Dementia risk: time matters
Authors: Geir Selbæk
Journal: The Lancet Public Health (2021)

Dementia is one of the major global health challenges. With the growing number of older adults in society, dementia poses an increasing threat to global health and has been defined as a public health and social care priority worldwide by WHO.1WHO and Alzheimer's Disease InternationalDementia: a public health priority. World Health Organization, Geneva2012Google Scholar Despite major advances in research on new treatments for dementia, no breakthrough regarding disease-modifying therapy is in sight. However, reports from 2020 indicate that, in theory, up to 40% of dementia cases could be prevented or delayed.2Livingston G Huntley J Sommerlad A et al.Dementia prevention, intervention, and care: 2020 report of the Lancet Commission.Lancet. 2020; 396: 413-446Summary Full Text Full Text PDF PubMed Scopus (1510) Google Scholar Several modifiable risk factors for dementia have been identified. However, conclusive evidence regarding their effect is scarce and difficult to obtain, as the risk is often established several decades before cognitive impairment or dementia can be diagnosed. Furthermore, the directionality of the association with some risk factors is disputed, and the issue of reverse causality has been raised. This possibility of reverse causality is particularly relevant as the degenerative process in Alzheimer's disease, the most common form of dementia, probably starts decades before cognitive impairment can be determined.3Jack Jr, CR Knopman DS Jagust WJ et al.Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers.Lancet Neurol. 2013; 12: 207-216Summary Full Text Full Text PDF PubMed Scopus (2483) Google Scholar To clarify associations and directionality, large population-based cohorts with appropriate assessments of risk, and long follow-up with valid assessments of cognition or dementia endpoints are needed. The UK Million Women Study4Floud S Balkwil A Sweetland S et al.Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.Lancet Public Health. 2021; 6: e116-e123Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar provides a unique opportunity to address this, with its huge sample size and long follow-up. In The Lancet Public Health, Sarah Floud and colleagues report that the association between dementia risk and non-participation in adult education, cultural or art activities, and voluntary work was attenuated with time, indicating that changes in preclinical dementia states could cause increasing inactivity as people age, rather than inactivity being a risk factor for later, clinically-diagnosed dementia. Previous publications have provided similar results regarding a proposed association between dementia risk and low body-mass index, depression, and physical exercise.5Sabia S Dugravot A Dartigues JF et al.Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study.BMJ. 2017; 357j2709Crossref PubMed Scopus (178) Google Scholar The study by Floud and colleagues is an important contribution to the literature but has some limitations, such as potentially imprecise self-reported measures of risk factor exposure, and registry-based outcome data. Further studies are needed to provide more information on the directionality, strength, and timing of the association between modifiable risk factors and dementia, from a lifecourse perspective. Cognitive impairment and dementia disorders are characterised by large heterogeneity in terms of risk factors, cognitive and behavioural symptoms, and pathophysiology. It is crucial to address this heterogeneity when developing precise and effective prevention or treatment strategies. In the expansive literature on the epidemiology of cognitive impairment and dementia, sex or gender have been poorly addressed. Studies usually include sex as an adjustment covariate, but rarely stratify according to sex. It is strongly advised that sex differences are addressed in all aspects of dementia research.6Ferretti MT Iulita MF Cavedo E et al.Sex differences in Alzheimer disease—the gateway to precision medicine.Nat Rev Neurol. 2018; 14: 457-469Crossref PubMed Scopus (273) Google Scholar Several studies have shown that women have an advantage over men in tests of verbal memory—the cognitive domain most often affected in Alzheimer's disease—and that this advantage persists into the stage of mild cognitive impairment. This difference between the sexes might affect the timing of diagnosis and treatment initiation.7Sundermann EE Biegon A Rubin LH Lipton RB Landau S Maki PM Does the female advantage in verbal memory contribute to underestimating Alzheimer's disease pathology in women versus men?.J Alzheimers Dis. 2017; 56: 947-957Crossref PubMed Scopus (59) Google Scholar Most studies on prevalence and incidence of dementia indicate that a higher proportion of women have dementia compared with men, but whether this difference can entirely be explained by women having longer life expectancy than men remains controversial.8Alzheimer's Association2020 Alzheimer's disease facts and figures.Alzheimers Dement. 2020; (published online March 10.)https://doi.org/10.1002/alz.12068Google Scholar Two large UK cohort studies with extensive follow-up, the English Longitudinal Study of Ageing (ELSA) and the Whitehall II study, have already generated several key publications on dementia risk, and in this issue of The Lancet Public Health, Mikaela Bloomberg and colleagues9Bloomberg M Dugravot A Dumurgier J et al.Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studies.Lancet Public Health. 2021; 6: e106-e115Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar report how education affects sex differences in cognitive ageing, across different levels of education and birth cohorts. The researchers confirmed previous findings regarding differences in cognitive function between the sexes, and that memory decline was slower in women than in men. Furthermore, their findings suggest that there are decreasing sex disparities in education due to secular increases in educational attainment among women, which might attenuate sex differences in future dementia risk. These findings are of great importance for the interpretation of secular trends in dementia epidemiology. The ELSA and Whitehall II studies measured immediate recall and semantic fluency, but further studies are needed to investigate whether these findings also apply to other cognitive domains, such as delayed recall, which is more closely associated with Alzheimer's disease, or if changing sex disparities in education across birth cohorts more directly impacts dementia risk. If access to education can explain some of the difference in dementia risk between sexes, this finding could have wide-ranging societal consequences. Although women are outperforming men in educational attainment in many high-income countries, there remains a large gap between sexes in terms of access to education in low-income and middle-income countries.10Evans DK Akmal M Jakiela P Gender gaps in education: the long view. Center for Global Development, Washington, DC2020Google Scholar Precision medicine garners increasing interest in dementia research, both in terms of prevention and treatment. The studies by Floud and colleagues and Bloomberg and colleagues contribute to increasing the knowledge base needed to develop a precision medicine approach for dementia. A thorough understanding of the timing and directionality of dementia risk factors and how demographic variables, such as sex and education, affect risk profile and disease phenotype is needed to implement precision medicine in dementia.6Ferretti MT Iulita MF Cavedo E et al.Sex differences in Alzheimer disease—the gateway to precision medicine.Nat Rev Neurol. 2018; 14: 457-469Crossref PubMed Scopus (273) Google Scholar GS reports personal fees from Biogen, outside the submitted work. Sex differences and the role of education in cognitive ageing: analysis of two UK-based prospective cohort studiesOur findings suggest that decreasing disparities between sexes in education, due to secular increases in educational opportunities, could attenuate sex differences in dementia risk and cognitive decline in the future. Full-Text PDF Open AccessCognitive and social activities and long-term dementia risk: the prospective UK Million Women StudyLife has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia. Full-Text PDF Open Access