Duke Scientists Formulate Improved Index For Predicting Alzheimer’s and Dementia Risk

More people are developing Alzheimer’s disease and related dementia as the global population ages. While the current estimate is that 50 million people worldwide have dementia, that number is expected to triple within 30 years.

Most interventions for dementia fail to prevent or meaningfully delay disease. One likely reason is that they are applied too late, after subtle brain changes and injury have been underway for many years, possibly decades. Scientists are now turning to preventive efforts in midlife, when it may be possible to effectively intervene before disease begins. But first we have to know: who in their 30s, 40s and 50s is actually “at-risk” for dementia decades down the road?

It is a tricky question, and one that researchers have been attempting to answer for a long while. Because we know what genetic and lifestyle factors appear to put a person at greater risk for diseases of the aging brain, a number of risk “indexes” have been developed to help identify who in midlife is at greatest risk for dementia later in life. While each of these existing indexes predicts dementia diagnoses fairly well, they only focus on a handful of the many potential risk factors. Often these indexes rely on risk factors that are easy to self-report (e.g., loneliness and social engagement) or measured at a doctor’s office (e.g., blood pressure readings).

To address this limitation, we produced the first comprehensive dementia risk “benchmark” called DunedinARB (the Dunedin Alzheimer’s disease and related dementias Risk Benchmark), which is comprised of nearly all known and proposed dementia risk factors, against which existing risk indexes can be compared. The goal was to find those risk factors that may matter most for brain aging in midlife, when interventions may be most effective. While existing dementia risk indexes assess only 8 to 15 risk factors, the DunedinARB assesses 48 separate risk factors, organized into 10 “domains” of risk, such as genetic risks, lifestyle risks, and harmful events and exposure, among other risks.

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We compared DunedinARB’s performance against the top four existing dementia risk indexes already on the market (CAIDE, LIBRA, ANU-ADRI, and risks selected by the Lancet Commission on Dementia).

We found that the DunedinARB and the other four risk indexes were all informative about subtle differences in brain health in midlife that forecast dementia, including being able to identify brains that looked “older,” had more damage in their white matter (critical for long-range communication within the brain), and had less tissue in regions related to memory and aging. All five predictive tools also identified middle-aged adults who fared worse on cognitive tests, reported more everyday problem cognitive problems (e.g., misplacing eyeglasses, getting easily distracted, etc.), and showed greater cognitive decline since childhood.

Despite performing well in their identification of middle-aged adults with faster-aging brains, all four current dementia risk indexes were ultimately outperformed by the DunedinARB, which showed the strongest statistical associations with the precursors of dementia that were used as outcome measures in this study (e.g., white matter damage, cognitive decline, etc.). This indicated that each existing index could be improved with the targeted addition of risk factors currently overlooked by the existing indexes.

Particularly informative were risk factors related to low socioeconomic status (e.g., low income and education), physical and sensory function (e.g., diminished sense of smell, poor balance, or slow gait), epigenetic aging (i.e., faster pace of aging as measured by cellular aging “clocks”), and poor subjective health (e.g., an individual’s own appraisal of their overall health as poor).

With this information it should be possible to better identify individuals most in-need of intervention against dementia, improve selection of participants for randomized controlled treatment trials, and support the work of clinicians who will be called upon to screen and diagnose dementia in the years to come.

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CITATION: “Improving risk indexes for Alzheimer’s disease and related dementias for use in midlife,” Reuben, A., Moffitt T.E., Abraham, C.W., Ambler, A., Elliott, M.L., Hariri, A.R., Harrington, H., Hogan, S., Houts, R.M., Ireland, D., Knodt, A.R., Leung, J., Pearson, A., Poulton, R., Purdy, S.C., Ramrakha, S., Rasmussen, L.J.H., Sugden, K., Thorne, P.R., Williams, B., Wilson, G., and Caspi, A. Brain Communications, Oct. 6, 2022. DOI: 10.1093/braincomms/fcac223