The Real Risks of Alzheimer’s
Preclinical AD does not always lead to dementia
William Aryitey |
The brain – both in terms of structure and function– is highly complex. And though decades of research have taught us much about the body’s control center, there is still a whole world of knowledge to uncover, especially when it comes to age-related neurological conditions, such as dementia. Alzheimer’s disease (AD) – the most common form of dementia – has become an increasingly significant issue as life expectancy in the developed world has risen. But the more we understand about the disease and its pathology, the closer we edge to a viable treatment.
A study by researchers at the University of California, Los Angeles (UCLA) has estimated the lifetime risk of AD for people with preclinical disease and found that they have a low likelihood of developing overt disease in their lifetime (1). To learn more about the findings and their clinical significance, we spoke with Ron Brookmeyer, first author of the study and Professor of Biostatistics at UCLA Fielding School of Public Health.
Why did you focus on preclinical risk?
We have been working on forecasting AD dementia globally for many years. With the development of new biomarker tests for preclinical disease, we started estimating the number of people with preclinical AD. In a companion paper we published several months ago, we determined that the number of people in the United States who have preclinical disease is about 46.7 million (2). We wondered how many of those would actually progress to AD dementia during their lifetimes. The preclinical period is long and variable, so in elderly populations, people may likely die of other causes before the disease expresses itself clinically – so we wanted to quantify the risk.
What are the clinical implications of your findings?
Lifetime risks help interpret the clinical significance of preclinical screening tests for AD. It may provide some reassurance to people that, despite positive results on some screening tests, their chances of actually developing dementia during their lifetime are low. For clinicians, our results emphasize a cautionary note that preclinical conditions may actually never become clinical. We find that age, gender, and preclinical disease state all affect the lifetime risk. For example, 90-year-olds with no preclinical symptoms (that is, without mild cognitive impairment) all have very low lifetime risk, regardless of their preclinical state. The low risk can be attributed to a short life expectancy. One message for the most elderly populations who do not have any other cognitive symptoms is: there may not be much to be gained from preclinical disease screening. On the other hand, if patients from the same population have mild cognitive impairment in the presence of amyloid and neurodegeneration, the risk becomes quite high.
How will your model develop over time?
We hope that it will be an evolving formula. Going forward, larger longitudinal cohorts will become available, which will help us refine the transition rates (from one disease state to the next) used in our model. Also, we expect to see the development of improved biomarkers with increased sensitivity and specificity. For example, the development of biomarkers for tau pathology is an area of active research.
Lifetime risk is a very useful concept that can be applied to many disease and neurodegenerative processes. It helps answer a critical question asked by patients and clinicians: what is the probability that an individual with a preclinical condition will develop clinical disease during their lifetime?
We want to further refine our model to incorporate other pathologies related to non-AD dementias. We need to better understand how multiple mixed pathologies interact with and affect the lifetime risks of developing dementia. We would like to incorporate other factors, such as the APOE-4 gene, into the model to further refine our risk estimates. It will also be important to have studies in more ethnically diverse populations to refine the risk estimates for various populations throughout the world.
- R Brookmeyer, N Abdalla, “Estimations of lifetime risks of Alzheimer’s disease dementia using biomarkers for preclinical”, Alzheimers Dement, [Epub ahead of print] (2018). PMID: 29802030.
- R Brookmeyer et al., “Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States”, Alzheimers Dement, 14, 121–129 (2018). PMID: 29233480.