As Health Problems Pile Up, Dementia Climbs on Top of the Heap
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The more chronic health conditions a person suffers from, the more likely they are to develop dementia. That is the main conclusion of a study published September 20 in JAMA Network Open. The finding is not new. It is newsworthy because it comes backed by an unprecedented sample size. Among more than 200,000 UK Biobank participants with at least 60 years of life behind them, those who had two or more long-term health problems were far more likely than those without so-called “multimorbidity” to develop dementia within the next 12 years.
- UK Biobank study found that people with two or more health conditions had a 63 percent higher risk of dementia.
- The combination of hypertension, heart disease, diabetes had strongest effect.
- Multimorbidity raised dementia risk more in ApoE4 noncarriers than in carriers.
Led by Thomas Littlejohns of the University of Oxford, U.K., and Elżbieta Kuźma of the University of Hamburg, Germany, the study identified distinct combinations of diseases that upped dementia risk more in women than in men, although hypertension and cardiovascular disease were among the top culprits for both. Multimorbidity boosted risk for dementia more among people who did not carry ApoE4, although carriers with multiple morbidities had the highest risk of subsequent dementia overall.
“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,” commented Jeff Williamson of Wake Forest University in Winston-Salem, North Carolina.
The findings jibe with those of other long-running, albeit smaller, observational studies, which have tied common age-related health scourges such as hypertension, cardiovascular disease, and diabetes to subsequent brain atrophy and/or dementia (Aug 2018 conference news; Aug 2019 news; Nov 2019 news). Because these chronic health problems increasingly co-occur in as people age, more studies are focusing on their combined effects, finding, perhaps unsurprisingly, that multimorbidity packs a wallop on future cognition (Jul 2011 news on Song et al., 2011; Grande et al., 2021; Ben Hassen et al., 2022). Most recently, another UK Biobank study tied a “cardiometabolic multimorbidity index” of stroke, diabetes, and myocardial infarction to a fivefold higher risk of dementia (Tai et al., 2022).
In the new study, first author Catherine Calvin and colleagues cast a wide net for comorbidities, checking for 42 chronic diseases among 206,960 participants. At baseline, 43 percent, or 89,201 participants, had at least two of these 42 conditions. Compared to people with one or none, those with multimorbidity were more likely to be older, female, and non-white. They tended to have less education and come from socioeconomically deprived areas. Over an average of 11.8 years of follow-up, 3 percent, or 6,182 participants, developed dementia.
People with multimorbidity at baseline were 63 percent more likely to be subsequently diagnosed with dementia than those with only one or none of the chronic health conditions. The more chronic diseases a person had at baseline, the likelier they were to develop dementia later. Dementia risk inched up with each new condition, such that people with six chronic diseases at baseline had more than triple the risk of dementia as those with one or none.
To find out if some combinations bode worse for brain health than others, the scientists looked at which diseases commonly co-occurred, and grouped these combinations together. They identified seven clusters for women, six for men. For women, a hypertension/diabetes/coronary heart disease cluster, and a pain/osteoporosis/dyspepsia cluster most powerfully foretold dementia. In men, a hypertension/diabetes cluster, and a CHD/hypertension/stroke cluster spelled bad news.
Were different types of dementia more heavily influenced by multimorbidity than others? In this study, dementia was inferred via hospital inpatient and death registry records. As such, most participants did not receive a diagnosis of a specific dementia subtype. That said, 1,786 people were specifically diagnosed with AD, 917 with vascular dementia. Multimorbidity upped vascular dementia risk by 2.57-fold, while it only raised AD risk by 1.33-fold. The finding suggests that multimorbidity more strongly leads to vascular dementia than to AD, although the authors cautioned that the accuracy of these specific diagnoses is uncertain.
To gauge how genetic risk might play into these relationships, the scientists analyzed carriers and noncarriers of the ApoE4 allele separately. They found that multimorbidity increased dementia risk among both carriers and noncarriers, but had a stronger influence among noncarriers. The authors noted that this could influence outcomes of dementia prevention trials targeting comorbidities, whereby including too many ApoE4 carriers might drown out a positive effect detectable among noncarriers.
“Overall, these findings could improve identification of individuals at high risk of dementia, and highlight the necessity of targeting clusters of diseases for dementia prevention rather than individual risk factors,” the authors wrote.
Along those lines, Williamson noted that scientists are increasingly discovering treatments that also happen to treat related syndromes. “For example, improved treatments for diabetes are dramatically reducing risk for co-occurring cardiovascular disease,” he wrote.
Xin Tai, University of Oxford, U.K., was not involved in the current study but has had similar results using a different research strategy in in the same cohort. The new paper reinforces the adage, “What is good for the heart is good for the brain,” he wrote to Alzforum.
David Knopman of the Mayo Clinic in Rochester, Minnesota, was unsurprised that vascular-related comorbidity clusters packed the biggest punch, given the wealth of prior evidence to support the association. He noted the small caveat that a 12-year observation period in a study with weak diagnostic methods means that early stage cases of a prevalent condition (i.e., AD at the MCI or subjective cognitive impairment stage) don't get picked up until years later, once dementia is overtly symptomatic, as apparent incident cases.
Exactly how nonspecific, non-vascular conditions predispose to dementia is an important enigma, Knopman wrote. “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?” Knopman noted that a Mayo clinic study tied multimorbidity to both AD and non-AD related neurodegeneration (Vassilaki et al., 2018). “Further pursuit of the non-vascular mechanisms will be difficult but could be very rewarding” he wrote (full comment below).—Jessica Shugart
References
News Citations
- Brain Damage from Cardiovascular Disease Starts Earlier Than You Think
- Blood Pressure: How Low to Prevent Dementia—and When?
- Already in Mid-30s, Poor Vascular Health Means Small Brain at 70
- Alzheimer’s Risk Factors Roundup: Does Poor Health Hurt the Brain?
Paper Citations
- Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011 Jul 19;77(3):227-34. PubMed.
- Grande G, Marengoni A, Vetrano DL, Roso-Llorach A, Rizzuto D, Zucchelli A, Qiu C, Fratiglioni L, Calderón-Larrañaga A. Multimorbidity burden and dementia risk in older adults: The role of inflammation and genetics. Alzheimers Dement. 2021 May;17(5):768-776. Epub 2021 Jan 6 PubMed.
- Ben Hassen C, Fayosse A, Landré B, Raggi M, Bloomberg M, Sabia S, Singh-Manoux A. Association between age at onset of multimorbidity and incidence of dementia: 30 year follow-up in Whitehall II prospective cohort study. BMJ. 2022 Feb 2;376:e068005. PubMed.
- Tai XY, Veldsman M, Lyall DM, Littlejohns TJ, Langa KM, Husain M, Ranson J, Llewellyn DJ. Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study. Lancet Healthy Longev. 2022 Jun;3(6):e428-e436. PubMed.
- Vassilaki M, Aakre JA, Kremers WK, Mielke MM, Geda YE, Alhurani RE, Dutt T, Machulda MM, Knopman DS, Vemuri P, Coloma PM, Schauble B, Lowe VJ, Jack CR Jr, Petersen RC, Roberts RO. 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.
Further Reading
Primary Papers
- Calvin CM, Conroy MC, Moore SF, Kuzma E, Littlejohns TJ. 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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Comments
Wake Forest University School of Medicine
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.
Oxford University
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.
Mayo Clinic College of Medicine
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.
References:
Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011 Jul 19;77(3):227-34. PubMed.
Vassilaki M, Aakre JA, Cha RH, Kremers WK, St Sauver JL, Mielke MM, Geda YE, Machulda MM, Knopman DS, Petersen RC, Roberts RO. Multimorbidity and Risk of Mild Cognitive Impairment. J Am Geriatr Soc. 2015 Sep;63(9):1783-90. Epub 2015 Aug 27 PubMed.
Vassilaki M, Aakre JA, Kremers WK, Mielke MM, Geda YE, Alhurani RE, Dutt T, Machulda MM, Knopman DS, Vemuri P, Coloma PM, Schauble B, Lowe VJ, Jack CR Jr, Petersen RC, Roberts RO. 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.
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