. Association of Multimorbidity, Disease Clusters, and Modification by Genetic Factors With Risk of Dementia. JAMA Netw Open. 2022 Sep 1;5(9):e2232124. PubMed.


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  1. This highly important study adds to the growing body of evidence that a large portion of the cognitive decline and dementia experienced by our patients, neighbors, and families occurs in the context of chronic conditions, often multiple chronic conditions. This has tremendous implications for the health system and for research funding in an aging society.

    Other disease syndromes are discovering that some specific approaches to treatment are better than other approaches in reducing common complications that occur in the context of the primary disease. For example, improved treatments for diabetes are dramatically reducing risk for co-occurring cardiovascular disease. Similarly, researchers in the disease clusters highlighted by this study should be encouraged to work more closely with cognitive health and dementia research colleagues to explore the impact of therapeutics for the primary condition on the devastating complication of cognitive impairment.

    View all comments by Jeff Williamson
  2. This very nice study complements our earlier work looking at cardiometabolic multimorbidity, polygenic risk, and dementia in the same cohort.

    We took a more hypothesis-driven approach, being specifically interested in cardiometabolic conditions of stroke, myocardial infarction and diabetes based on clinical experience and prior literature. By contrast, Calvin et al. performed a more data-driven approach to identify these disease clusters while considering other conditions. It is encouraging, and important, that the clusters that were associated with the highest risk of dementia closely followed our cardiometabolic theme of interest.

    An important message would be the relationship between cardiovascular health and dementia risk, i.e., what is good for the heart is good for the brain. The risk of dementia increases with multiple conditions, so an individual with one condition, such as diabetes, should be mindful of their health and avoid developing other problems. Several conditions that were examined likely share similar mechanistic pathways. 

    Considering modifiable risk factors offers a tangible approach for patients and their doctors to follow, and highlights overall health.

    View all comments by Xin Tai
  3. That apparently non-specific multi-morbidities are associated with dementia risk is not a novel observation, but the large sample size of the UK Biobank enabled a detailed look at this enigmatic but very important observation. Apart from the fact that the authors fail to acknowledge important prior work, especially that of Ken Rockwood (2011),  my colleague Maria Vassilaki (2015) and several others, the authors make a strong case for the cumulative risk associated with a variety of vascular and non-vascular chronic conditions. I particularly want to call out Ken Rockwood for his early observations on multimorbidity.

    While I believe the result is fundamentally strong, there are some caveats to the use of the UK Biobank. First, the diagnoses of dementia are largely derived from administrative sources and thus likely underrepresent milder cases. Second, the duration of follow-up, average nearly 12 years, may result in some prevalent but undiagnosed dementia cases to be included among the incident ones, thereby possibly mixing the direction of causality. However, neither of these issues is likely to detract from the main conclusion.

    It is interesting, and unsurprising, that the vascular-related cluster of co-morbidities carried the strongest risk. There is a wealth of evidence to support that assertion, and a reasonable mechanism to link it to. (That said, exactly what the vascular lesion is remains uncertain.)

    What is interesting, but quite unclear to me, is the mechanism by which the nonspecific, non-vascular conditions predispose to dementia. Do they generate some sort of inflammatory response in the brain that very gradually erodes neuronal and synaptic homeostasis? Could these nonspecific conditions merely be proxies for early life deprivations or for social determinants of health?

    Vassilaki et al., using the more deeply phenotyped Mayo Clinic Study of Aging, showed AD biomarker data suggesting that there could be one pathway that could be additive with AD pathology but there was a non-AD pathway, as well (Vassilaki et al., 2018).

    Further pursuit of the non-vascular mechanisms will be difficult but could be very rewarding.


    . Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011 Jul 19;77(3):227-34. PubMed.

    . Multimorbidity and Risk of Mild Cognitive Impairment. J Am Geriatr Soc. 2015 Sep;63(9):1783-90. Epub 2015 Aug 27 PubMed.

    . The Association of Multimorbidity With Preclinical AD Stages and SNAP in Cognitively Unimpaired Persons. J Gerontol A Biol Sci Med Sci. 2018 Aug 13; PubMed.

    View all comments by David Knopman

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  1. As Health Problems Pile Up, Dementia Climbs on Top of the Heap