Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population

Licher, Silvan; Ahmad, Shahzad; Karamujić‐Čomić, Hata; Voortman, Trudy; Leening, Maarten J.G.; Ikram, M. Arfan; Ikram, Mohammad Kamran

doi:10.1038/s41591-019-0547-7

Cited by 142 publications

(132 citation statements)

References 42 publications

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“…A consistent finding for all cancers was that individuals in the top 20% of the PRS distribution with an unfavorable modifiable risk factor profile had the highest level of risk, with evidence that the effects of PRS and modifiable risk factors may be synergistic. Similar risk stratification results based on genetic and modifiable risk factors have also been reported for coronary disease 28 and Alzheimer's 29 . Taken together, our results suggest that PRS can provide more accurate risk estimates for individuals with wide variation in cancer predisposition based on lifestylerelated risk factors.…”

Section: Discussionsupporting

confidence: 78%

Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction

Kachuri¹,

Graff²,

Smith‐Byrne

et al. 2020

Preprint

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Cancer risk is determined by a complex interplay of genetic and modifiable risk factors. Combining individual germline risk variants into polygenic risk scores (PRS) creates a personalized genetic susceptibility profile that can be leveraged for disease prediction. Using data from the UK Biobank cohort (413,753 individuals; 22,755 incident cases), we systematically quantify the added predictive value of augmenting conventional cancer risk factors with PRS for 16 cancer types. Our results indicate that incorporating PRS in addition to family history of cancer and modifiable risk factors improves prediction accuracy, but the magnitude of incremental improvement varies substantially between cancers. We also demonstrate the utility of PRS for risk stratification. Individuals with high genetic risk (PRS≥80 th percentile) have significantly divergent 5-year absolute risk trajectories across strata based on family history and modifiable risk factors. Finally, we estimate that high genetic risk accounts for 4.0% to 30.3% of new cancer cases, which exceeds the impact of many lifestyle-related risk factors. In summary, we provide novel quantitative data illustrating the importance of integrating PRS into personalized cancer risk assessment.

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Section: Discussionsupporting

confidence: 78%

Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction

Kachuri¹,

Graff²,

Smith‐Byrne

et al. 2020

Preprint

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“…However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset an increased genetic risk. Using long-term data on genetic and modifiable risk factors [226], we demonstrated that in individuals at low and intermediate genetic risk, favourable modifiable-risk profiles, including no current smoking, absence of depression, absence of diabetes, regular physical activity, absence of social isolation and adherence to a healthy diet, were related to a lower risk of dementia compared to unfavourable profiles. In contrast, these protective associations were not found in those at high genetic risk.…”

Section: Main Findings In the Last 3 Yearsmentioning

confidence: 98%

Objectives, design and main findings until 2020 from the Rotterdam Study

et al. 2020

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The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

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“…Age is, therefore, considered to be the strongest non-modifiable risk factor for development of dementia. Numerous clinical studies have proposed that a low level of apolipoprotein E (APOE) genotype [ 51 , 52 , 53 ] along with its genetic variations [ 54 , 55 ] increases the risk of dementia; especially for individuals where dementia has been diagnosed in first-degree relatives (see Table 2 ). The APOE, which is co-responsible for carrying various fats such as cholesterol through the bloodstream, plays an important role in regulation of the neurotoxic amyloid beta (Aβ) peptide.…”

Section: Other Established (Non-)modifiable Risk Factors and Possimentioning

confidence: 99%

Association of Late Life Depression, (Non-) Modifiable Risk and Protective Factors with Dementia and Alzheimer’s Disease: Literature Review on Current Evidences, Preventive Interventions and Possible Future Trends in Prevention and Treatment of Dementia

Kuo

Stachiv

Nikolai

2020

IJERPH

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The number of people living with dementia and Alzheimer’s disease is growing rapidly, making dementia one of the biggest challenges for this century. Many studies have indicated that depression plays an important role in development of dementia, including Alzheimer’s disease; depression, especially, during the late life may either increase the risk of dementia or even being its prodromal stage. Despite a notably large number of carried observational studies and/or clinical trials, the association between the late life depression and dementia remains, due to the complexity of their relationship, still unclear. Moreover, during past two decades multiple other (non-)modifiable risk and possibly protective factors such as the hypertension, social engagement, obesity, level of education or physical (in)activity have been identified and their relationship with the risk for development of dementia and Alzheimer’s disease has been extensively studied. It has been proposed that to understand mechanisms of dementia and Alzheimer’s disease pathogeneses require their multifactorial nature represented by these multiple factors to be considered. In this review, we first summarize the recent literature findings on roles of the late life depression and the other known (non-)modifiable risk and possibly protective factors in development of dementia and Alzheimer’s disease. Then, we provide evidences supporting hypotheses that (i) depressive syndromes in late life may indicate the prodromal stage of dementia (Alzheimer’s disease) and, (ii) the interplay among the multiple (non-)modifiable risk and protective factors should be considered to gain a better understanding of dementia and Alzheimer’s disease pathogeneses. We also discuss the evidences of recently established interventions considered to prevent or delay the prodromes of dementia and provide the prospective future directions in prevention and treatment of dementia and Alzheimer’s disease using both the single-domain and multidomain interventions.

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Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population

Cited by 142 publications

References 42 publications

Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction

Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction

Objectives, design and main findings until 2020 from the Rotterdam Study

Association of Late Life Depression, (Non-) Modifiable Risk and Protective Factors with Dementia and Alzheimer’s Disease: Literature Review on Current Evidences, Preventive Interventions and Possible Future Trends in Prevention and Treatment of Dementia

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