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Due to the high prevalence of Alzheimer's disease (AD) in adults with Down syndrome (DS), trisomy 21 is now considered a genetic form of AD (DSAD). A better understanding of factors that can prevent or delay AD is vital to improve outcomes for adults with DS. In this narrative review, we apply AD and cognitive aging research frameworks to study resistance and resilience in DSAD. Given the variability in the timing of pathology and symptoms, we discuss the evidence supporting the role of genetic, biological, socio‐behavioral, lifestyle, and environmental factors in resistance and resilience to DSAD. We also consider how co‐occurring health conditions in DS may influence resistance and resilience, and how methods from AD research can be applied to DSAD. Ultimately, this framework aims to guide future research and translate findings into clinical interventions to improve outcomes in DSAD. Highlights Definitions of resistance and resilience in the genetic form of Alzheimer's disease (DSAD) are proposed for guiding the field. Variability in the timing of AD pathology and symptoms suggests the potential for resistance and resilience mechanisms in DSAD. Genetic, biological, socio‐behavioral, lifestyle, and environmental factors have the potential to build resistance or resilience in DSAD. Future research will require longitudinal and experimental designs, life course approaches, and large cohort studies.

Background Leveraging Alzheimer’s disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo . Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. Methods We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). Results The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. Conclusion These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Background Stronger default mode (DMN) and bilateral frontoparietal control network (FPCN) resting‐state functional connectivity are associated with reduced β‐amyloid (Aβ)‐related cognitive decline in cognitively unimpaired older adults, who were predominantly Aβ negative. This suggests that these networks might support cognitive resilience in the face of early AD pathology but it remains unclear whether these effects are apparent in preclinical AD. We investigated whether left‐FPCN, right‐FPCN, and DMN connectivity moderated the effect of Aβ on cognitive decline using a large multi‐site dataset from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study. Method Cognitively unimpaired participants with elevated Aβ on screening amyloid‐PET (n=1,062, mean age=71.9 years, 60% women, see Table 1), underwent functional MRI (3T) at baseline. We obtained connectivity estimates of the left‐FPCN, right‐FPCN, and DMN using template‐based rotation (Figure 1). Cognition was measured using the Preclinical Alzheimer’s Cognitive Composite (PACC; average follow‐up including open‐label extension period =280 weeks [SD=115]). We examined three‐way linear and quadratic interactions between functional connectivity and Aβ burden with time in mixed effects models (model 2 = DMN, 3 = left‐FPCN, 4 = right‐FPCN). 1. PACC∼time + covariates×time 2‐4A. PACC∼FC×time + covariates×time 2‐4B. PACC∼FC×Aβ×time + covariates×time 2‐4C. PACC∼FC×Aβ×time + FC×Aβ×time2 + covariates×time Covariates included age, education, APOEe4 status, ICV‐adjusted gray matter volume, treatment group (Solanezumab vs placebo), and head motion. We modeled random effects of intercept and slope for each participant and included scanner as a random effect. Result The three‐way quadratic interaction of connectivity and Aβ burden with time was statistically significant for the left FPCN (p‐value corrected for multiple comparisons =.047, Figure 2), with a moderate effect size. That is, stronger left FPCN connectivity was associated with less cognitive decline in those with elevated Aβ. The pattern of effects were similar, but not statistically significant once all covariates were included, for the right FPCN and DMN. Conclusion In a very large multi‐site clinical trial dataset, individuals with stronger left FPCN connectivity showed reduced Aβ‐related cognitive decline. This effect was specific to the left‐FPCN, in line with previous cross‐sectional findings. Our finding demonstrates that this protective effect of left FPCN connectivity can be observed in preclinical AD.

Background Stronger default mode (DMN) and bilateral frontoparietal control network (FPCN) resting‐state functional connectivity are associated with reduced ß‐amyloid (Aß)‐related cognitive decline in cognitively unimpaired older adults, who were predominantly Aß negative. This suggests that these networks might support cognitive resilience in the face of early AD pathology but it remains unclear whether these effects are apparent in preclinical AD. We investigated whether left‐FPCN, right‐FPCN, and DMN connectivity moderated the effect of Aß on cognitive decline using a large multi‐site dataset from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study. Method Cognitively unimpaired participants with elevated Aß on screening amyloid‐PET (n = 1,062, mean age = 71.9 years, 60% women, see Table1), underwent functional MRI (3T) at baseline. We obtained connectivity estimates of the left‐FPCN, right‐FPCN, and DMN using template‐based rotation (Fig.1). Cognition was measured using the Preclinical Alzheimer’s Cognitive Composite (PACC; average follow‐up including open‐label extension period = 280 weeks [SD = 115]). We examined three‐way linear and quadratic interactions between functional connectivity and Aß burden with time in mixed effects models (model 2 = DMN, 3 = left‐FPCN, 4 = right‐FPCN). 1. PACC∼time + covariates×time 2‐4A. PACC∼FC×time + covariates×time 2‐4B. PACC∼FC×Aß×time + covariates×time 2‐4C. PACC∼FC×Aß×time + FC×Aß×time2 + covariates×time Covariates included age, education, APOEe4 status, ICV‐adjusted gray matter volume, treatment group (Solanezumab vs placebo), and head motion. We modeled random effects of intercept and slope for each participant and included scanner as a random effect. Result The three‐way quadratic interaction of connectivity and Aß burden with time was statistically significant for the left FPCN (p‐value corrected for multiple comparisons = .047, Fig.2), with a moderate effect size. That is, stronger left FPCN connectivity was associated with less cognitive decline in those with elevated Aß. The pattern of effects were similar, but not statistically significant once all covariates were included, for the right FPCN and DMN. Conclusion In a very large multi‐site clinical trial dataset, individuals with stronger left FPCN connectivity showed reduced Aß‐related cognitive decline. This effect was specific to the left‐FPCN, in line with previous cross‐sectional findings. Our finding demonstrates that this protective effect of left FPCN connectivity can be observed in preclinical AD.

Irrigated agriculture contributes 40% of total global food production. In the US High Plains, which produces more than 50 million tons per year of grain, as much as 90% of irrigation originates from groundwater resources, including the Ogallala aquifer. In parts of the High Plains, groundwater resources are being depleted so rapidly that they are considered nonrenewable, compromising food security. When groundwater becomes scarce, groundwater withdrawals peak, causing a subsequent peak in crop production. Previous descriptions of finite natural resource depletion have utilized the Hubbert curve. By coupling the dynamics of groundwater pumping, recharge, and crop production, Hubbert-like curves emerge, responding to the linked variations in groundwater pumping and grain production. On a state level, this approach predicted when groundwater withdrawal and grain production peaked and the lag between them. The lags increased with the adoption of efficient irrigation practices and higher recharge rates. Results indicate that, in Texas, withdrawals peaked in 1966, followed by a peak in grain production 9 y later. After better irrigation technologies were adopted, the lag increased to 15 y from 1997 to 2012. In Kansas, where these technologies were employed concurrently with the rise of irrigated grain production, this lag was predicted to be 24 y starting in 1994. In Nebraska, grain production is projected to continue rising through 2050 because of high recharge rates. While Texas and Nebraska had equal irrigated output in 1975, by 2050, it is projected that Nebraska will have almost 10 times the groundwater-based production of Texas.

The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain–optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

Health maintenance organizations' (HMOs') restrictions on the size of their physician networks may facilitate cost containment and quality improvement activities but may also impede access to care and impose barriers to those wishing to switch health plans or jobs. We examine the extent, variation, and predictors of overlap in HMO physician networks. We predict that people who switch HMOs have a reasonable likelihood (50 percent) of being able to retain their physician. Overlap ranges from an upper quartile of 69 percent to a lower quartile of 34 percent. Group/staff-model HMOs have little overlap, while younger plans, for-profit plans, and plans in small markets have greater overlap. [PUBLICATION ABSTRACT]

Bordetella pertussis releases the monomeric peptidoglycan (PGN) fragment tracheal cytotoxin (TCT) due to inefficient recycling by the permease AmpG. Releasing this PGN is metabolically costly and potentially immune alarming and the benefits to B. pertussis are unclear. While TCT has been characterized as a potent NOD1 agonist capable of causing the extrusion of ciliated cells, in vitro, the consequences of its release have yet to be studied in vivo. Here we show that selective PGN release by B. pertussis biases host PGN sensing toward NOD1 and away from NOD2, suppressing IL-1β-driven inflammation and blunting adaptive immune recruitment. Mice infected with a TCT over-releasing strain (TCT(+)) exhibit reduced pulmonary immunopathology relative to wild type (WT) and a TCT-under-releasing strain (TCT(-)), despite similar bacterial burdens. NOD reporter assays demonstrate that TCT release enhances NOD1 activation and inversely correlates with NOD2 activation. Bulk transcriptomic analysis of infected lungs shows that B. pertussis PGN release dampens pro-inflammatory transcriptional programs. Single-cell transcriptomic determined Nod2 expression is limited to inflammatory myeloid subsets. IL-1 family genes were highly enriched in Nod2- but not Nod1 expressing alveolar macrophages. Upstream regulator analysis predicted IL-1β as a major driver of B. pertussis inflammation, which was enhanced by the absence of PGN release. Flow cytometry shows that PGN release skews macrophages polarization toward M2 and away from M1 in a NOD1 dependent manner. Finally, extracellular release of PGN and subsequent reduced IL-1 production facilitated the suppression fibroblast chemokine programs (e.g., CXCL13, CCL19), diminished recruitment of B and T cells, reduced iBALT formation, and limited immune memory development. Conversely, IL-1R1 deficiency impairs adaptive recruitment and bacterial clearance despite similar innate infiltration. Together, these data suggest PGN release by B. pertussis is an immune-evasion strategy, favoring NOD1 activation over NOD2, reducing IL-1–dependent fibroblast reprogramming, and curtailing chemokine-driven adaptive responses. Graphic Abstract B. pertussis can produce both NOD1 and NOD2 activating PGNs. Release of TCT promotes NOD1 activation and diminishes NOD2 activation. NOD2 activation in myeloid cells drives M1 polarization of macrophages and IL-1 family cytokine production. IL-1 family cytokines skew fibroblasts towards an inflammatory phenotype, leading to chemokine release, extracellular remodeling, and recruitment of lymphocytes. Therefore, TCT release tempers long-term immunity to B. pertussis.

Examines the extent to which health plan quality measures capture physician practice patterns rather than plan characteristics.