Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P =  0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Aß) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aß removal therapy have a pattern of more severe neurodegenerative process.

Generating real-world evidence in Alzheimer's disease: Considerations for establishing a core dataset.

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real-world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real-world settings.

Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: An instrumental variable meta-analysis.

INTRODUCTION: Whether the reduction in brain amyloid beta (Aß) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer's disease (AD) remains debated. METHODS: An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aß standardized uptake value ratio (SUVR) on cognitive and functional decline. RESULTS: Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aß SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively. DISCUSSION: This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aß plaque and a reduction in cognitive and functional decline in patients with AD. HIGHLIGHTS: A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.

Species-specific recognition of Aspergillus fumigatus by Toll-like receptor 1 and Toll-like receptor 6.

BACKGROUND: Aspergillus fumigatus causes invasive aspergillosis, a potentially fatal infection in oncohematological patients. Innate immune detection of A. fumigatus involves Toll-like receptor (TLR) 4 and TLR2, which forms a heterodimer with either TLR1 or TLR6. The role of those coreceptors in Aspergillus sensing is unknown. METHODS: Cytokine production was measured in bone marrow-derived macrophages (BMDMs) from wild-type (WT) and TLR-deficient mice after incubation with a WT and an immunogenic RodA-deficient (ΔrodA-47) strain of A. fumigatus and in lungs from these mice after intranasal mold inoculation. Aspergillus fumigatus-mediated NF-κB activation was measured in HEK293T cells transfected with plasmids expressing mouse or human TLRs. RESULTS: Bone marrow-derived macrophages from TLR1- and TLR6-deficient mice produced lower amounts of interleukin 12p40, CXCL2, interleukin 6, and tumor necrosis factor α than BMDMs from WT mice after stimulation with A. fumigatus. Lungs from TLR1- and TLR6-deficient mice had diminished CXCL1 and CXCL2 production and increased fungal burden after intranasal inoculation of ΔrodA A. fumigatus compared with lungs from WT mice. ΔrodA strain-mediated NF-κB activation was observed in HEK293T cells expressing mouse TLR2/1, mouse TLR2/6, and human TLR2/1 but not human TLR2/6. CONCLUSIONS: Innate immune detection of A. fumigatus is mediated by TLR4 and TLR2 together with TLR1 or TLR6 in mice and TLR1 but not TLR6 in humans.

Histone deacetylase inhibitors impair antibacterial defenses of macrophages.

Histone deacetylases (HDACs) control gene expression by deacetylating histones and nonhistone proteins. HDAC inhibitors (HDACi) are powerful anticancer drugs that exert anti-inflammatory and immunomodulatory activities. We recently reported a proof-of-concept study demonstrating that HDACi increase susceptibility to bacterial infections in vivo. Yet, still little is known about the effects of HDACi on antimicrobial innate immune defenses. Here we show that HDACi belonging to different chemical classes inhibit at multiple levels the response of macrophages to bacterial infection. HDACi reduce the phagocytosis and the killing of Escherichia coli and Staphylococcus aureus by macrophages. In line with these findings, HDACi decrease the expression of phagocytic receptors and inhibit bacteria-induced production of reactive oxygen and nitrogen species by macrophages. Consistently, HDACi impair the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and inducible nitric oxide synthase. These data indicate that HDACi have a strong impact on critical antimicrobial defense mechanisms in macrophages.

Economic and caregiver impact of Alzheimer's disease across the disease spectrum: a cohort study.

BACKGROUND: Alzheimer's disease (AD) substantially increases health-related costs. This study investigates direct medical costs and characterizes the caregiver burden across AD stages. METHODS: This study analyzed data from the French Primary Health Insurance Fund claims database and reflected this public payer perspective. Outpatients (N = 1998) visiting a memory clinic at Lyon University Hospital in France between 2014 and 2019 were included. Real healthcare costs (ie, ambulatory medicine, paramedical care, pharmaceutical treatment, public and private hospital stays, and medical transportation) were collected for patients 1 year prior to the date of the first memory visit and 2 years following the first visit (reference year: 2019). Patients were grouped based on a clinical diagnosis of cognitively normal with a subjective cognitive complaint (SCC), all-cause mild cognitive impairment (MCI), or AD dementia. The severity of AD dementia was defined by the Mini-Mental State Examination score. Caregiver burden was measured using the mini Zarit Burden Interview. A generalized linear model was used for statistical analyses. Other patient nonmedical and indirect costs and caregiver costs were not included. RESULTS: The study sample included patients with SCC (n = 640), MCI (n = 630), mild (n = 212), moderate (n = 256), or moderately severe/severe AD dementia (n = 260). One year after the first consultation, mean total costs were higher with progressive cognitive deficit, with little difference between dementia groups (SCC = €8028; MCI = €9758; mild AD dementia = €10,558; moderate AD dementia = €10,544; moderately severe/severe AD dementia = €10,345; P < .001). Public hospital stays comprised the majority of direct medical costs during the first semester following the visit (49.4% of the total costs), regardless of the severity of cognitive deficit. Caregiver burden increased with the severity of cognitive deficit (P < .0001). CONCLUSIONS: Direct medical costs and caregiver burden rose from SCC to AD dementia; in patients with AD dementia, the direct medical costs increased over the 2 years after the first consultation. These results, in conjunction with data from other care components, will be critical to elucidate the potential economic value of a therapeutic intervention that slows AD progression.

Immunogenetics of invasive aspergillosis.

Invasive aspergillosis is one of the most important infections in hematopoietic stem cell transplant recipients, with an incidence rate of 5-15% and an associated mortality of 30-60%. It remains unclear why certain patients develop invasive aspergillosis while others, undergoing identical transplant regimen and similar post transplant immunosuppression, do not. Over the last decade, pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) have emerged as critical components of the innate immune system. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are strategically located at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and downstream signaling molecules have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming years. Infectious risk stratification may be particularly relevant for patients with hematologic malignancies, because of the high prevalence and severity of infections in this population. This review summarizes the innate immune mechanisms involved in Aspergillus fumigatus detection and the role of host genetic polymorphisms in susceptibility to invasive aspergillosis.

Early Stages of Alzheimer's Disease: Evolving the Care Team for Optimal Patient Management.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease that creates complex challenges and a significant burden for patients and caregivers. Although underlying pathological changes due to AD may be detected in research studies decades prior to symptom onset, many patients in the early stages of AD remain undiagnosed in clinical practice. Increasing evidence points to the importance of an early and accurate AD diagnosis to optimize outcomes for patients and their families, yet many barriers remain along the diagnostic journey. Through a series of international working group meetings, a diverse group of experts contributed their perspectives to create a blueprint for a patient-centered diagnostic journey for individuals in the early stages of AD and an evolving, transdisciplinary care team. Here, we discuss key learnings, implications, and recommendations.

Assessing what matters most to patients with or at risk for Alzheimer's and care partners: a qualitative study evaluating symptoms, impacts, and outcomes.

BACKGROUND: The What Matters Most (WMM) study was initiated to evaluate symptoms, AD-related impacts, treatment-related needs, preferences, and priorities among individuals with or at risk for Alzheimer's disease (AD) and their care partners. The objective of this qualitative study phase was to identify a comprehensive set of concepts of interest that are meaningful to individuals across the AD continuum. METHODS: Interviews were conducted with 60 clinically referred individuals and care partners across 5 AD stages (n = 12 each): group 1 (non-clinically impaired individuals with AD pathology), group 2 (individuals with mild cognitive impairment and AD pathology), group 3 (individuals with mild AD), group 4 (individuals with moderate AD and their care partners), and group 5 (care partners of individuals with severe AD). Interviews were conducted by experienced interviewers, audio-recorded, and transcribed. Dominant trends were identified in each interview and compared across subsequent interviews to generate themes or patterns in descriptions of AD symptoms, impacts, and desired treatment outcomes. RESULTS: All participants endorsed current issues related to memory; nearly all participants (n = 55; 92%) across the five groups endorsed symptoms related to communication and language. Groups 1-3 reported an impact on mood/emotions (n = 23; 64%) and a decrease in social activities or outgoingness (n = 17; 47%). Current and future concerns reported by the overall sample included memory (n = 48; 80%), dependence (n = 40; 67%), and "other" concerns (n = 33; 55.0%) (e.g., uncertainty about the future, burdening others). The most desired AD treatment outcomes were improvement or restoration of memory (n = 40; 67%) and stopping AD progression (n = 35; 58.3%). Group-level differences were observed in the symptoms, impacts, and desired treatment outcomes among patients and care partners across the AD continuum. CONCLUSIONS: Cognitive functioning issues-particularly in memory and communication-are present even in preclinical and early-stage AD, including among those without a formal AD diagnosis. While the impacts of AD vary across the disease-severity spectrum, improved memory and disease modification were treatment outcomes considered most important to participants across all 5 AD stages. Neuropsychological assessments traditionally used in AD clinical trials may not evaluate the often-subtle concepts that are important to patients and care partners. Results from this study will inform the second phase of the WMM project-a quantitative study to elicit the relative importance of these concepts of interest to people at risk for and living with AD and their care partners.