17 November 2017
To the Editor:
We would like to thank Vos and colleagues for valuable research on the topic of modifiable risk factors for dementia . However, we feel three topics need to be addressed in order to interpret the results with due nuance.
First, the authors state that the aim of their research is “to test the ability of the LIBRA index to assess the prevention potential by investigating the predictive validity” and “C-statistics were calculated as a measure of predictive accuracy”, indicating this as the main analysis. The c-statistics for predictive models with the LIBRA-index in the three different age groups are respectively 0.53, 0.56 and 0.50, reflecting the predictive accuracy of the model to predict who will get dementia and who will not. Provided that rolling a dice equals a c-statistic of 0.50, and that c-statistics usually are down-sized when models are applied to external datasets, the performance of the models is hardly convincing.
Second, each age group is split into tertiles of the LIBRA index, and the survival probabilty for progression to dementia is plotted against time. We have two comments on this analysis. The first is the chosen time frame. Average follow-up is 7.2 years, yet the time frame in the Kaplan-Meier plots extends until 15 years. This practice is questionable, especially in the higher age groups, because this exceeds life expectancy for that group. Furthermore, the large stepwise changes with longer follow-up in these plots suggest there were very few people left in the analysis after approximately 8 years, resulting in imprecise or inaccurate estimates . The divergence between the three risk groups clearly only arises after this timepoint. We believe it would be interesting to see results of Log-Rank tests for plots limited to 8 years of follow-up, and it would be necessary to add ‘number at risk’-tables to these data. Moreover, the data show that the LIBRA index is not successful in discriminating between all three risk groups, especially in higher age groups, as indicated by the Cox models. It would be interesting to identify risk groups based on maximum discrimination instead of tertiles, to see if those groups would perform better.
Third, the authors state that based on this research, it can be concluded that elderly people should attempt to obtain a LIBRA index score as low as possible, in order to avoid dementia. We would like to point out that decreasing LIBRA scores for individuals does not necessarily decrease incidence. Assuming the causal relation between those risk factors and dementia (the study merely shows associations), eliminating any of those risk factors as component causes does not necessarily mean that remaining risk factors do not constitute sufficient cause for dementia . Moreover, achieving a lower LIBRA scale involves cardiovascular risk management, which in a recent large trial in older age was unsuccessful in reducing dementia incidence . This does not support the notion that reducing a LIBRA score in elderly would lower dementia risk. Such actions may be more fruitful when started at much earlier age (the ‘historical’ midlife 40-50 years).
To conclude, given the limited predictive accuracy of the LIBRA index and the limited ability to discriminate risk groups (which may also be distorted by the long time frame in the analysis), we think this work would benefit from more cautious conclusions.
Anke Richters, MSc1,2, Jurgen A.H. Claassen, MD, PhD1,2
1Donders Institute for Brain, Cognition and Behaviour, Department of Geriatric Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2Radboud Alzheimer Centre, Nijmegen, The Netherlands
 Vos SJB, van Boxtel MPJ, Schiepers OJG, Deckers K, de Vugt M, Carrière I, Dartigues JF, Peres K, Artero S, Ritchie K, Galluzzo L, Scafato E, Frisoni GB, Huisman M, Comijs HC, Sacuiu SF, Skoog I, Irving K, O'Donnell CA, Verhey FRJ, Visser PJ, Köhler S (2017) Modifiable risk factors for prevention of dementia in midlife, late life and the oldest-old: validation of the LIBRA Index. J Alzheimers Dis 58, 537-547.
 Rich JT, Neely JG, Paniello RC, Voelker CC, Nussenbaum B, Wang EW (2010) A practical guide to understanding Kaplan-Meier curves. Otolaryngol Head Neck Surg 143, 331-336.
 Rothman KJ (1995) Causes. 1976. Am J Epidemiol 141, 90-95; discussion 89.
 van Dalen JW, Moll van Charante EP, Caan MWA, Scheltens P, Majoie CBLM, Nederveen AJ, van Gool WA, Richard E (2017) Effect of long-term vascular care on progression of cerebrovascular lesions: magnetic resonance imaging substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care). Stroke 48, 1842-1848.