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Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10−8. We additionally detected 14 novel loci at P < 5 × 10−7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer’s, and Parkinson’s (F5, MAP1B, and BCAS3), with Alzheimer’s pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

Higher plasma total-tau level is associated with incident dementia, but its relationship with stroke risk is unknown. In this prospective community-based study, we evaluated plasma total-tau level as a biomarker of stroke risk in 2,794 Framingham Heart Study participants. Persons with plasma total-tau levels in the top quintile, versus the bottom 4, had an increased risk of incident stroke over a mean follow-up of 8.3 years (hazard ratio = 2.01; 95% confidence interval = 1.32-3.08) following adjustments for age, sex, and stroke risk factors. Our findings demonstrate that plasma total-tau relates to the risk of stroke in a community sample. ANN NEUROL 2019;86:463-467.

© 2021 - IOS Press. All rights reserved. Background: The apolipoprotein E (APOE) ϵ4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ϵ4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ϵ4 heterozygotes; 50 ϵ4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ϵ4 heterozygotes; 31 ϵ4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ϵ4 homozygotes compared with ϵ4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ϵ4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ϵ4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ϵ4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ϵ4 homozygosity increases with older age. APOE ϵ4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.

ObjectiveGiven the potential therapeutic effect of vascular disease control timing to reduce dementia risk, we investigated the age-related influences of vascular risk factor burden on brain structure throughout the lifespan.MethodsWe studied participants from the community-based prospective Framingham Heart Study. Overall vascular risk factor burden was calculated according to the Framingham Stroke Risk Profile, a validated algorithm that predicts stroke risk. Brain volume was estimated by MRI. We used cross-sectional data to examine how the strength of association between vascular risk factor burden and brain volume changed across each age decade from age 45-54 years through to 85-94 years (N = 2,887). Second, we leveraged up to 40 years of longitudinal data to determine how the strength of association between vascular risk factor burden and brain volume changed when vascular risk factors were examined at progressively earlier ages (N = 7,868).ResultsIn both cross-sectional and longitudinal analyses, higher vascular risk factor burden was associated with lower brain volume across each age decade. In the cross-sectional analysis, the strength of this association decreased with each decade of advancing age (p for trend < 0.0001). In longitudinal analysis, the strength of association between vascular risk factor burden and brain volume was stronger when vascular risk factors were measured at younger ages. For example, vascular risk factor burden was most strongly associated with lower brain volume in later life when vascular risk factors were measured at age 45 years.ConclusionVascular risk factors at younger ages appear to have detrimental effects on current and future brain volume.

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95% CI, 1.22-1.95] and 1.37 [95% CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95% CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, in

BackgroundWe determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample.MethodsWe measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.ResultsDuring a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures.ConclusionsHigher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95% CI, 1.22-1.95] and 1.37 [95% CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95% CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, in

BackgroundWe determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample.MethodsWe measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.ResultsDuring a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures.ConclusionsHigher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

ObjectiveTo determine the association between plasma insulin-like growth factor binding protein 2 (IGFBP-2) and cognitive outcomes.MethodsWe measured plasma IGFBP-2 levels in 1596 (53% women, mean age 68.7 [SD 5.7] years) dementia-free Framingham Offspring cohort participants between 1998 and 2001. Multivariable Cox proportional hazards models related plasma IGFBP-2 to subsequent risk of incident dementia and Alzheimer's disease. MRI brain measures and cognitive performance were included as secondary outcomes.ResultsDuring a median follow-up of 11.8 (Q1, Q3: 7.1, 13.3) years, 131 participants developed incident dementia, of whom 98 were diagnosed with Alzheimer's disease. The highest tertile of IGFBP-2, compared to the lowest tertile, was associated with an increased risk of incident all-cause dementia (hazard ratio [HR] 2.89, 95% CI 1.63-5.13) and Alzheimer's disease (HR 3.63, 95% CI 1.76-7.50) in multivariable analysis. Higher circulating IGFBP2 levels were also cross-sectionally associated with poorer performance on tests of abstract reasoning but not with MRI-based outcomes. After adding plasma IGFBP-2 levels to a conventional dementia prediction model, 32% of individuals with dementia were correctly assigned a higher predicted risk, while 8% of individuals without dementia were correctly assigned a lower predicted risk (overall net reclassification improvement index, 0.40, 95% CI 0.22-0.59).InterpretationElevated circulating IGFBP-2 levels were associated with an increased risk of both all-cause dementia and Alzheimer's disease. Addition of IGFBP2 plasma levels to a model of traditional risk factors significantly improved dementia risk classification. Manipulation of insulin-like growth factor signaling via IGFBP-2 may be a promising therapeutic target for dementia.

ObjectiveTo determine the association between plasma insulin-like growth factor binding protein 2 (IGFBP-2) and cognitive outcomes.MethodsWe measured plasma IGFBP-2 levels in 1596 (53% women, mean age 68.7 [SD 5.7] years) dementia-free Framingham Offspring cohort participants between 1998 and 2001. Multivariable Cox proportional hazards models related plasma IGFBP-2 to subsequent risk of incident dementia and Alzheimer's disease. MRI brain measures and cognitive performance were included as secondary outcomes.ResultsDuring a median follow-up of 11.8 (Q1, Q3: 7.1, 13.3) years, 131 participants developed incident dementia, of whom 98 were diagnosed with Alzheimer's disease. The highest tertile of IGFBP-2, compared to the lowest tertile, was associated with an increased risk of incident all-cause dementia (hazard ratio [HR] 2.89, 95% CI 1.63-5.13) and Alzheimer's disease (HR 3.63, 95% CI 1.76-7.50) in multivariable analysis. Higher circulating IGFBP2 levels were also cross-sectionally associated with poorer performance on tests of abstract reasoning but not with MRI-based outcomes. After adding plasma IGFBP-2 levels to a conventional dementia prediction model, 32% of individuals with dementia were correctly assigned a higher predicted risk, while 8% of individuals without dementia were correctly assigned a lower predicted risk (overall net reclassification improvement index, 0.40, 95% CI 0.22-0.59).InterpretationElevated circulating IGFBP-2 levels were associated with an increased risk of both all-cause dementia and Alzheimer's disease. Addition of IGFBP2 plasma levels to a model of traditional risk factors significantly improved dementia risk classification. Manipulation of insulin-like growth factor signaling via IGFBP-2 may be a promising therapeutic target for dementia.

Background and purposeThe American Heart Association developed the ideal cardiovascular health (CVH) index as a simple tool to promote CVH; yet, its association with brain atrophy and dementia remains unexamined.MethodsOur aim was to investigate the prospective association of ideal CVH with vascular brain injury, including the 10-year risks of incident stroke and dementia, as well as cognitive decline and brain atrophy on magnetic resonance imaging, measured for ≈7 years. We studied 2750 stroke- and dementia-free Framingham Heart Study Offspring cohort participants (mean age, 62±9 years; 45% men). Ideal CVH was quantified on a 7-point scale with 1 point awarded for each of the following: nonsmoking status, ideal body mass index, regular physical activity, healthy diet, as well as optimum blood pressure, cholesterol, and fasting blood glucose. Both recent (baseline) and remote (6.9 years earlier) ideal CVH scores were examined.ResultsRecent ideal CVH was associated with stroke (hazard ratio, 0.80; 95% confidence interval, 0.67-0.95), vascular dementia (hazard ratio, 0.49; 95% confidence interval, 0.30-0.81), frontal brain atrophy (P=0.003), and cognitive decline on tasks measuring visual memory and reasoning (P<0.05). In addition to predicting stroke, vascular dementia, whole-brain atrophy, and cognitive decline, remote ideal CVH was associated with the incidence of all-cause dementia (hazard ratio, 0.80; 95% confidence interval, 0.67-0.97) and Alzheimer disease (hazard ratio, 0.79; 95% confidence interval, 0.64-0.98).ConclusionsAdherence to the American Heart Association's ideal CVH factors and behaviors, particularly in midlife, may protect against cerebrovascular disease and dementia.

Background and purposePrevious reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid-femoral pulse wave velocity (CFPWV) and systolic blood pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts.MethodsIn 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses.ResultsCFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040; P<0.001, and a'=0.020; P>0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=-0.092; P<0.001, and b'=0.012; P>0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246; P<0.001, and c'=0.116; P>0.05).ConclusionsFrom these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.

Background and purposePrevious work from the Framingham Heart Study suggests that brain changes because of arterial aging may begin in young adulthood and that such changes precede cognitive deficits. The objective of this study was to determine the association of arterial stiffness with measures of white matter and gray matter (GM) integrity in young adults.MethodsOne thousand nine hundred three participants from the Framingham Heart Study Third Generation (mean age, 46±8.7 years) had complete tonometry measurements and brain magnetic resonance imaging (T1-weighted and diffusion tensor imaging). Tonometry measures included carotid-femoral pulse wave velocity, augmentation index, carotid-brachial pressure amplification, and central pulse pressure. Fractional anisotropy and GM density images were computed from diffusion tensor imaging and T1 images. Registration to a common anatomic template enabled voxel-based linear regressions relating measures of fractional anisotropy and GM to tonometry measures, adjusting for relevant covariables.ResultsHigher carotid-femoral pulse wave velocity was associated with lower regional fractional anisotropy, including the corpus callosum and the corona radiata (8.7 and 8.6 cc, respectively, P<0.001), as well as lower GM density in the thalamus region (0.9 cc, P<0.001). Analyses did not reveal significant associations between other tonometry measures and fractional anisotropy or GM.ConclusionsAmong young healthy adults, higher aortic stiffness was associated with measures of reduced white matter and GM integrity in areas implicated in cognitive decline and Alzheimer's disease. Greater aortic stiffness may result in subclinical vascular brain injury at ages much younger than previously described.

There is growing evidence that certain plants have evolved to contain bioactive compounds that can modulate behaviour, including cognitive performance. This chapter briefly summarises the evidence pertaining to selected herbal extracts ginseng, Ginkgo biloba, Salvia, L-theanine, green tea catechins, Bacopa and guarana. The focus is on evidence from well-controlled human trials examining the acute effects of supplementation in healthy adults. Although not discussed here, it should be noted that there is emerging evidence that some herbal extracts may also have chronic cognitive benefits in various clinical and non-clinical populations. Certain botanical extracts have reliable cognition-enhancing properties in various populations. These appear to be similar in magnitude to the effects of pharmaceutical cognitive enhancers. In some cases, the mechanisms of action are reasonably well established, for example, pro-cholinergic (e.g. cholinesterase inhibiting) effects of sage. In most cases, multiple synergistic actions are likely to be involved. One constant challenge for the psychopharmacology of herbal extracts is the use of standardised extracts to allow rigorous and replicable evaluation of their behavioural properties.

There is growing evidence that certain plants have evolved to contain bioactive compounds that can modulate behaviour, including cognitive performance. This chapter briefly summarises the evidence pertaining to selected herbal extracts ginseng, Ginkgo biloba, Salvia, L-theanine, green tea catechins, Bacopa and guarana. The focus is on evidence from well-controlled human trials examining the acute effects of supplementation in healthy adults. Although not discussed here, it should be noted that there is emerging evidence that some herbal extracts may also have chronic cognitive benefits in various clinical and non-clinical populations. Certain botanical extracts have reliable cognition-enhancing properties in various populations. These appear to be similar in magnitude to the effects of pharmaceutical cognitive enhancers. In some cases, the mechanisms of action are reasonably well established, for example, pro-cholinergic (e.g. cholinesterase inhibiting) effects of sage. In most cases, multiple synergistic actions are likely to be involved. One constant challenge for the psychopharmacology of herbal extracts is the use of standardised extracts to allow rigorous and replicable evaluation of their behavioural properties.

The present randomized, placebo-controlled, double-blind, parallel-groups clinical trial examined the effects of fish oil and multivitamin supplementation on the incorporation of n-3 and n-6 fatty acids into red blood cells. Healthy adult humans (n = 160) were randomized to receive 6 g of fish oil, 6 g of fish oil plus a multivitamin, 3 g of fish oil plus a multivitamin or a placebo daily for 16 weeks. Treatment with 6 g of fish oil, with or without a daily multivitamin, led to higher eicosapentaenoic acid (EPA) composition at endpoint. Docosahexaenoic acid (DHA) composition was unchanged following treatment. The long chain LC n-3 PUFA index was only higher, compared to placebo, in the group receiving the combination of 6 g of fish oil and the multivitamin. Analysis by gender revealed that all treatments increased EPA incorporation in females while, in males, EPA was only significantly increased by the 6 g fish oil multivitamin combination. There was considerable individual variability in the red blood cell incorporation of EPA and DHA at endpoint. Gender contributed to a large proportion of this variability with females generally showing higher LC n-3 PUFA composition at endpoint. In conclusion, the incorporation of LC n-3 PUFA into red blood cells was influenced by dosage, the concurrent intake of vitamin/minerals and gender.

Background One of the major challenges associated with our ageing population is the increasing incidence of age-associated cognitive decline, which has significant implications for an individual's ability to lead a productive and fulfilling life. In pure economic terms the costs of ageing reflects decreased productivity and engagement with the workforce. The maintenance of brain health underpinning intact cognition is a key factor to maintaining a positive, engaged, and productive lifestyle. In light of this, the role of diet, including supplementation with nutritional and even pharmacological interventions capable of ameliorating the neurocognitive changes that occur with age constitute vital areas of research. Methods In order to reduce cognitive ageing, the ARC longevity intervention (ARCLI) was developed to examine the effects of two promising natural pharmacologically active supplements on cognitive performance. ARCLI is a randomized, placebo-controlled, double-blind, 3-arm clinical trial in which 465 participants will be randomized to receive an extract of Bacopa monnieri (CDRI08 300 mg/day), Pycnogenol (150 mg/day), or placebo daily for 12 months. Participants will be tested at baseline and then at 3, 6 and 12 months post-randomization on a wide battery of cognitive, neuropsychological and mood measures, cardiovascular (brachial and aortic systolic and diastolic blood pressures as well as arterial stiffness), biochemical (assays to measure inflammation, oxidative stress and safety) as well as genetic assessments (telomere length and several Single Nucleotide Polymorphisms). The primary aim is to investigate the effects of these supplements on cognitive performance. The secondary aims are to explore the time-course of cognitive enhancement as well as potential cardiovascular and biochemical mechanisms underpinning cognitive enhancement over the 12 months of administration. ARCLI will represent one of the largest and most comprehensive experimental clinical tri

Parmenter, B. H., Croft, K. D., Cribb, L., Cooke, M. B., Bondonno, C. P., Lea, A., . . . Bondonno, N. P. (2021). Higher habitual dietary flavonoid intake associates with lower central blood pressure and arterial stiffness in healthy older adults. British Journal of Nutrition. Advance online publication. https://doi.org/10.1017/S000711452100324X