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The accumulation of oxidized ApoB-100-containing lipoproteins in the vascular intima and its subsequent recognition by macrophages results in foam cell formation and inflammation, key events during atherosclerosis development. Agents targeting this process are considered potentially atheroprotective. Since natural biflavonoids exert antioxidant and anti-inflammatory effects, we evaluated the atheroprotective effect of biflavonoids obtained from the tropical fruit tree . To this end, the pure biflavonoid aglycones morelloflavone (Mo) and volkensiflavone (Vo), as well as the morelloflavone's glycoside fukugiside (Fu) were tested in primary macrophages, whereas a biflavonoid fraction with defined composition (85% Mo, 10% Vo, and 5% Amentoflavone) was tested and . All biflavonoid preparations were potent reactive oxygen species (ROS) scavengers in the oxygen radical absorbance capacity assay, and most importantly, protected low-density lipoprotein particle from both lipid and protein oxidation. In biflavonoid-treated macrophages, the surface expression of the oxidized LDL (oxLDL) receptor CD36 was significantly lower than in vehicle-treated macrophages. Uptake of fluorescently labeled oxLDL and cholesterol accumulation were also attenuated in biflavonoid-treated macrophages and followed a pattern that paralleled that of CD36 surface expression. Fu and Vo inhibited oxLDL-induced ROS production and interleukin (IL)-6 secretion, respectively, whereas all aglycones, but not the glucoside Fu, inhibited the secretion of one or more of the cytokines IL-1β, IL-12p70, and monocyte chemotactic protein-1 (MCP-1) in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, in macrophages primed with low-dose LPS and stimulated with cholesterol crystals, IL-1β secretion was significantly and comparably inhibited by all biflavonoid preparations. Intraperitoneal administration of the defined biflavonoid fraction into ApoE mice was atheroprotective, as evidenced by the reduction of the atheromatous lesion size and the density of T cells and macrophages infiltrating the aortic root; moreover, this treatment also lowered the circulating levels of cholesterol and the lipid peroxidation product malondialdehyde. These results reveal the potent atheroprotective effects exerted by biflavonoids on key events of the oxLDL-macrophage interphase: (i) atheroligand formation, (ii) atheroreceptor expression, (iii) foam cell transformation, and (iv) prooxidant/proinflammatory macrophage response. Furthermore, our results also evidence the antioxidant, anti-inflammatory, hypolipemiant, and atheroprotective effects of 's biflavonoids .

Thirteen PSEN1 genetic variants associated with Autosomal Dominant Alzheimer's Disease (ADAD) have been identified in Colombia, providing valuable insights into the preclinical stages of the disease. This study characterizes the clinical and neuropsychological phenotypes of carriers and non-carriers from families with nine pathogenic PSEN1 variants: Glu280Ala, Gln223Lys, His163Arg, Ile162Ser, Ile416Thr, Leu173Phe, Pro264Leu, Pro284Leu, and Thr119Ile. We analyzed baseline clinical and neuropsychological characteristics of participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study (DIAN-OBS), including individuals at both preclinical and symptomatic stages. Descriptive statistics were used to summarize sociodemographic, clinical, and cognitive features, depending on data distribution, and we used Kruskal-Wallis to explore differences between groups. Group comparisons were based on PSEN1 variant and clinical diagnosis, and the age at onset (AAO) of the affected parent was used to determine each subject's estimated years to symptom onset (EYO). The sample included 61 participants (55.7% female), aged 18-58, with a median education of 12 years (IQR: 10-14). Of these, 77% were cognitively unimpaired (MMSE: 30, IQR: 29-30; CDR-SB: 0), 15% had mild cognitive impairment (MMSE: 25.1, SD: 3.6; CDR-SB: 1.9, SD: 1.1), and 8% had dementia (MMSE: 21, SD: 6.5; CDR-SB: 3.9, SD: 3.1). All symptomatic individuals exhibited primarily amnestic symptoms, and one carrier of the PSEN1-Pro284Leu variant presented motor signs. As expected-given that most participants were in preclinical stages-no statistically significant differences in clinical or cognitive features were observed across variants. Twenty-eight participants were in the primary prevention range (EYO: -11 to -35 years) and thirty-three in the secondary prevention range (EYO: -10 to +13 years). Parental age at onset differed by variant location: intramembranous (50 years, IQR: 46-53), cytoplasmic (40.5 years, SD: 4.6), and extracellular (45 years, IQR: 45-48). These findings are consistent with existing literature and underscore the value of characterizing preclinical ADAD cohorts, supported by biomarkers, to guide early diagnostic and therapeutic strategies, especially in the context of clinical trials. We expect to have complete fluid and neuroimaging biomarker and follow-up data for the presentation of these results.

This study evaluates a tailored genetic counseling and testing (GTC) protocol for families at risk of Autosomal Dominant Alzheimer ´s Disease (ADAD) in Latin America, focusing on the essential cultural and regional adaptations. Several factors may influence the decision of whether family members decide to learn genetic status. Although the main drivers influencing the decisions to seek genetic testing have been widely studied in High-Income Counties (HIC), these questions remain relatively unknown in Low and Middle-Income countries (LMICs) such as those in Latin America (LatAm). The primary aim of this study was to investigate the psychosocial impact of genetic testing in asymptomatic individuals from families with ADAD. We conducted a non randomized, controlled trial among ADAD families in Colombia and Argentina. The primary outcome included change from baseline in depression and general anxiety in the test group relative to the control group. Participants were categorized based on their decision to learn their genetic status, with further comparisons between mutation-positive versus mutation-negative individuals within those informed. Psychological impacts were measuring using validated scales for depression and anxiety in the group relative to the control group. Of the 122 eligible participants, 97 completed the GTC protocol; 87 opted to learn their genetic status. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation-positive and mutation-negative individuals. Mutation-positive carriers who learned their genetic status experienced a statistically significant increase in depression scores but remained below the cut-off point considered indicative of clinically significant depression. Our primary finding is showed no clinically meaningful differences in distress-related outcomes between individuals learning their genetic status relative to those who didn't. Our findings confirm that genetic testing is well-tolerated when using a protocol that provides screening, education, counseling, and follow-up sessions. In addition, we provide preliminary insights into the psychological impact associated with learning one's genetic status in familial AD, contributing significantly to the field of medical genetics in the region.

We previously estimated the age of amyloid plaque onset at 28.2 years using florbetapir PET measurements of cerebral amyloid deposition in a cross-sectional study of a convenience sample of PSEN1 E280A carriers and non-carriers, ages 20-56, recruited from the world's largest autosomal dominant Alzheimer's disease (ADAD) cohort. Here we capitalized on longitudinal data from a different sample than used previously, to estimate the age of amyloid onset (EOA) in carriers who were cognitively unimpaired at baseline and examine differences associated with apolipoprotein ε4 (APOE4) status and between men and women. We analyzed baseline, 2-year, and 5-year florbetapir PET scans from 161 initially cognitively unimpairedPSEN1 E280A carriers (ages 30-56) enrolled in the Alzheimer's Prevention Initiative (API) ADAD Colombia Trial of crenezumab vs placebo, in which crenezumab did not lower brain amyloid (NCT01998841). We included PSEN1 E280A carriers with at least 1 amyloid-positive (A+) PET scan, using cortical-to-pontine standard-uptake value ratios converted to centiloids (CL). Out of the 169 PSEN1 E280A carriers in the trial, 12 were A- and 149 were A+ at baseline, we excluded 1 PSEN1 E280A carrier who did not have A+ longitudinal data and 7 who did not have A+ scans at baseline or follow-up. The Sample Iterative Local Approximation (SILA) model was applied to estimate EOA using a 20 CL threshold for positivity. We estimated amyloid chronicity and compared EOAs, adjusted for baseline age, between A+ male (n =68) and female (n =98) PSEN1 E280A carriers and between A+ PSEN1 E280A APOE4-carriers (n =35) and non-carriers (n =126). Median EOA was 26.1 years (SD ±7.89, range 1-54) and estimates were normally distributed. PSEN1 E280A females had a mean EOA of 25.8 years which was not significantly different than the estimates in males (M=27.8 years). PSEN1 E280A APOE4 carriers had an EOA about 3 years younger (M=24.1) than APOE4 non-carriers (M=27.3, p =0.03). This study illustrates the ability to use longitudinal biomarker data to characterize the onset of biomarker changes and impact of putative disease modifiers like APOE4 in ADAD mutation carriers.

Chlorogenic acids (CGA) are the most abundant phenolic compounds in green coffee beans and in the human diet and have been suggested to mitigate several cardiometabolic risk factors. Here, we aimed to evaluate the effect of a water-based standardized green coffee extract (GCE) on cardiometabolic parameters in ApoE-/- mice and to explore the potential underlying mechanisms. Mice were fed an atherogenic diet without (vehicle) or with GCE by gavage (equivalent to 220 mg/kg of CGA) for 14 weeks. We assessed several metabolic, pathological, and inflammatory parameters and inferred gut microbiota composition, diversity, and functional potential. Although GCE did not reduce atherosclerotic lesion progression or plasma lipid levels, it induced important favorable changes. Specifically, improved metabolic parameters, including fasting glucose, insulin resistance, serum leptin, urinary catecholamines, and liver triglycerides, were observed. These changes were accompanied by reduced weight gain, decreased adiposity, lower inflammatory infiltrate in adipose tissue, and protection against liver damage. Interestingly, GCE also modulated hepatic IL-6 and total serum IgM and induced shifts in gut microbiota. Altogether, our results reveal the cooccurrence of these beneficial cardiometabolic effects in response to GCE in the same experimental model and suggest potential mediators and pathways involved.

Background Thirteen PSEN1 genetic variants associated with Autosomal Dominant Alzheimer’s Disease (ADAD) have been identified in Colombia, providing valuable insights into the preclinical stages of the disease. This study characterizes the clinical and neuropsychological phenotypes of carriers and non‐carriers from families with nine pathogenic PSEN1 variants: Glu280Ala, Gln223Lys, His163Arg, Ile162Ser, Ile416Thr, Leu173Phe, Pro264Leu, Pro284Leu, and Thr119Ile. Method We analyzed baseline clinical and neuropsychological characteristics of participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study (DIAN‐OBS), including individuals at both preclinical and symptomatic stages. Descriptive statistics were used to summarize sociodemographic, clinical, and cognitive features, depending on data distribution, and we used Kruskal‐Wallis to explore differences between groups. Group comparisons were based on PSEN1 variant and clinical diagnosis, and the age at onset (AAO) of the affected parent was used to determine each subject's estimated years to symptom onset (EYO). Results The sample included 61 participants (55.7% female), aged 18–58, with a median education of 12 years (IQR: 10–14). Of these, 77% were cognitively unimpaired (MMSE: 30, IQR: 29–30; CDR‐SB: 0), 15% had mild cognitive impairment (MMSE: 25.1, SD: 3.6; CDR‐SB: 1.9, SD: 1.1), and 8% had dementia (MMSE: 21, SD: 6.5; CDR‐SB: 3.9, SD: 3.1). All symptomatic individuals exhibited primarily amnestic symptoms, and one carrier of the PSEN1‐Pro284Leu variant presented motor signs. As expected—given that most participants were in preclinical stages—no statistically significant differences in clinical or cognitive features were observed across variants. Twenty‐eight participants were in the primary prevention range (EYO: ‐11 to ‐35 years) and thirty‐three in the secondary prevention range (EYO: ‐10 to +13 years). Parental age at onset differed by variant location: intramembranous (50 years, IQR: 46–53), cytoplasmic (40.5 years, SD: 4.6), and extracellular (45 years, IQR: 45–48). Conclusion These findings are consistent with existing literature and underscore the value of characterizing preclinical ADAD cohorts, supported by biomarkers, to guide early diagnostic and therapeutic strategies, especially in the context of clinical trials. We expect to have complete fluid and neuroimaging biomarker and follow‐up data for the presentation of these results.

Background This study evaluates a tailored genetic counseling and testing (GTC) protocol for families at risk of Autosomal Dominant Alzheimer ´s Disease (ADAD) in Latin America, focusing on the essential cultural and regional adaptations. Several factors may influence the decision of whether family members decide to learn genetic status. Although the main drivers influencing the decisions to seek genetic testing have been widely studied in High‐Income Counties (HIC), these questions remain relatively unknown in Low and Middle‐Income countries (LMICs) such as those in Latin America (LatAm). Method The primary aim of this study was to investigate the psychosocial impact of genetic testing in asymptomatic individuals from families with ADAD. We conducted a non randomized, controlled trial among ADAD families in Colombia and Argentina. The primary outcome included change from baseline in depression and general anxiety in the test group relative to the control group. Participants were categorized based on their decision to learn their genetic status, with further comparisons between mutation‐positive versus mutation‐negative individuals within those informed. Psychological impacts were measuring using validated scales for depression and anxiety in the group relative to the control group. Result Of the 122 eligible participants, 97 completed the GTC protocol; 87 opted to learn their genetic status. There were no clinically significant differences in psychological distress between those who learned their status and those who did not, nor between mutation‐positive and mutation‐negative individuals. Mutation‐positive carriers who learned their genetic status experienced a statistically significant increase in depression scores but remained below the cut‐off point considered indicative of clinically significant depression. Conclusion Our primary finding is showed no clinically meaningful differences in distress‐related outcomes between individuals learning their genetic status relative to those who didn’t. Our findings confirm that genetic testing is well‐tolerated when using a protocol that provides screening, education, counseling, and follow‐up sessions. In addition, we provide preliminary insights into the psychological impact associated with learning one's genetic status in familial AD, contributing significantly to the field of medical genetics in the region.

Background We previously estimated the age of amyloid plaque onset at 28.2 years using florbetapir PET measurements of cerebral amyloid deposition in a cross‐sectional study of a convenience sample of PSEN1 E280A carriers and non‐carriers, ages 20‐56, recruited from the world's largest autosomal dominant Alzheimer’s disease (ADAD) cohort. Here we capitalized on longitudinal data from a different sample than used previously, to estimate the age of amyloid onset (EOA) in carriers who were cognitively unimpaired at baseline and examine differences associated with apolipoprotein ε4 (APOE4) status and between men and women. Method We analyzed baseline, 2‐year, and 5‐year florbetapir PET scans from 161 initially cognitively unimpairedPSEN1 E280A carriers (ages 30–56) enrolled in the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial of crenezumab vs placebo, in which crenezumab did not lower brain amyloid (NCT01998841). We included PSEN1 E280A carriers with at least 1 amyloid‐positive (A+) PET scan, using cortical‐to‐pontine standard‐uptake value ratios converted to centiloids (CL). Out of the 169 PSEN1 E280A carriers in the trial, 12 were A‐ and 149 were A+ at baseline, we excluded 1 PSEN1 E280A carrier who did not have A+ longitudinal data and 7 who did not have A+ scans at baseline or follow‐up. The Sample Iterative Local Approximation (SILA) model was applied to estimate EOA using a 20 CL threshold for positivity. We estimated amyloid chronicity and compared EOAs, adjusted for baseline age, between A+ male (n =68) and female (n =98) PSEN1 E280A carriers and between A+ PSEN1 E280A APOE4‐carriers (n =35) and non‐carriers (n =126). Result Median EOA was 26.1 years (SD ±7.89, range 1‐54) and estimates were normally distributed. PSEN1 E280A females had a mean EOA of 25.8 years which was not significantly different than the estimates in males (M=27.8 years). PSEN1 E280A APOE4 carriers had an EOA about 3 years younger (M=24.1) than APOE4 non‐carriers (M=27.3, p =0.03). Conclusion This study illustrates the ability to use longitudinal biomarker data to characterize the onset of biomarker changes and impact of putative disease modifiers like APOE4 in ADAD mutation carriers.