Multimorbidity refers to co-occurring conditions in the same person of more-or-less equal importance,1 and dementia is perhaps the paradigmatic multimorbid disorder. The related concept of comorbidity is also germane to dementia, wherein a co-occurring condition modifies the impact of a primary condition.1

Dementia represents the loss of memory or other mental ability severe enough to interfere with independence in everyday activities. It is an age-related disorder, whose prevalence and incidence double about every five to six years after age 60 years, at least until the tenth decade of life. It is a leading cause of disability. The global prevalence of dementia, estimated at about 57 million people in 2019, is projected to exceed 150 million by 2050.2 Worldwide, Alzheimer’s disease and other dementias are the second leading cause of neurological death after stroke3 and the seventh leading cause of death overall.4

Alzheimer’s disease is the most common cause of dementia.5 At the microscopic level, it is characterized by neuritic plaques and neurofibrillary tangles in vulnerable regions of the brain, and at the biochemical level by the accumulation of two abnormal proteins: amyloid-beta and hyperphosphorylated tau.6 Other causes of dementia have different, distinct microscopic and biochemical features. Clinical manifestations can differ as well.

In early-onset disease, i.e., when dementia symptoms appear before age 60 years, the plaque and tangle pathology of Alzheimer’s disease can occur in isolation, but in later life multiple neurodegenerative and vascular pathologies are the rule rather than the exception.7 These other pathologies include Lewy bodies (found in Parkinson’s disease and dementia with Lewy bodies), TAR DNA-binding protein-43 inclusions (associated with hippocampal sclerosis and a form of frontotemporal dementia), and pathologies linked to vascular disease in the brain. In a US autopsy study of more than 500 older people (mean age 90 years) with and without dementia, 69% of brains met criteria for the pathological diagnosis of Alzheimer’s disease, but stroke, other forms of vascular disease, hippocampal sclerosis or TAR DNA-binding protein-43 pathology, and Lewy body pathology were also common.8 Alzheimer pathology was nearly 12 times more likely to be accompanied by at least one of these pathologies than to occur alone.

The clear inference is that late-onset dementia is a multimorbid disorder in which the pathology of Alzheimer’s disease may predominate but infrequently occurs in isolation. Each dementia morbidity on its own has the potential to impair cognition, and each is characterized by a unique profile of predisposing genetic and non-genetic factors. Although there is some controversy, the effect of multiple pathologies on cognitive impairment is usually interpreted as additive rather than synergistic.

Many medical and psychiatric disorders are linked to risks of Alzheimer’s disease or all-cause dementia. Examples of common comorbid conditions include diabetes, heart failure, visual impairment, kidney disease, depression, and stress disorders.9–14 In most instances, it is not known whether the effect of a particular comorbid condition is in causal pathways that culminate in a dementia pathology, e.g., the abnormal accumulation of amyloid and tau proteins.

Socioeconomic status, environmental exposures, and lifestyle practices are associated with dementia risk. Socioeconomic status —reflected by educational attainment, wealth and income, housing, occupation, and avocational activities — is related to a variety of health outcomes, including dementia.15 Environmental exposures such as air pollution may play roles,16 as might lifestyle practices such as sedentary behavior, unhealthy dietary choices, heavy alcohol use, smoking, and poor sleep hygiene.17,18 The impact of these exposures over the life course is difficult to quantify, but there are potential effects on the initiation and progression of dementia pathologies and on resilience in the setting of these pathologies. Further, socioeconomic status affects the detection and diagnosis of dementia and the access to treatment and supportive services.19,20

Each of these factors – socioeconomic, environmental, and behavioral — has a social gradient. Gradients are manifest in comorbidity burden and perhaps in dementia pathologies themselves. They often find greater expression in minority or minoritized populations.21 For example, neighborhood disadvantage, defined by a paucity of economic and social resources and by unhealthy environmental exposures, is associated with postmortem amyloid plaque and neurofibrillary tangle burden.22

Multimorbidity is a common feature of chronic conditions of old age, and late-onset dementia is almost always a multimorbid disorder. Alzheimer’s disease is important and common, but the cognitive impairment of plaque and tangle pathology usually emerges in the presence of other dementia pathologies. To varying extents, comorbid disease, socioeconomic factors, environmental exposures, and lifestyle practices may contribute to disease pathogenesis, clinical manifestations, and disease progression. These risk factors affect populations differently, with burdens weighing most heavily on disadvantaged groups. Effective approaches to treatment and prevention will need to consider the unequal distribution of these factors over the life course and the disadvantaged populations most affected. In future research, it will also be important to continue the search for new factors that impart risk and benefit and to devise interventions to reduce adverse exposures and mitigate harmful effects. Effective strategies will be those that address the multimorbid nature of dementia and take into consideration health inequalities and inequities that add to risk, delay diagnosis, and diminish treatment effectiveness.

1. Academy of Medical Sciences. Multimorbidity: a priority for global health research https://acmedsci.ac.uk/file-download/82222577. Accessed January6, 2023.

2. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022;7(2):e105–e125.

3. Feigin VL, Vos T, Nichols E, et al. The global burden of neurological disorders: translating evidence into policy. The Lancet Neurology. 2020;19(3):255–265.

4. World Health Organization. Global status report on the public health response to dementia. Published 2021. Accessed January2, 2024.

5. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;377(9770):1019–1031.

6. Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021; 397(10284):1577–1590.

7. Schneider JA. Neuropathology of dementia disorders. Continuum (Minneap Minn). 2022;28(3):834–851.

8. Yu L, Boyle PA, Dawe RJ, Bennett DA, Arfanakis K, Schneider JA. Contribution of TDP and hippocampal sclerosis to hippocampal volume loss in older-old persons. Neurology. 2020; 94(2):e142–e152.

9. Xue M, Xu W, Ou YN, et al. Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing Res Rev. 2019;55: 100944.

10. Adelborg K, Horváth-Puhó E, Ording A, Pedersen L, Sørensen HT, Henderson VW. Heart failure and risk of dementia: a Danish nationwide population-based cohort study. Eur J Heart Fail. 2017;19(2):253–260.

11. Tran EM, Stefanick ML, Henderson VW, et al. Association of visual impairment with risk of incident dementia in a Women's Health Initiative population. JAMA Ophthalmol. 2020;138(6):624–633.

12. Kjaergaard AD, Ellervik C, Witte DR, Nordestgaard BG, Frikke-Schmidt R, Bojesen SE. Kidney function and risk of dementia: Observational study, meta-analysis, and two-sample mendelian randomization study. Eur J Epidemiol. 2022;37(12):1273–1284.

13. Elser H, Horváth-Puhó E, Gradus JL, et al. Association of early-, middle-, and late-life depression with incident dementia in a Danish cohort. JAMA Neurol. 2023;80(9):949–958.

14. Gradus JL, Horváth-Puhó E, Lash TL, et al. Stress disorders and dementia in the Danish population. Am J Epidemiol. 2019;188(3):493–499.

15. Wang AY, Hu HY, Ou YN, et al. Socioeconomic status and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 39 prospective studies. J Prev Alzheimers Dis. 2023;10(1):83–94.

16. Zhao YL, Qu Y, Ou YN, Zhang YR, Tan L, Yu JT. Environmental factors and risks of cognitive impairment and dementia: a systematic review and meta-analysis. Ageing Res Rev. 2021;72:101504.

17. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–446.

18. Sabia S, Fayosse A, Dumurgier J, et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun. 2021;12(1):2289.

19. Tsoy E, Kiekhofer RE, Guterman EL, et al. Assessment of racial/ethnic disparities in timeliness and comprehensiveness of dementia diagnosis in California. JAMA Neurol. 2021;78(6):657–665.

20. Jones IR. Social class, dementia and the fourth age. Sociol Health Illn. 2017;39(2):303–317.

21. Shiekh SI, Cadogan SL, Lin LY, Mathur R, Smeeth L, Warren-Gash C. Ethnic differences in dementia risk: A systematic review and meta-analysis. J Alzheimers Dis. 2021;80(1):337–355.

22. Powell WR, Zuelsdorff M, Keller SA, et al. Association of neighborhood-level disadvantage with neurofibrillary tangles on neuropathological tissue assessment. JAMA Netw Open. 2022;5(4):e228966.

Professor Victor Henderson reports grants from National Institutes of Health, grants from Health IQ, personal fees from Institute for Clinical and Economic Review, personal fees from Aarhus University, University of Southern California, University of Kansas, personal fees from American Academy of Neurology, personal fees from Oregon Health Sciences University, during the conduct of the study. The authors report no other conflicts of interest in this work.