Research Paper Volume 11, Issue 4 pp 1163—1176
Alzheimer’s disease as a multistage process: an analysis from a population-based cohort study
- 1 Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
- 2 Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
- 3 Department of Radiology and Nuclear Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
- 4 Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands
- 5 Department of Neurology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands
received: December 14, 2018 ; accepted: February 1, 2019 ; published: February 27, 2019 ;https://doi.org/10.18632/aging.101816
How to Cite
Copyright: Licher et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
In cancer research, multistage models are used to assess the multistep process that leads to the onset of cancer. In view of biological and clinical similarities between cancer and dementia, we used these models to study Alzheimer’s disease (AD). From the population-based Rotterdam Study, we included 9,362 non-demented participants, of whom 1,124 developed AD during up to 26 years of follow-up. Under a multistage model, we regressed the logarithm of AD incidence rate against the logarithm of five-year age categories. The slope in this model reflects the number of steps (n–1) required for disease onset before the final step leading to disease manifestation. A linear relationship between log incidence rate and log age was observed, with a slope of 12.82 (95% confidence interval: 9.01-16.62), equivalent to 14 steps. We observed fewer steps for those at high genetically determined risk: 12 steps for APOE-ε4 carriers, and 10 steps for those at highest genetic risk based on APOE and a genetic risk score. The pathogenesis of AD complies with a multistage disease-model, requiring 14 steps before disease manifestation. Genetically predisposed individuals require fewer steps indicating that they already inherited multiple of these steps. Unravelling these steps in AD pathogenesis could benefit the development of intervention strategies.