Patient-Derived Tumor Xenograft Study with CDK4/6 Inhibitor Plus AKT Inhibitor for the Management of Metastatic Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

Could nudges reduce health literacy disparities in CVD prevention? An experiment using alternative messages for CVD risk assessment screening.

OBJECTIVE: To explore the effect of SMS nudge messages amongst people with varying health literacy on their intention to get a Heart Health Check. METHODS: A 3 (Initial SMS: scarcity, regret, or control nudge) x 2 (Reminder SMS: social norm or control nudge) factorial design was used in a hypothetical online experiment. 705 participants eligible for Heart Health Checks were recruited. Outcomes included intention to attend a Heart Health Check and psychological responses. RESULTS: In the control condition, people with lower health literacy had lower behavioural intentions compared to those with higher health literacy (p = .011). Scarcity and regret nudges closed this gap, resulting in similar intention levels for lower and higher health literacy. There was no interactive effect of the reminder nudge and health literacy (p = .724). CONCLUSION: Scarcity and regret nudge messages closed the health literacy gap in behavioural intentions compared to a control message, while a reminder nudge had limited additional benefit. Health literacy should be considered in behavioural intervention evaluations to ensure health equity is addressed. PRACTICE IMPLICATIONS: Results informed a national screening program using a universal precautions approach, where messages with higher engagement for lower health literacy groups were used in clinical practice.

Risk of Acute Kidney Injury Based on Vancomycin Target Trough Attainment Strategy: Area-Under-the-Curve-Guided Bayesian Software, Nomogram, or Trough-Guided Dosing.

BACKGROUND: Guidelines support area-under-the-curve (AUC) monitoring for vancomycin dosing which may lower overall doses and reduce acute kidney injury (AKI). OBJECTIVE: The aim of this study was to compare incidence of AKI across 3 vancomycin dosing modalities: AUC-targeted Bayesian pharmacokinetic software, AUC-targeted empiric dosing nomogram, and trough-guided dosing using clinical pharmacists' judgment. METHODS: This retrospective study included adult patients with a pharmacy dosing consult who received ≥1 dose of vancomycin and ≥1 serum vancomycin level documented between January 1, 2018, and December 31, 2019. Patients with baseline serum creatinine ≥2 mg/dL, weight ≥100 kg, receiving renal replacement therapy, AKI prior to vancomycin therapy, or vancomycin ordered only for surgical prophylaxis were excluded. The primary analysis was incidence of AKI adjusted for baseline serum creatinine, age, and intensive care unit admission. A secondary outcome was adjusted incidence of an abnormal trough value (<10 or >20 µg/mL). RESULTS: The study included 3459 encounters. Incidence of AKI was 21% for Bayesian software (n = 659), 22% for the nomogram (n = 303), and 32% for trough-guided dosing (n = 2497). Compared with trough-guided dosing, incidence of AKI was lower in the Bayesian (adjusted odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.58-0.89) and the nomogram (adjusted OR = 0.71, 95% CI: 0.53-0.95) groups. Compared with trough-guided dosing, abnormal trough values were less common in the Bayesian group (adjusted OR = 0.83, 95% CI: 0.69-0.98). CONCLUSION AND RELEVANCE: Study results suggest that use of AUC-guided Bayesian software reduces the incidence of AKI and abnormal trough values compared with trough-guided dosing.

REMAP Periop: a randomised, embedded, multifactorial adaptive platform trial protocol for perioperative medicine to determine the optimal enhanced recovery pathway components in complex abdominal surgery patients within a US healthcare system.

INTRODUCTION: Implementation of enhanced recovery pathways (ERPs) has resulted in improved patient-centred outcomes and decreased costs. However, there is a lack of high-level evidence for many ERP elements. We have designed a randomised, embedded, multifactorial, adaptive platform perioperative medicine (REMAP Periop) trial to evaluate the effectiveness of several perioperative therapies for patients undergoing complex abdominal surgery as part of an ERP. This trial will begin with two domains: postoperative nausea/vomiting (PONV) prophylaxis and regional/neuraxial analgesia. Patients enrolled in the trial will be randomised to arms within both domains, with the possibility of adding additional domains in the future. METHODS AND ANALYSIS: In the PONV domain, patients are randomised to optimal versus supraoptimal prophylactic regimens. In the regional/neuraxial domain, patients are randomised to one of five different single-injection techniques/combination of techniques. The primary study endpoint is hospital-free days at 30 days, with additional domain-specific secondary endpoints of PONV incidence and postoperative opioid consumption. The efficacy of an intervention arm within a given domain will be evaluated at regular interim analyses using Bayesian statistical analysis. At the beginning of the trial, participants will have an equal probability of being allocated to any given intervention within a domain (ie, simple 1:1 randomisation), with response adaptive randomisation guiding changes to allocation ratios after interim analyses when applicable based on prespecified statistical triggers. Triggers met at interim analysis may also result in intervention dropping. ETHICS AND DISSEMINATION: The core protocol and domain-specific appendices were approved by the University of Pittsburgh Institutional Review Board. A waiver of informed consent was obtained for this trial. Trial results will be announced to the public and healthcare providers once prespecified statistical triggers of interest are reached as described in the core protocol, and the most favourable interventions will then be implemented as a standardised institutional protocol. TRIAL REGISTRATION NUMBER: NCT04606264.

Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.

Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.

Radiosynthesis and Preliminary Evaluation of [11C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1.

Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme for converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) and plays a key role in endogenous (de novo) fatty acid metabolism. Given that this pathway is broadly upregulated across many tumor types with an aggressive phenotype, SCD1 has emerged as a compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potent and highly specific SCD1 inhibitor with a strong binding affinity for SCD1 at our laboratory. We herein report the radiosynthesis of [11C]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model. Radiotracer [11C]SSI-4 was labeled at the carbamide position via the direct [11C]CO2 fixation on the Synthra MeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellular carcinoma (HCC) cell lines and three renal cell carcinoma (RCC) cell lines. Additionally, in vivo small animal PET/CT imaging with [11C]SSI-4 and the biodistribution were carried out in a mouse model bearing HCC xenografts. Radiotracer [11C]SSI-4 afforded a 4.14 ± 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [11]CO2 radioactivity. The [11C]SSI-4 radiosynthesis time including HPLC purification and SPE formulation was 25 min from the end of bombardment to the end of synthesis (EOS). The radiochemical purity of [11C]SSI-4 was 98.45 ± 1.43% (n = 10) with a molar activity of 225.82 ± 33.54 GBq/µmol (6.10 ± 0.91 Ci/µmol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cell line uptakes demonstrate specific uptake and are blocked by standard compound SSI-4. Preliminary small animal PET/CT imaging study showed high specific uptake and block of [11C]SSI-4 uptake with co-injection of cold SSI-4 in high SCD1-expressing organs including lacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer [11C]SSI-4 was rapidly and automatedly radiosynthesized by direct [11C]CO2 fixation. Our preliminary biological evaluation results suggest [11C]SSI-4 could be a promising radiotracer for PET imaging of SCD1 overexpressing tumor tissues.

The Year in Cardiothoracic Transplant Anesthesia: Selected Highlights From 2021 Part II: Cardiac Transplantation.

This article spotlights the research highlights of this year that specifically pertain to the specialty of anesthesia for heart transplantation. This includes the research on recent developments in the selection and optimization of donors and recipients, including the use of donation after cardiorespiratory death and extended criteria donors, the use of mechanical circulatory support and nonmechanical circulatory support as bridges to transplantation, the effect of COVID-19 on heart transplantation candidates and recipients, and new advances in the perioperative management of these patients, including the use of echocardiography and postoperative outcomes, focusing on renal and cerebral outcomes.

Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology.

BACKGROUND: The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer's disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies. METHODS: We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing. RESULTS: Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-ß (Aß) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aß. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology. CONCLUSION: Taken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.

Pre-Habilitation of Cardiac Surgical Patients, Part 2: Frailty, Malnutrition, Respiratory disease, Alcohol/Smoking cessation and Depression.

The concept of "pre-habilitation" comprises screening for and identification of pre-existing disorders followed by medical optimization. This is performed for many types of surgeries, but may have profound impacts on outcomes, particularly in cardiac surgery given the multiple comorbidities typically carried by these patients. Components of pre-habilitation include direct medical intervention by preoperative specialists as well as significant care coordination and shared decision-making. In this second part of a two-part review, the authors describe existing evidence to support the optimization of various preoperative problems and present a few institutional protocols utilized at out center for cardiac presurgical care. This second installment will focus on alcohol and smoking cessation and the management of frailty, malnutrition, respiratory disease, and depression.

Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia.

TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.

Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.

Prehabilitation of Cardiac Surgical Patients, Part 1: Anemia, Diabetes Mellitus, Obesity, Sleep Apnea, and Cardiac Rehabilitation.

The concept of "prehabilitation" consists of screening for and identification of pre-existing disorders followed by medical optimization. This is performed for many types of surgery, but may have profound impacts on outcomes particularly in cardiac surgery given the multiple comorbidities typically carried by these patients. Components of prehabilitation include direct medical intervention by preoperative specialists as well as significant care coordination and shared decision making. In this two-part review, the authors describe existing evidence to support the optimization of various preoperative problems and present a few institutional protocols utilized by our center for cardiac presurgical care. This first installment will focus on the management of anemia, obesity, sleep apnea, diabetes, and cardiac rehabilitation prior to surgery. The second will focus on frailty, malnutrition, respiratory disease, alcohol and smoking cessation, and depression.

Patient factors associated with the offering of telehealth appointments from primary care physicians among Medicare Beneficiaries: Results from a national survey.

INTRODUCTION: This study assessed patient factors associated with self-reported telehealth offerings from their primary care physicians (PCPs) among Medicare beneficiaries during the COVID-19 pandemic, and compared potential telehealth accessibility of telehealth appointments from PCP by US census region before and during the COVID-19 pandemic. METHODS: Data were from the Medicare Current Beneficiary Survey (MCBS) 2021 Winter COVID-19 Supplement. We conducted a multivariable logistic regression to examine patient-level factors associated with telehealth offerings. RESULTS: Overall, 78% Medicare beneficiaries reported that they had access to telehealth appointments from their PCPs during the COVID-19 pandemic. Majority beneficiary respondents reported to have Internet access (82.1%) and own at least one type of computer device (81.5%). Respondents with Internet access (Adjusted Odds Ratio (AOR) = 1.66, 95% Confidence Interval (CI): 1.38, 2.00; p < 0.0001) and owning a device (AOR = 1.43, 95 %CI: 1.19, 1.72; p < 0.0001) were more likely to report PCP telehealth offerings controlling for patient characteristic variables in the model. Respondents who were female (AOR = 1.16, 95 %CI: 1.02, 1.31; p = 0.020), age group of 65-74 years (AOR = 1.29, 95 %CI: 1.07, 1.56; p = 0.008), income ≥$25,000 (AOR = 1.36, 95 %CI: 1.18 1.56; p < 0.0001), metropolitan residence (AOR = 1.96, 95 %CI: 1.72, 2.24; p < 0.0001), and with a history of weakened immune system (AOR = 1.46, 95 %CI: 1.18, 1.80; p < 0.0001) or diabetes (AOR = 1.20, 95 %CI: 1.06, 1.37; p = 0.005) were more likely to report PCP telehealth offerings compared to their counterparts. Non-Hispanic Black (AOR = 0.70, 95 %CI: 0.58, 0.85; p < 0.0001) (compared to Non-Hispanic-White) and beneficiaries living in the South (compared to those living in the Northwest, Midwest, and West) were less likely to report PCP telehealth offerings. DISCUSSION: Key findings suggested health disparities existed in telehealth offerings from PCPs in terms of Internet access, device owning, age, race/ethnicity, income, residential locations, and census regions. Policy makers should consider these health disparities and provide targeted incentives and/or interventions when expanding and encouraging utilization of telehealth among Medicare beneficiaries.

Intraoperative Hypoxia Independently Associated With the Development of Acute Kidney Injury Following Bilateral Orthotopic Lung Transplantation.

BACKGROUND: Acute kidney injury (AKI) is a common postoperative complication in bilateral orthotopic lung transplant (BOLTx) recipients, but the contribution of intraoperative variables is not well defined. The authors hypothesized that intraoperative hypotension as well as hypoxia and vasopressor use would be associated with the development of postoperative AKI after BOLTx in patients without pre-existing renal dysfunction. METHODS: The authors performed a retrospective analysis of patients undergoing BOLTx at a single center between 2013 and 2017. Intraoperative variables of hemodynamics included duration of mean arterial pressure <55, <60, and <65 mm Hg; duration of oxygen saturation <90%; and vasoactive-inotropic score (VIS). Associations between the occurrence of AKI and intraoperative hypotension, hypoxemia, and VIS were evaluated while controlling for significant confounding variables. RESULTS: AKI occurred in 177 (72%) of 245 patients in postoperative days 1-7. Notable significant differences in univariate analyses included cumulative mechanical support time, maximum VIS, peripheral oxygen saturation <90% for >15 min, total minutes oxygen saturation <90%, and surgery duration in minutes. There was no significant difference in intraoperative hypotension measured as a duration >15 min for mean arterial pressure <55, <60, or <65 mm Hg. Multivariate logistic regression revealed preoperative creatinine (Odds ratio [OR], 7.77; confidence interval [CI], 1.96-30.83; P = 0.004), surgery duration (OR, 1.004; CI, 1.002-1.007; P = 0.002), and oxygen saturation (OR, 2.06; CI, 1.01-4.24; P = 0.049) <90% for >15 min to be independently associated with AKI. CONCLUSIONS: This study revealed that >15 min of intraoperative hypoxia was independently associated with postoperative AKI after BOLTx.

An Approach to Standard Perioperative Transthoracic Echocardiography Practice for Anesthesiologists-Perioperative Transthoracic Echocardiography Protocols.

The use of intraoperative transesophageal echocardiography (TEE) has become the standard of care for most cardiac surgical procedures. There are guidelines established for training, practice, and quality improvement in perioperative TEE by the joint efforts of the American Society of Echocardiography and Society of Cardiovascular Anesthesiologists. Cardiac point-of-care ultrasound (POCUS) increasingly is being incorporated into anesthesiologists' training and practice. While a special "certification in Critical Care Echocardiography" was created by the National Board of Echocardiography in 2019, there currently exist no guidelines for training, certification, and practice of perioperative TTE by anesthesiologists. In this review, the authors describe the categories, indications and applications of perioperative TTE and provide a recommended sequence for performing an examination tailored to the evaluation of perioperative patients. Although the authors describe a protocol utilized at their institution, there are no standards described in the literature for PTTE. Cardiac anesthesiologists and cardiac anesthesia societies (Society of Cardiovascular Anesthesiologists, European Association of Cardiothoracic Anesthesiologists) must come forward to establish standards working in collaboration with echocardiography societies (American Society of Echocardiography, European Society of Cardiology).

Successful Treatment of Invasive Mucormycosis in Orthotopic Liver Transplant Population.

Mucormycosis is caused by ubiquitous fungi and encompasses a variety of different opportunistic syndromes in humans that disproportionately affect immunocompromised patients. Mortality has been documented to range between 50 and 100%; however, location of infection greatly dictates likelihood of survival. Treatment of mucormycosis involves aggressive surgical intervention and combination therapy of antifungal agents. In solid organ transplant recipients, immunosuppressive agents used to prevent rejection of the transplanted organ pose additional obstacles in the treatment of invasive fungal infections. We report on 3 high models for end-stage liver disease (MELD-Na) score orthotopic liver transplant (OLT) recipients who all were diagnosed with Rhizopus spp. infections with positive, 1-year outcomes after aggressive, individualized treatment.

APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia.

Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer's disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.