02761nas a2200241 4500008004100000022001400041245009800055210006900153260001600222520200500238100002902243700001802272700002102290700002502311700002402336700001902360700001902379700001902398700001702417700002402434700002502458856003602483 2023 eng d a1875-890800aCirculating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.0 aCirculating Omega3 and Omega6 Fatty Acids Cognitive Decline and  c2023 Aug 233 a

BACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.

OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study.

METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.

RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.

CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.

1 aOtto, Marcia, C de Olive1 aH Y Wu, Jason1 aThacker, Evan, L1 aLai, Heidi, Tsz Mung1 aLemaitre, Rozenn, N1 aPadhye, Nikhil1 aSong, Xiaoling1 aKing, Irena, B1 aLopez, Oscar1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/947706165nas a2200505 4500008004100000245012200041210006900163260001600232520464400248100003304892700002104925700001904946700001704965700002204982700001705004700001905021700001605040700001605056700002605072700002605098700001905124700002305143700002105166700002305187700002105210700002005231700002205251700001705273700002005290700002405310700002205334700002005356700002805376700002705404700002405431700001705455700002405472700002005496700002205516700002005538700002005558700002205578700002305600856003605623 2023 eng d00aComplexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.0 aComplexities of cerebral small vessel disease blood pressure and c2023 Aug 133 a

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.

DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.

MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.

RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.

CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

1 aSargurupremraj, Muralidharan1 aSoumaré, Aïcha1 aBis, Joshua, C1 aSurakka, Ida1 aJürgenson, Tuuli1 aJoly, Pierre1 aKnol, Maria, J1 aWang, Ruiqi1 aYang, Qiong1 aSatizabal, Claudia, L1 aGudjonsson, Alexander1 aMishra, Aniket1 aBouteloup, Vincent1 aPhuah, Chia-Ling1 aDuijn, Cornelia, M1 aCruchaga, Carlos1 aDufouil, Carole1 aChene, Geneviève1 aLopez, Oscar1 aPsaty, Bruce, M1 aTzourio, Christophe1 aAmouyel, Philippe1 aAdams, Hieab, H1 aJacqmin-Gadda, Hélène1 aIkram, Mohammad, Arfan1 aGudnason, Vilmundur1 aMilani, Lili1 aWinsvold, Bendik, S1 aHveem, Kristian1 aMatthews, Paul, M1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/950502508nas a2200517 4500008004100000022001400041245015900055210006900214260001300283300001000296490000800306520102300314653000901337653002201346653002001368653001401388653002601402653001901428653001301447653003101460653001101491653002201502653001101524653000901535653001601544653000901560653001701569100002601586700002201612700002101634700002101655700002801676700002001704700001701724700002401741700002001765700001901785700002301804700002401827700001801851700002101869700002201890700001801912700002401930856003601954 2025 eng d a1558-149700aCirculating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.0 aCirculating nonesterified fatty acids risk of dementia and cogni c2025 Apr a71-790 v1483 a

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 % CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.'

10aAged10aAged, 80 and over10aAtherosclerosis10aCognition10aCognitive Dysfunction10aCohort Studies10aDementia10aFatty Acids, Nonesterified10aFemale10aFollow-Up Studies10aHumans10aMale10aMiddle Aged10aRisk10aRisk Factors1 aMoseholm, Kristine, F1 aJensen, Majken, K1 aBůzková, Petra1 aAroner, Sarah, A1 aFitzpatrick, Annette, L1 aLongstreth, W T1 aLopez, Oscar1 aSiscovick, David, S1 aKizer, Jorge, R1 aIx, Joachim, H1 aHughes, Timothy, M1 aHayden, Kathleen, M1 aNomura, Sarah1 aTsai, Michael, Y1 aMcClelland, Robyn1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/9913