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Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.
Thursday,2024-07-11 11:44 America/Los_Angeles — ecterry
| Title | Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Sargurupremraj, M, Soumaré, A, Bis, JC, Surakka, I, Jürgenson, T, Joly, P, Knol, MJ, Wang, R, Yang, Q, Satizabal, CL, Gudjonsson, A, Mishra, A, Bouteloup, V, Phuah, C-L, van Duijn, CM, Cruchaga, C, Dufouil, C, Chene, G, Lopez, OL, Psaty, BM, Tzourio, C, Amouyel, P, Adams, HH, Jacqmin-Gadda, H, Ikram, MArfan, Gudnason, V, Milani, L, Winsvold, BS, Hveem, K, Matthews, PM, Longstreth, WT, Seshadri, S, Launer, LJ, Debette, S |
| Journal | JAMA Netw Open |
| Volume | 7 |
| Issue | 5 |
| Pagination | e2412824 |
| Date Published | 2024 May 01 |
| ISSN | 2574-3805 |
| Keywords | Aged, Aged, 80 and over, Alzheimer Disease, Blood Pressure, Cerebral Small Vessel Diseases, Dementia, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Prospective Studies, Risk Factors, Stroke |
| Abstract | <p><b>IMPORTANCE: </b>Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain.</p><p><b>OBJECTIVE: </b>To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases.</p><p><b>DESIGN, SETTING, AND PARTICIPANTS: </b>This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022.</p><p><b>EXPOSURES: </b>Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations.</p><p><b>MAIN OUTCOMES AND MEASURES: </b>The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses.</p><p><b>RESULTS: </b>In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke.</p><p><b>CONCLUSIONS: </b>These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.</p> |
| DOI | 10.1001/jamanetworkopen.2024.12824 |
| Alternate Journal | JAMA Netw Open |
| PubMed ID | 38776079 |
| PubMed Central ID | PMC11112447 |
ePub date:
24/05