06165nas 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/9505