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Stroke is the second leading cause of mortality globally with higher burden and younger age in low‐middle income countries (LMICs) than high‐income countries (HICs). However, it is unclear to what extent differences in healthcare access and quality (HAQ) and prevalence of risk factors between LMICs and HICs contribute to younger age of stroke in LMICs. In this systematic review, we conducted meta‐analysis of 67 articles and compared the mean age of stroke between LMICs and HICs, before and after adjusting for HAQ index. We also compared the prevalence of main stroke risk factors between HICs and LMICs. The unadjusted mean age of stroke in LMICs was significantly lower than HICs (63.1 vs. 68.6), regardless of gender (63.9 vs. 66.6 among men, and 65.6 vs. 70.7 among women) and whether data were collected in population‐ (64.7 vs. 69.5) or hospital‐based (62.6 vs. 65.9) studies (all p < 0.01). However, after adjusting for HAQ index, the difference in the mean age of stroke between LMICs and HICs was not significant (p ≥ 0.10), except among women (p = 0.048). In addition, while the median prevalence of hypertension in LMICs was 23.4% higher than HICs, the prevalence of all other risk factors was lower in LMICs than HICs. Our findings suggest a much larger contribution of HAQ to the younger mean age of stroke in LMICs, as compared with other potential factors. Additional studies on stroke care quality and accessibility are needed in LMICs.

Bacterial resistance is propagated in part by metallo-β-lactamases, which hydrolyze and inactivate β-lactam antibiotics. An unusual cysteine residue in the active site is now shown to be critical for retaining the second metal ion, and thus enzyme activity, at low zinc concentrations. A number of multiresistant bacterial pathogens inactivate antibiotics by producing Zn( II )-dependent β-lactamases. We show that metal uptake leading to an active dinuclear enzyme in the periplasmic space of Gram-negative bacteria is ensured by a cysteine residue, an unusual metal ligand in oxidizing environments. Kinetic, structural and affinity data show that such Zn( II )-cysteine interaction is an adaptive trait that tunes the metal binding affinity, thus enabling antibiotic resistance at restrictive Zn( II ) concentrations.

Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations. We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP, PSEN1, and PSEN2 and with two or more individuals with EOAD. We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 (CLN3) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.

The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4 ; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4- mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain ( COL6A2 ) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P  = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P  = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4 -mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b —the ortholog for human FN1 . We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4 , and LOF variants in FN1 may reduce APOEε4 -related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

Existing initiatives to improve physical, mental, and social condition of senior citizens, which in Europe fall under the name of Active and Healthy Ageing, are including technological paradigms as main driver for innovation uptake. Among these paradigms, Smart Cities and the Internet of Things are of utmost importance. However, these initiatives may benefit from unified visions, efforts, and frameworks when it comes to defining technological solutions that take the most of both paradigms. We have defined an iterative approach, which combines user centred design techniques, technological development approaches, and a multifaceted adaptation process, to define a solution for Active and Healthy Ageing that makes use of the two paradigms. The solution is being defined in the context of two research and innovation projects, City4Age and ACTIVAGE, during which a solution is going to be defined and evaluated in the city of Madrid. Results show how Smart Cities and Internet of Things contribute to the solution, from a user (user needs and use cases) and a service delivery (technologies, architecture, and suppliers) perspective. In conclusion, we find the cocreation framework extremely useful for the Active and Health Ageing domain, and the proposed implementation of it is functioning, although there is room for improvement.

Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P  = 4.06 × 10 –8 ), the intergenic region between VRTN and SYNDIG1L (Score = − 37.67, P  = 2.25 × 10 –9 ), SPG7 (16q24.3) (Score = 40.51, P  = 2.23 × 10 –8 ), PVRL2 (Score = 125.86, P  = 1.64 × 10 –9 ), TOMM40 (Score = − 18.58, P  = 4.61 × 10 –8 ), and APOE (Score = 75.12, P  = 7.26 × 10 –26 ). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20 , CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L ( P  = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH ( P  < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

Background Hispanics, one of the fastest‐growing populations in the United States, are disproportionately affected by Alzheimer’s disease (AD). Understanding the variations in AD risk associated with sex and the impact of relocation from their home country is crucial in designing interventions to address health disparities. This study explores the differential impact of sex and geographic relocation on dementia risk and its associated factors among Hispanics. Method We utilized data from two observational samples, encompassing 4,960 individuals from the Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), primarily based in the Dominican Republic, and 2,614 individuals enrolled in the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP), based in the US. In both, we evaluated AD‐related risk factors and biomarker concentrations by sex and disease status, using two‐sample t‐tests and chi‐squared tests. We assessed AD risk across the full sample and conducted sex‐stratified logistic regression analyses, along with linear regression to compare biomarker concentrations and disease onset age among sexes. Results In the EFIGA study, the risk of AD was found to be lower among women (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI]: 0.75‐0.98), whereas in WHICAP, no significant sex‐based differences were observed. Concerning the age of onset, women in EFIGA exhibited an earlier onset (β = ‐1.42, p < 0.001), contrasting with a later onset in WHICAP (β = 1.02, p = 0.007). In the sex‐stratified analyses, both men (OR = 1.66, 95% CI: 1.32‐2.09) and women (OR = 1.64, 95% CI: 1.40‐1.91) in EFIGA showed distinct associations of AD with APOE ε4, a pattern only seen among women in WHICAP (OR = 1.34, 95% CI: 1.06‐1.68). With respect to biomarker concentrations, sex‐related differences were noted in Ab42/40 ratio, total tau, phosphorylated tau, glial fibrillary acidic protein, and neurofilament light, although the specific patterns varied between WHICAP and EFIGA. Conclusion Sex‐related differences in AD risk and associated factors among Hispanics, were evident in both EFIGA and WHICAP studies, and are potentially further influenced by geographic relocation and migration patterns.

Background Plasma biomarkers may be utilized to assist in diagnosis of Alzheimer's disease. However, in a cohort of Caribbean Hispanic individuals we have shown that there are both individuals who are biomarker positive but without dementia, and biomarker negative but diagnosed with dementia. Here we examine education and neuropsychological testing performance in these subgroups with biomarker‐inconsistent dementia diagnosis. Method Adults of Caribbean Hispanic ethnicity were recruited in both New York City and the Dominican Republic. The group reported here includes 1173 individuals. Plasma biomarkers including AB40, AB42, total tau, phosphorylated‐tau181, Neurofilament light chain (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured in samples processed, stored at ‐80°C, and thawed for analysis. Measurements were made using the Simoa Quanterix HD‐X platform. Result In this group of 1172 individuals, 885 (75.5%) were assessed as clinically without dementia, and 288 (24.5%) as clinically with dementia. Of those without dementia, 627 (70.8%) were biomarker negative, and 258 (29.2%) were biomarker positive for p‐tau181. Of those with dementia, 173 (60.1%) were biomarker positive, and 115 (39.9%) were biomarker negative for p‐tau181. For those without dementia, there was no significant difference in education level or performance on most neuropsychological measures between those biomarker positive or negative, except that delayed recall on the SRT word‐list‐learning test was lower in those with higher p‐tau181 (mean 4.25 ± 2.27 vs. 4.65 ± 1.98; p=0.009). For those with dementia, education was significantly lower in those that were p‐tau181 negative (2.87 ± 3.36 vs. 4.18 ± 4.73 yr;p=0.011), but these individuals also performed significantly better in neuropsychological tests including SRT immediate (p=0.003) and delayed recall (p<0.001), orientation (p=0.002), and Benton‐matching (p=0.012). Conclusion Plasma biomarkers may perform well in diagnosis of dementia in clinic populations, but less well in underserved populations, with more persons without dementia but with positive biomarkers, and with dementia but with negative biomarkers. For those without dementia but with positive biomarkers, likely many have pre‐symptomatic Alzheimer's; lower performance on memory tests supports this explanation. For those with dementia, but without positive biomarkers, explanations may include lower cognitive reserve/educational attainment level, increased comorbidities affecting functional status, and the presence of non‐Alzheimer's brain disorders.

Background Despite concerns about the transferability of polygenic risk scores (PRS) derived from European ancestry data to Hispanics, recent research suggests that many genetic loci identified through European ancestry genome‐wide association studies (GWAS) for complex traits are also relevant in Hispanics. Furthermore, studies on dementia have shown improved PRS performance in this group, even with PRS developed from European GWAS. Recent research also indicates that APOE ε4‐independent PRS associations vary depending on APOE ε4 status. This study evaluates the relationship between multiple recent European GWAS‐derived APOE‐independent PRS in Hispanics and the interaction between APOE ε4 and PRS in relation to Alzheimer’s Disease (AD). Methods We constructed a range of PRS based on three recently published GWAS (Kunkle et al., 2019, Bellenguez et al., 2022, FinnGen) of European ancestry among 1,429 Hispanics from the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP) using clumping and thresholding methods. For each GWAS, we first evaluated the associations of several P‐value thresholds with AD to determine the threshold for further analysis. Empirical P‐values were used to avoid overfitting for the optimized PRS. We then tested whether and how APOE ε4 can modify the association between PRS and AD. All associations were fitted by logistic regression with sex, age, education, and the first 5 principal components as covariates. Results Across all European GWAS, the optimal P‐threshold for the most predictive PRS is at a conservative P‐threshold (Kunkle: 2.87e‐6, Bellenguez: 1.11e‐6, FinnGen: 1.80e‐5). PRS constructed based on the Bellenguez GWAS are most strongly associated with AD (OR = 1.29, 95% CI: 1.17‐1.42), and the FinnGen‐derived PRS show the least association (OR = 1.06, 95% CI: 0.98‐1.14). The association of all three PRSs is stronger among APOΕ ε4 carriers (ORKunkle: 1.51, 95% CI: 1.26‐1.81; ORBellenguez: 1.60, 95% CI: 1.35‐1.91; ORFinnGen: 1.12, 95% CI: 0.97‐1.26) compared to non‐carriers (ORKunkle: 1.09, 95% CI: 0.96‐1.23; ORBellenguez: 1.16, 95% CI: 1.03‐1.31; ORFinnGen: 1.03, 95% CI: 0.93‐1.14). Similar findings were observed concerning cognition and progression to dementia. Conclusion PRS derived from a European GWAS identified individuals at high risk for AD dementia among Hispanics, and the association is strongest among APOE ε4 carriers.