Séverine Sabia and Archana Singh-Manoux explain what the findings of their latest study tell us about preventing dementia

The amyloid cascade hypothesis—which proposes that excessive accumulation of peptide amyloid-beta causes Alzheimer’s disease—continues to dominate research on Alzheimer’s disease, the primary cause of dementia. Despite considerable research over the past three decades, it remains unclear whether extra- and intra-neuronal protein aggregation is a cause, consequence, or correlate of disease. The failure of several drug trials on amyloid-beta have highlighted the need to consider other approaches, particularly those that reflect the multifactorial aetiology of dementia. 

The onset of dementia due to Alzheimer’s disease, the most common form of dementia, is preceded by a long preclinical phase, as long as 15 to 20 years, which includes changes in biomarkers and metabolic and behavioural parameters. This long pathological process offers opportunities for prevention, but the precise risk factors that ought to be targeted remain unclear. 

Primary prevention (treating risk factors to prevent the occurrence of a clinical event) has been used successfully for cardiovascular disease, leading to large reductions in age-standardized rates of the disease over the past five decades. In the past 10 years, “primordial” prevention, where the aim is to prevent the development of cardiovascular risk factors at the earliest stages, has been promoted by the American Heart Association using the Life’s Simple 7 score.

The four behavioural and three biological risk factors that comprise Life’s Simple 7 are categorised into poor, intermediate, and optimal levels. The aim of primordial prevention is to promote risk factors at optimal levels. For several risk factors these optimum targets are stricter than the current clinical prevention guidelines. Thus, optimal blood pressure is defined as untreated systolic/diastolic blood pressure <120/80 mmHg; optimal body mass index as being below 25Kg/m2; optimal diet as consumption of fruit and vegetables twice a day or more along with consumption of high fibre bread; optimal physical activity as ≥150 min of moderate activity or ≥75 min of vigorous activity or ≥150 min of moderate and vigorous activity; optimal fasting glucose as untreated <100 mg/dL; optimal cholesterol as untreated <200 mg/dL. 

Given the evidence on vascular contributions to dementia, we examined the association between Life’s Simple 7 at age 50 with the incidence of dementia over a 25 year follow-up period. By measuring all of our participants’ risk factors at age 50 and having a long follow-up period, we hoped to minimise reverse causation bias. Studies that have measured risk factors at older ages and where the follow-up is less than 10 years cannot rule out reverse causation as an explanation of their findings because of changes in cardiometabolic and behavioural risk factors in the preclinical phase of dementia. We have previously shown that systolic blood pressure and obesity at age 50, but not age 70, is associated with the risk of dementia.

In our recent study, we found a dose-response relationship between Life’s Simple 7 score and risk of dementia over a 25-year follow-up. This association was also found among participants who did not develop cardiovascular disease over the follow-up period, suggesting that the association was not completely mediated by clinical cardiovascular disease. The use of magnetic resonance imaging data confirmed these findings, showing that Life’s Simple 7 score at age 50 is associated with brain volume 20 years later.

Taken together, these findings suggest that the promotion of cardiovascular health in midlife might be important for preventing dementia. Of course, Life’s Simple 7 was developed for the prevention of cardiovascular disease, not dementia, and further research is required to identify the risk factors and relevant thresholds that carry a risk for dementia. In two previous studies, we did not find midlife physical activity and diet quality at currently recommended levels to be associated with incidence of dementia. It is possible that the observed associations are driven by the categorisation of risk factors in Life’s Simple 7. For example, the “poor” physical activity category in Life’s Simple 7 refers to no moderate or vigorous physical activity rather than activity below the current recommendation of 2.5 hours per week. The association of Life’s Simple 7 with dementia is also likely to be due to the synergistic effect of seven risk factors. Research on dementia typically examines the effects of single risk factors, treating other risk factors as covariates and adjusting for their effects in the analysis.

It is worth considering the most recent European guideline on defeating dementia, which stated “Prevention studies need to start in midlife and have a long duration to identify windows of opportunity for effective interventions.” We agree. Careful attention to the role of age at risk factor measurement, consideration of multiple risk factors, and analysis of the thresholds that carry risk are important for developing tools and strategies that could be used for dementia prevention.

Séverine Sabia is a research associate at the Department of Epidemiology and Public Health, University College London and at the Université de Paris, specialising in the epidemiology of ageing and neurodegenerative diseases.

Competing interests: See linked research paper

 

Archana Singh-Manoux is a research professor at the Department of Epidemiology and Public Health, University College London and at the Université de Paris, specialising in the epidemiology of ageing and neurodegenerative diseases.

Competing interests: See linked research paper