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Given the evidence of the health benefits of plant-based diets and long-chain n-3 (ω-3) fatty acids, there is keen interest in better understanding the role of α-linolenic acid (ALA), a plant-derived n-3 fatty acid, on cardiometabolic diseases and cognition. There is increasing evidence for ALA largely based on its major food sources (i.e., walnuts and flaxseed); however, this lags behind our understanding of long-chain n-3 fatty acids. Meta-analyses of observational studies have shown that increasing dietary ALA is associated with a 10% lower risk of total cardiovascular disease and a 20% reduced risk of fatal coronary heart disease. Three randomized controlled trials (RCTs) [AlphaOmega trial, Prevención con Dieta Mediterránea (PREDIMED) trial, and Lyon Diet Heart Study] all showed benefits of diets high in ALA on cardiovascular-related outcomes, but the AlphaOmega trial, designed to specifically evaluate ALA effects, only showed a trend for benefit. RCTs have shown that dietary ALA reduced total cholesterol, LDL cholesterol, triglycerides, and blood pressure, and epidemiologic studies and some trials also have shown an anti-inflammatory effect of ALA, which collectively account for, in part, the cardiovascular benefits of ALA. A meta-analysis reported a trend toward diabetes risk reduction with both dietary and biomarker ALA. For metabolic syndrome and obesity, the evidence for ALA benefits is inconclusive. The role of ALA in cognition is in the early stages but shows promising evidence of counteracting cognitive impairment. Much has been learned about the health benefits of ALA and with additional research we will be better positioned to make strong evidence-based dietary recommendations for the reduction of many chronic diseases.

Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline. The project leading to this study has received funding from “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN17/50300004. Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant number 2017-SGR-892. EMAU is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018-026053-I).

Background and objectives: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers. Methods: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers. Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions. Discussion: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration. The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Alzheimer's Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under grant 2017-SGR-892. J.D.G. holds a “Ramón y Cajal” fellowship (RYC-2013-13054). E. Arenaza-Urquijo is supported by the Spanish Ministry of Science, Innovation and Universities–Spanish State Research Agency (RYC2018-026053-I). N. Vilor-Tejedor is funded by a postdoctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. Her research has received additional support of “la Caixa” Foundation (LCF/PR/GN17/10300004) and the Health Department of the Catalan Government (Health Research and Innovation Strategic Plan 2016–2020 grant SLT002/16/00201). All Centre for Genomic Regulation authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya. O. Grau-Rivera is supported by the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437) and receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). A. Sala-Vila is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship (CP II 17/00029). H. Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (No. 2018-02532), European Research Council (No. 681712), Swedish State Support for Clinical Research (No. ALFGBG-720931), Alzheimer Drug Discovery Foundation (No. 201809-2016862), and the UK Dementia Research Institute at UCL. K. Blennow is supported by the Swedish Research Council (No. 2017-00915), Alzheimer Drug Discovery Foundation (No. RDAPB-201809-2016615), Swedish Alzheimer Foundation (No. AF-742881), Hjärnfonden, Sweden (No. FO2017-0243), the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (No. ALFGBG-715986), European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), and NIH (No. 1R01AG068398-01). M. Suárez-Calvet receives funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement 948677). M. Suárez-Calvet also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I)

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration. The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/GN17/1030 0 0 04) and the Alzheimer’s Association and an international anonymous char ity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2017-SGR-892. MS-C received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I ). EMA-U is supported by the Spanish Ministry of Science, Innovation and Universities - Spanish State Research Agency ( RYC2018-026053-I ) and is recipient of the Alzheimer’s Association Research Grant ( AARC 2019-AARG 6 446 41). OG-R is supported by the Spanish Ministry of Science, Innovation and Universities ( FJCI-2017-33437 ). JDG holds a ‘Ramón y Cajal’ fellowship ( RYC-2013-13054 ). NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme ( FJC2018-038085-I ), Ministry of Science and Innovation–Spanish State Research Agency. ASV is the recipient of an Instituto de Salud Carlos III Miguel Servet II fellowship ( CP II 17/0 0 029 ). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (# 2018-02532 ), the European Research Council (# 681712 ), Swedish State Support for Clinical Research (# ALFGBG-720931 ), the Alzheimer Drug Discovery Foundation (ADDF), USA (# 201809-2016862 ), and the UK Dementia Research Institute at UCL. KB is supported by the Alzheimer Drug Discovery Foundation (ADDF), USA (# RDAPB-201809-2016615 ), the Swedish Alzheimer Foundation (# AF-742881 ), Hjärnfonden, Sweden (# FO2017-0243 ), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (# ALFGBG-715986 ), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236 )

Information on the association between diet and cardiovascular disease (CVD) in type 1 diabetes (T1D) is scarce. We assessed the association between biomarkers of fatty acid (FA) intake and the presence of carotid plaques (a surrogate marker of future CVD events) in this high-risk population. Cross-sectional study in 167 consecutive T1D patients without CVD and with at least one of the following: ≥ 40 years, diabetic nephropathy, or ≥ 10 years of T1D duration with another CVD risk factor. The FA profile of erythrocyte membranes was determined by gas chromatography, and the number of carotid plaques (intima-media thickness ≥ 1.5 mm) was assessed by ultrasonography. Regression models were constructed adjusting for classical (age, gender, blood pressure, smoking habit, LDL-cholesterol, body mass index and statins) and T1D-specific risk factors (diabetes duration, HbA1c and chronic complications). A total of 58.7% were men (mean age 48.3 ± 10.3 years, T1D duration 27.2 ± 10.1 years). Sixty-one patients (36.5%) showed carotid plaque. Linoleic acid decreased and all-C18:1trans increased with the number of carotid plaques (none, 1–2, ≥ 3 plaques; p for trend

Background RBC long-chain omega-3 (n–3) fatty acid (FA) percentages (of total fatty acids) are associated with lower risk for total mortality, but it is unknown if a suite of FAs could improve risk prediction. Objectives The objective of this study was to compare a combination of RBC FA levels with standard risk factors for cardiovascular disease (CVD) in predicting risk of all-cause mortality. Methods Framingham Offspring Cohort participants without prevalent CVD having RBC FA measurements and relevant baseline clinical covariates (n = 2240) were evaluated during 11 y of follow-up. A forward, stepwise approach was used to systematically evaluate the association of 8 standard risk factors (age, sex, total cholesterol, HDL cholesterol, hypertension treatment, systolic blood pressure, smoking status, and prevalent diabetes) and 28 FA metrics with all-cause mortality. A 10-fold cross-validation process was used to build and validate models adjusted for age and sex. Results Four of 28 FA metrics [14:0, 16:1n–7, 22:0, and omega-3 index (O3I; 20:5n–3 + 22:6n–3)] appeared in ≥5 of the discovery models as significant predictors of all-cause mortality. In age- and sex-adjusted models, a model with 4 FA metrics was at least as good at predicting all-cause mortality as a model including the remaining 6 standard risk factors (C-statistic: 0.778; 95% CI: 0.759, 0.797; compared with C-statistic: 0.777; 95% CI: 0.753, 0.802). A model with 4 FA metrics plus smoking and diabetes (FA + Sm + D) had a higher C-statistic (0.790; 95% CI: 0.770, 0.811) compared with the FA (P

There is an urgent need for cost-effective strategies to promote quality of life in patients with heart failure (HF). Several studies reported benefits in HF prognosis for marine omega-3 fatty acids and plant-based dietary patterns.The aim of this study was to explore whether dietary alpha-linolenic acid (ALA), the main plant omega-3, relates to a better HF prognosis.ALA was determined in serum phospholipids (which reflect long-term dietary ALA intake and metabolism) by gas chromatography in 905 ambulatory patients with HF caused by different etiologies.After a median follow-up of 2.4 years (range: 0.02-3 years), 140 all-cause deaths, 85 cardiovascular (CV) deaths, and 141 first HF hospitalizations (composite of all-cause death and first HF hospitalization, n = 238) were documented. Using Cox regression analyses, we observed that, compared with patients at the lowest quartile of ALA in serum phospholipids (Q1), those at the 3 upper quartiles (Q2-Q4) exhibited a reduction in the risk of composite of all-cause death and first HF hospitalization (HR: 0.61; 95% CI: 0.46-0.81). Statistically significant reductions were observed for all-cause death (HR: 0.58; 95% CI: 0.41-0.82), CV death (HR: 0.51; 95% CI: 0.32-0.80), first HF hospitalization (HR: 0.58; 95% CI: 0.40-0.84), and the composite of CV death and HF hospitalization (HR: 0.58; 95% CI: 0.42-0.79).HF patients with bottom 25% ALA levels in serum phospholipids had a worse prognosis during a mid-term follow-up compared with those with the highest levels. This might be a target population in whom to test dietary ALA-rich interventions to promote quality of life.

Omega-3 fatty acids are critical for brain function. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. In contrast to the abundant research on the omega-3 docosahexaenoic acid (DHA) in cognition, research on DHA and attention in healthy adolescents is scarce. In addition, the role of alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid, is unexplored. We examined associations between DHA and ALA and attention function among a healthy young population. In this cross-sectional study conducted in 372 adolescents (13.8 ± 0.9 years-old), we determined the red blood cell proportions of DHA and ALA by gas chromatography (objective biomarkers of their long-term dietary intake) and measured attention scores through the Attention Network Test. We constructed multivariable linear regression models to analyze associations, controlling for known confounders. Compared to participants at the lowest DHA tertile (reference), those at the highest DHA tertile showed significantly lower hit reaction time-standard error (higher attentiveness) (28.13 ms, 95% confidence interval [CI] = – 52.30; – 3.97), lower hit reaction time ( – 38.30 ms, 95% CI = – 73.28; – 3.33) and lower executive conflict response ( – 5.77 ms, 95% CI = – 11.44; – 0.09). In contrast, higher values were observed in those at the top tertile of ALA in hit reaction time compared to the lowest one (46.14 ms, 95% CI = 9.90; 82.34). However, a beneficial association was observed for ALA, with decreasing impulsivity index across tertiles. Overall, our results suggest that DHA (reflecting its dietary intake) is associated with attention performance in typically developing adolescents. The role of dietary ALA in attention is less clear, although higher blood levels of ALA appear to result in lower impulsivity. Future intervention studies are needed to determine the causality of these associations and to better shape dietary recommendations for brain health during the adolescence period.