The incidence of dementia increases with advancing age.1 In association with increasing life expectancy, the absolute number of persons with dementia has been increasing worldwide. In the face of that statistic, the article by Tom et al2 in JAMA Network Open reports a slight reduction in dementia incidence rates among persons born after 1929 compared with those born earlier. Multiple investigations in Europe and the US1,3 have made similar observations. The consistency of the finding across multiple epidemiological cohorts, although not universal, raises the question of how such a favorable but unexpected trend developed. While it is not possible to exclude variations in diagnostic approaches over time, it is worth considering which advances in health care delivery or sociocultural trends could be associated with a decreasing rate of incident dementia.
Managing the societal burden of later-life cognitive impairment, of which dementia represents the more impaired end of the spectrum, is one of the great public health challenges of the 21st century, notwithstanding the coronavirus disease 2019 pandemic. Advances in identifying the biological underpinnings of later-life cognitive impairment have given us a greater understanding of the specific etiologic processes that are associated with impairment. The major role of Alzheimer disease in cognitive impairment is generally appreciated, but there is also greater recognition that non-Alzheimer conditions often coexist and moderate the clinical expression of Alzheimer pathology.4 In the eighth decade of life and beyond, multiple etiologies are the norm for persons with later-life cognitive impairment.
If Alzheimer pathology is indeed the dominant etiology of later-life cognitive impairment, the first place to look for an explanation for the reduction in dementia incidence would be in the Alzheimer pathway. Alas, the known risk factors for sporadic late-onset Alzheimer disease, specifically the disease defined by β-amyloid plaques and tau-containing neurofibrillary tangles and not cognitive impairment in general, include only age and genetic variables. No environmental risk factors for biologically defined Alzheimer disease are known. However, 1 study has examined Alzheimer pathology over several decades and found that the burden of brain β-amyloid plaques decreased in more recent autopsied cases.5 While one could hypothesize that a reduced burden of Alzheimer pathology could be associated with the reduction in the incidence of dementia, it is not possible to make any causal claims from this single set of neuropathological observations. If blood-based biomarkers of brain β-amyloid were to become widely available in the future to track a biological feature of Alzheimer disease in real time, perhaps this hypothesis could eventually be tested.
Although cerebrovascular pathology is rarely the sole etiologic feature of later-life cognitive impairment, its presence has inverse consequences for the amount of Alzheimer or other neurodegenerative pathology needed to produce overt cognitive impairment. Since the mid-20th century, reductions in mortality and morbidity associated with cardiovascular and cerebrovascular disease have been well documented. Stroke rates decreased substantially in the last decades of the 20th century.6 Improvements in cardiovascular health have roughly paralleled decreases in dementia incidence in western Europe and the US. Yet, neither in the article by Tom et al2 nor in previous analyses have proxies for vascular health emerged as the likely antecedents.1,3 Perhaps the proxies for vascular health—history of stroke, hypertension, and diabetes—are not mechanistically close enough to the true underlying vascular pathophysiological factors associated with the decreasing incidence rates; alternately, changing patterns of brain vascular disease may not be relevant to changing patterns of dementia incidence.
Improvements in survival in late adulthood within the past 50 years7 can be plausibly accounted for by improvements in the general medical care of no single particular disease but rather by a slight reduction in multimorbidity. Multimorbidity is associated with later-life cognitive impairment8 and could be associated with the reduction in dementia incidence. To my knowledge, this hypothesis has never been tested.
Social, cultural, and educational life experiences may have an association with the clinical expression of later-life cognitive impairment that is independent from neurobiological determinants, such as Alzheimer disease or cerebrovascular disease. Educational level is an excellent proxy for some of the sociocultural determinants of dementia risk. The quantity and quality of educational opportunities in Europe and the US have undoubtedly improved in the past 100 years and could plausibly be hypothesized to have an association with a reduction in the appearance of overt dementia among persons who received their education in the last 60 years of the 20th century. However, using years of education as the indicator has not been able to account for the reduction in dementia incidence observed in the previous studies as well as the present one.2
In the context of the role of life experiences as modulators of the clinical expression of later-life cognitive impairment, Tom et al2 explored previously unexamined aspects of childhood health and well-being as sociocultural modifiers of the clinical expression of later-life cognitive impairment. The authors used the health records of participants in the Adult Changes in Thought study, which has been investigating incident dementia since the 1980s. With access to information about family financial stability and household density in childhood as well as educational level and midlife vascular risk factors, the authors tested the hypothesis that childhood well-being might represent the elusive mechanism by which dementia incidence rates decreased. Unfortunately, the data did not support the hypothesis. In analyses dependent on information collected decades ago, the authors did not have the opportunity to design an optimal measure for childhood well-being; instead, they had to assume that some of the previously collected information in the participants’ medical records could be used to approximate childhood sociocultural status.
We are left with the enigma of the unexpected trend of a decrease in dementia incidence rates in the past 30 years. Why have cohorts born after 1929, during the disruption of the Great Depression and World War II, experienced a slight reduction in incident dementia? Does this trend offer any insights into future dementia incidence? We have run out of time for prospective studies of the pre-1929 birth cohorts, but new medical and cultural forces are at work. Tom et al2 also noted that a stabilization in dementia incidence has occurred in persons born after 1929. Just as other societal trends, such as increasing rates of obesity and decreases in cancer-associated deaths, may have implications for dementia incidence, future research should include provisions to look across birth cohorts for new or different trends.
Published: July 27, 2020. doi:10.1001/jamanetworkopen.2020.11199
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Knopman DS. JAMA Network Open.
Corresponding Author: David S. Knopman, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 (firstname.lastname@example.org).
Conflict of Interests Disclosure: Dr Knopman reported receiving grants from Biogen and Lilly outside the submitted work, serving on a data safety monitoring board for a tau therapeutic for Biogen (without compensation), and serving as a consultant for Alzeca Biosciences, Samus Therapeutics, and Third Rock Ventures (without compensation).
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Knopman DS. The Enigma of Decreasing Dementia Incidence. JAMA Netw Open. 2020;3(7):e2011199. doi:10.1001/jamanetworkopen.2020.11199
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