretase inhibitor or astrocyte conditioned medium.

Altered brain structural networks in the APP/PS1 mice: evidence from multi-shell diffusion imaging

Altered brain structural networks in the APP/PS1 mice: evidence from multi-shell diffusion imaging

Amyloid β Is Not the Major Factor Accounting for Impaired Adult Hippocampal Neurogenesis in Mice Overexpressing Amyloid Precursor Protein.

SummaryAdult hippocampal neurogenesis was impaired in several Alzheimer's disease models overexpressing mutant human amyloid precursor protein (hAPP). However, the effects of wild-type hAPP on adult neurogenesis and whether the impaired adult hippocampal neurogenesis was caused by amyloid β (Aβ) or APP remained unclear. Here, we found that neurogenesis was impaired in the dentate gyrus (DG) of adult mice overexpressing wild-type hAPP (hAPP-I5) compared with controls. However, the adult hippocampal neurogenesis was more severely impaired in hAPP-I5 than that in hAPP-J20 mice, which express similar levels of hAPP mRNA but much higher levels of Aβ. Furthermore, reducing Aβ levels did not affect the number of doublecortin-positive cells in the DG of hAPP-J20 mice. Our results suggested that hAPP was more likely an important factor inhibiting adult neurogenesis, and Aβ was not the major factor affecting neurogenesis in the adult hippocampus of hAPP mice.

Preclinical Assessment of Young Blood Plasma for Alzheimer Disease

Alzheimer disease (AD) pathology starts long before clinical symptoms manifest, and there is no therapy to treat, delay, or prevent the disease. A shared blood circulation between 2 mice (aka parabiosis) or repeated injections of young blood plasma (plasma from 2- to 3-month-old mice) into old mice has revealed benefits of young plasma on synaptic function and behavior. However, to our knowledge, the potential benefit of young blood has not been tested in preclinical models of neurodegeneration or AD. To determine whether young blood plasma ameliorates pathology and cognition in a mouse model for AD and could be a possible future treatment for the disease. In this preclinical study, mice that harbor a human mutant APP gene, which causes familial AD, were aged to develop AD-like disease including accumulation of amyloid plaques, loss of synaptic and neuronal proteins, and behavioral deficits. The initial parabiosis studies were done in 2010, and the final studies were conducted in 2014. Alzheimer disease model mice were then treated either by surgically connecting them with a young healthy mouse, thus providing a shared blood circulation through parabiosis, or through repeated injections of plasma from young mice. Neuropathological parameters and changes in hippocampal gene expression in response to the treatment were assessed. In addition, cognition was tested in AD model mice intravenously injected with young blood plasma. Aged mutant amyloid precursor protein mice with established disease showed a near complete restoration in levels of synaptic and neuronal proteins after exposure to young blood in parabiosis (synaptophysin P = .02; calbindin P = .02) or following intravenous plasma administration (synaptophysin P < .001; calbindin P = .14). Amyloid plaques were not affected, but the beneficial effects in neurons in the hippocampus were accompanied by a reversal of abnormal extracellular receptor kinase signaling (P = .05), a kinase implicated in AD. Moreover, young plasma administration was associated with improved working memory (P = .01) and associative memory (P = .02) in amyloid precursor protein mice. Factors in young blood have the potential to ameliorate disease in a model of AD.

ALTERNATIVE CLEAVAGE MECHANISM OF HUMAN APP BY BACE1

ALTERNATIVE CLEAVAGE MECHANISM OF HUMAN APP BY BACE1

Decreased Plasma Aβ in Hyperlipidemic APPSL Transgenic Mice Is Associated with BBB Dysfunction.

Besides the continued focus on Aβ and Tau in Alzheimer's disease (AD), it is increasingly evident that other pathologic characteristics, such as vascular alterations or inflammation, are associated with AD. Whether these changes are an initial cause for the onset of AD or occur as a result of the disease in late stages is still under debate. In the present study, the impact of the high-fat diet (HFD) induced vascular risk factor hyperlipidemia on Aβ levels and clearance as well as cerebral vasculature and blood-brain barrier (BBB) integrity was examined in mice. For this purpose, human APP transgenic (APPSL) and wildtype (WT) mice were fed a HFD for 12 weeks. Plasma and tissues were subsequently investigated for Aβ distribution and concentrations of several vascular markers. Decreased plasma Aβ together with increased levels of insoluble Aβ and amyloid plaques in the brains of HFD fed APPSL mice point toward impaired Aβ clearance due to HFD. Additionally, HFD induced manifold alterations in the cerebral vasculature and BBB integrity exclusively in human APP overexpressing mice but not in wildtype mice. Therefore, HFD appears to enhance Aβ dependent vascular/BBB dysfunction in combination with an increased proportion of cerebral to plasma Aβ in APPSL mice.

Mobile big-data-driven rating framework: measuring the relationship between human mobility and app usage behavior

Smart devices bring us ubiquitous mobile access to the Internet, making it possible to surf the Internet in mobile environments. With the pervasiveness of mobile Internet, much evidence shows that human mobility has heavy impact on app usage behavior. However, the relationship between them has not been quantified in any form. In this article, a rating framework is presented to demonstrate the existence of their connection. The core idea of a rating framework selects the most significant mobility features that may influence app usage behavior. In particular, we focus on three aspects of human mobility in urban areas: individual mobility characteristics, location, and travel behavior, from both the crowd and individual points of view. At last, by using a limited number of selected mobility and time features, high forecast accuracy is achieved in terms of app usage behavior of crowds and individuals, which verifies the effectiveness of the rating framework.

Amyloid β accumulation and inner retinal degenerative changes in Alzheimer’s disease transgenic mouse

The APP-PS1ΔE9 mouse model of Alzheimer’s disease (AD) exhibits age dependent amyloid β (Aβ) plaque formation in their central nervous system due to high expression of mutated human APP and PSEN1 transgenes. Here we evaluated Aβ deposition and changes in soluble Aβ accumulation in the retinas of aged APP-PS1 mice using a combination of immunofluorescence, retinal flat mounts and western blotting techniques. Aβ accumulation in the retina has previously been shown to be associated with retinal ganglion cell apoptosis in animal models of glaucoma. This study investigated changes in the inner retinal function and structure in APP-PS1 mice using electrophysiology and histological approaches respectively. We report for the first time a significant decline in scotopic threshold response (STR) amplitudes which represents inner retinal function in transgenic animals compared to the wild type counterparts (p<0.0001). Thinning of the retina particularly involving inner retinal layers and reduction in axonal density in the optic nerve was also observed. TUNEL staining was performed to examine neuronal apoptosis in the inner retina. Intraocular pressure (IOP) measurements showed that APP-PS1ΔE9 mice had a slightly elevated IOP, but the significance of this finding is not yet known. Together, these results substantiate previous observations and highlight that APP-PS1ΔE9 mice show evidence of molecular, functional and morphological degenerative changes in the inner retina.

The amyloid hypothesis of Alzheimer's disease at 25years.

Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.