Polygenic Score Integrating Neurodegenerative and Vascular Risk Informs Dementia Risk Stratification

Introduction: An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high-risk individuals and improve risk prediction.

Methods: We developed an iPRS for dementia (iPRS-DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [APOE]). iPRS-DEM was evaluated across cohorts comprising older community-dwelling people (N = 3702), a multi-ancestry biobank (N = 130,797 Europeans; 105,404 non-Europeans), and dementia-free memory clinic participants (N = 2032).

Results: iPRS-DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR]= 1.15, 95% confidence interval [CI]: 1.03 to 1.28), which generalized to Europeans (EUR-sHR= 1.28, 95% CI: 1.09 to 1.51]), East-Asians (EAS-sHR= 5.29, 95% CI: 1.43 to 34.36), and memory-clinic participants (sHR= 1.25, 95% CI: 1.11 to 1.42). Prediction was comparable to clinical risk factors in older community-dwelling people, with improved performance among memory-clinic patients. Risk stratification was enhanced by defining four genetic risk groups with iPRS-DEM and APOE ε4, reaching five-fold increased risk in APOE ε4+/iPRS-DEM+ memory-clinic participants.

Discussion: Alongside APOE ε4, iPRS-DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs.

Highlights: iPRS-DEM reflects neurodegenerative and vascular contribution to dementia. We show iPRS-DEM captures additional dementia genetic risk beyond APOE and AD-PRS. iPRS-DEM, in combination with APOE ε4, shows promise for dementia risk stratification. Our results generalize across both population-based and memory-clinic settings. We show transportability of iPRS-DEM to East Asian ancestry.

References

Solomon A, Turunen H, Ngandu T, Peltonen M, Levalahti E, Helisalmi S . Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle Intervention: A Subgroup Analysis of a Randomized Clinical Trial. JAMA Neurol. 2018; 75(4):462-470. PMC: 5885273. DOI: 10.1001/jamaneurol.2017.4365. View

van der Lee S, Wolters F, Ikram M, Hofman A, Ikram M, Amin N . The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study. Lancet Neurol. 2018; 17(5):434-444. DOI: 10.1016/S1474-4422(18)30053-X. View

Weuve J, Proust-Lima C, Power M, Gross A, Hofer S, Thiebaut R . Guidelines for reporting methodological challenges and evaluating potential bias in dementia research. Alzheimers Dement. 2015; 11(9):1098-109. PMC: 4655106. DOI: 10.1016/j.jalz.2015.06.1885. View

Prive F, Arbel J, Vilhjalmsson B . LDpred2: better, faster, stronger. Bioinformatics. 2020; 36(22-23):5424-5431. PMC: 8016455. DOI: 10.1093/bioinformatics/btaa1029. View

Kattan M, Gerds T . The index of prediction accuracy: an intuitive measure useful for evaluating risk prediction models. Diagn Progn Res. 2019; 2:7. PMC: 6460739. DOI: 10.1186/s41512-018-0029-2. View

. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022; 7(2):e105-e125. PMC: 8810394. DOI: 10.1016/S2468-2667(21)00249-8. View

Cholerton B, Larson E, Quinn J, Zabetian C, Mata I, Keene C . Precision Medicine: Clarity for the Complexity of Dementia. Am J Pathol. 2016; 186(3):500-6. PMC: 4816691. DOI: 10.1016/j.ajpath.2015.12.001. View

Denz R, Klaassen-Mielke R, Timmesfeld N . A comparison of different methods to adjust survival curves for confounders. Stat Med. 2023; 42(10):1461-1479. DOI: 10.1002/sim.9681. View

Snyder H, Corriveau R, Craft S, Faber J, Greenberg S, Knopman D . Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement. 2014; 11(6):710-7. PMC: 4731036. DOI: 10.1016/j.jalz.2014.10.008. View

10.

Park S, Park J, Kim H, Park S . Review of Statistical Methods for Evaluating the Performance of Survival or Other Time-to-Event Prediction Models (from Conventional to Deep Learning Approaches). Korean J Radiol. 2021; 22(10):1697-1707. PMC: 8484151. DOI: 10.3348/kjr.2021.0223. View

11.

Friedman J, Hastie T, Tibshirani R . Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw. 2010; 33(1):1-22. PMC: 2929880. View

12.

Harrison J, Mistry S, Muskett N, Escott-Price V . From Polygenic Scores to Precision Medicine in Alzheimer's Disease: A Systematic Review. J Alzheimers Dis. 2020; 74(4):1271-1283. PMC: 7242840. DOI: 10.3233/JAD-191233. View

13.

Austin P, Lee D, Fine J . Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation. 2016; 133(6):601-9. PMC: 4741409. DOI: 10.1161/CIRCULATIONAHA.115.017719. View

14.

Frisoni G, Altomare D, Ribaldi F, Villain N, Brayne C, Mukadam N . Dementia prevention in memory clinics: recommendations from the European task force for brain health services. Lancet Reg Health Eur. 2023; 26:100576. PMC: 9989648. DOI: 10.1016/j.lanepe.2022.100576. View

15.

Hansson O, Blennow K, Zetterberg H, Dage J . Blood biomarkers for Alzheimer's disease in clinical practice and trials. Nat Aging. 2023; 3(5):506-519. PMC: 10979350. DOI: 10.1038/s43587-023-00403-3. View

16.

Choi S, OReilly P . PRSice-2: Polygenic Risk Score software for biobank-scale data. Gigascience. 2019; 8(7). PMC: 6629542. DOI: 10.1093/gigascience/giz082. View

17.

Ware E, Faul J, Mitchell C, Bakulski K . Considering the APOE locus in Alzheimer's disease polygenic scores in the Health and Retirement Study: a longitudinal panel study. BMC Med Genomics. 2020; 13(1):164. PMC: 7607711. DOI: 10.1186/s12920-020-00815-9. View

18.

Myserlis E, Georgakis M, Demel S, Sekar P, Chung J, Malik R . A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage. Stroke. 2023; 54(4):973-982. PMC: 10050100. DOI: 10.1161/STROKEAHA.122.041701. View

19.

Debette S, Seshadri S . Vascular risk factors and dementia revisited. J Neurol Neurosurg Psychiatry. 2009; 80(11):1183-4. PMC: 2837356. DOI: 10.1136/jnnp.2009.181289. View

20.

Marston N, Pirruccello J, Melloni G, Koyama S, Kamanu F, Weng L . Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention. JAMA Cardiol. 2022; 8(2):130-137. PMC: 9857431. DOI: 10.1001/jamacardio.2022.4466. View