INTRODUCTION
Until recently, studies of individuals who reached the tenth and eleventh decade of life have been relatively rare, in part because individuals reaching this age group were themselves quite rare. However, with the extension of life expectancy over the past century, individuals over age 90 are now the fastest growing segment of the population in the United States and most of the world. With the risk of dementia profoundly age-related, these individuals have the highest rates of dementia and portend an enormous public health burden in coming decades. While we tend to assume that dementia-related factors identified in younger elderly also apply to the oldest-old, current research suggests otherwise and provides some surprising observations that can contribute insight into dementia occurring at all ages.
In addition to investigations of cognitive loss, studies in very old individuals have also promoted the concepts of resilience and resistance. Resilience is most frequently defined as the presence of dementia-related pathological brain changes, most frequently Alzheimer disease (AD), in individuals who are cognitively normal. Paradoxically, this definition also serves to identify people who are presumably in the preclinical phase of their dementing illness [1]. The exceptionally high rate of this occurrence in people over 90, where approximately 40% of people without dementia have intermediate and high levels of AD, provides an ideal platform to investigate and understand these fundamental issues. We briefly summarize some of these issues and recent findings below.
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TEXT OF REVIEW
The oldest-old are the fastest growing segment of the population throughout much of the world. Projections from the United Nations for the coming decades estimate that the number of people aged 90 and older will increase more than 5-fold from 21 million in 2020 to 113 million in 2060. In addition to Brazil and the United States, three of the top 5 countries expected to have the largest number of 90+ year-olds are in Asia, and by far the country with the largest number will be China, where the population of 90+ year-olds will grow from 2.8 million to a stunning 31 million (Fig. 1) [2]. Given that the oldest-old have the highest rates of cognitive impairment, functional disability, and comorbidities, the oldest-old present an immense public health and financial challenge for many parts of the world.
FIGURE 1: Projected oldest-old population (90+) from 2020 to 2060: top five countries. Created from information extracted from United Nations Department of Economics and Social Affairs Population Division. World Population Prospects 2019
[2].
Prevalence and incidence of dementia in the oldest-old
The incidence and prevalence of dementia increase exponentially with age beginning at age 65. We now know that this increase with age extends into ages 90 and above. Although some early studies suggested declines in dementia incidence at advanced ages, most recent studies, with larger sample sizes and more frequent visits, show a continued exponential rise with age reaching a staggering 40% per year among centenarians [3]. Prevalence of dementia is approximately 30% at ages 90–94 and reaches above 70% in centenarians. Women show higher prevalence of dementia than men primarily due to greater longevity in women. In terms of incidence, however, most large studies and meta-analyses do not show a difference between women and men [4▪].
Dementia and diversity in the oldest-old
Information about dementia prevalence and incidence comes almost exclusively from studies of White individuals in the US and Europe with very limited information from diverse populations. In one of the only incidence studies of the oldest-old to include ethnic minorities, the patterns of racial and ethnic disparities in dementia incidence seen in younger older adults persisted after the age of 90 [5▪▪]. In electronic medical records from an integrated healthcare system in Northern California, dementia incidence was lowest among Asians and Whites and highest among Latinos and Black individuals. The difference in incidence rates persisted after adjusting for sociodemographic and life course health conditions suggesting that differences may be due to other factors including early life adversity, vascular health, or underlying dementia associated neuropathologies [5▪▪].
There will be 9.5 million individuals aged 90 and older in the US by 2060 and more than one in every three individuals at this age will be from racial and ethnic minorities making studies of cognition and dementia in racially and ethnically diverse individuals crucial. The Life After 90 Study is a one-of-a-kind multiethnic cohort of individuals 90 and older established to help address the lack of knowledge in ethnically and racially diverse oldest-old individuals [6▪]. With more than 500 ethnically diverse participants 90 and older, the study has the potential to redefine our knowledge of cognition, dementia, and neuropathology in the oldest-old, provide new insights into early life risk and protective factors, and uncover etiological underpinnings of late-onset dementia and cognitive impairment in the oldest-old.
Factors contributing to dementia and cognition
Risk and protective factors for dementia and cognitive impairment have primarily been studied in younger elderly with the assumption that they are generalizable to the oldest-old. There is growing evidence that risk factors for dementia and cognitive impairment in the oldest-old differ from younger older individuals [7▪]. For example, the ε4 allele of the apolipoprotein E gene (APOEε4) represents the strongest susceptibility gene for dementia and AD at younger ages. However, its effect appears to lessen with age and in people who survive to very old age without dementia, the APOEε4 allele is no longer associated with an increased dementia risk [7▪,8]. Notably, several studies have reported that some midlife risk factors appear to become protective when developed in late life [9,10▪].
Cardiovascular diseases in midlife, which are commonly associated with increased risk of cognitive impairment and dementia in later life, also seem to have weaker or no associations later in life. A recent investigation that included more than 400,000 individuals aged ≥65 years from a primary care database studied the risk of hypertension, diabetes mellitus, dyslipidemia, stroke, myocardial infarction, heart failure, and atrial fibrillation for all-cause dementia [11▪▪]. The results indicated that the risk for dementia decreased with increasing age for all vascular disorders and was no longer significant in individuals aged ≥90 years (Fig. 2). Another study, with more than 2,000 cognitively healthy individuals aged ≥ 55 years, investigated the age dependency of genetic and cardiovascular risk factors, depressive symptoms, inflammation markers and lifestyle risk factors for cognitive decline [12]. In general, there was a trend towards a decreasing adverse effect of various risk factors on cognitive decline with increasing age. A similar change with age has been observed in studies of BMI [10▪], cholesterol [13], and triglycerides levels [14▪] with some of these risk factors appearing protective in late life.
FIGURE 2: Risk of incident dementia in the presence of a risk factor per 5-year age group. For individuals ≥ 90 no upper age limit was used. Hazard Ratio 1 (HR1) determined with Cox regression analyses adjusted for age at study entry and sex; Hazard Ratio 2 (HR2) determined with competing risk analyses adjusted for age at study entry and sex; the HR on the y-axis is graphed on a log scale. CI, confidence interval;
∗HRs changed significantly (
P < 0.0071) between age groups as determined with trend analysis including the interaction of age group with risk factor. Figure previously published in
[11▪▪].
Several hypotheses have been proposed to explain the age-dependent relationship of risk factors to cognition. These hypotheses can be divided in risk factor-specific explanations and explanations that are generalizable to all risk factors. With regard to hypertension, it has been hypothesized that with increasing age a higher blood pressure is necessary to ensure adequate cerebral blood flow [15]. Reverse causality, in which neurodegeneration leads to a decrease in blood pressure, may also play a role. However, as the age-dependency of risk factors is not specific for hypertension, generalizable explanations might be likely. First, selective survival may lead to a selection of oldest-old individuals who are less susceptible to the negative consequences of risk factors. Second, the higher prevalence of risk factors in the oldest-old may dilute the distinction between individuals with and without a risk factor. Third, neuropathological studies indicate that in the oldest-old pathologies other than AD contribute to dementia risk such as TAR DNA-binding protein 43 kDa (TDP-43) and hippocampal sclerosis (HS). These pathologies may relate to different risk factors, attenuating the effect of risk factors for AD on dementia risk in the oldest-old. Last, studies focusing on older individuals need to consider potential biases that are more likely to occur in an aging population. For example, competing risk by mortality (which describes the potentially lower chance in individuals with a vascular disorder to develop dementia as they may die faster than individuals without a vascular disorder) and the selection towards healthier individuals during follow-up. Nevertheless, despite these concerns, evidence is mounting that what is normal or what should be recommended for optimal cognition in the oldest-old may be very different from younger elderly in many of the risk factors [14▪,16].
Although the importance of some risk factors for dementia appears to decline with increasing age, other risk factors have drawn attention in the oldest-old. Lower physical strength and performance, less participation in cognitive stimulating activities, and lower kidney function have been associated with cognitive impairment in the oldest-old [17▪,18▪,19]. Although it is difficult to disentangle cause and effect in these relationships, preserving physical health seems to be of utmost importance to preserve cognitive health in the oldest-old [20].
Multiple pathologies in dementia
Although it is now appreciated that the majority of individuals with dementia have two or more dementia-related pathological findings at autopsy, research has tended to focus on AD, overlooking many of the concomitant pathologies. Non-AD pathologies including microvascular disease (microinfarcts, atherosclerosis, arteriosclerosis), HS, and TDP-43 are related to cognitive performance independently of AD and account for at least half of the attributable risk of dementia in the oldest-old [21,22▪▪]. Moreover, the number of pathologies is highly associated with dementia severity as well as risk [23,24▪]. Unlike AD, these pathologies continue to increase in prevalence with age (Fig. 3) [25▪▪] and their high prevalence in the oldest-old makes them an optimal group for investigations of these lesions. At present, these processes cannot be diagnosed without an autopsy, nor do we understand factors related to their presence and expression. For example, microinfarcts, a presumed form of vascular disease, are not related to traditional vascular risk factors in the oldest-old [26]. In HS, the clinical profile suggest that HS dementia is associated with cognitive deficits similar to AD but often progress more slowly [27▪]. Pathologies, such as HS, TDP-43 and AD frequently co-occur but are each known to cause dementia even when not accompanied by the other pathologies [28]. Our understanding of these pathologic contributions to dementia is modest and represents an area with potentially great public health impact.
FIGURE 3: Estimated probability of Alzheimer's dementia, cognitive impairment, and various neuropathologies according to age. Panel A) Alzheimer dementia, cognitive impairment, and AD neuropathology. Panel B) non-AD neuropathologies. Data are from separate models. Figures previously published in
[25▪▪].
Limbic-predominant age-associated TDP-43 encephalopathy (LATE)
First recognized as the disease protein in amyotrophic lateral sclerosis (ALS) and many cases of frontotemporal lobar degeneration (FTLD-TDP), phosphorylated TDP-43 was subsequently identified in the brains of many people with dementia and HS over age 80 [28]. Despite frequent co-occurrence with AD at this advanced age, autopsy studies in the oldest-old have identified many individuals with dementia who have HS or limbic-predominant TDP-43 without the presence of AD pathology. In 2019, a consensus working group proposed a sampling and staging system for routine autopsy diagnosis to characterize the anatomical distribution of TDP-43 proteinopathy in these individuals [29▪▪]. Dubbed Limbic-predominant Age-associated TDP-43 Encephalopathy (LATE), the progressive amnestic syndrome associated with this pathology is most frequently diagnosed during life as Alzheimer dementia even when AD pathology is not present. In autopsy studies, LATE accounts for at least 20% of dementia in the oldest-old [29▪▪]. Currently, we are not able to effectively diagnose this disorder during life, but TDP-43 biomarker development is an active area of research [30,31▪,32] and would greatly facilitate research in this understudied disorder. Pathologically, TDP-43 has been shown to be associated with atherosclerosis and Lewy bodies, despite the latter being relatively infrequent in this age group [33▪▪]. It is likely that phosphorylated TDP-43 and other, as yet unidentified, pathologic processes account for the 30–50% of dementia of unknown origin that has been noted in the oldest-old [22▪▪,34].
Biomarkers in the oldest-old
Most studies about the utility of biomarkers for dementia in the oldest-old have been in relation to imaging biomarkers. A recent review of neuroimaging findings in the oldest-old (Woodworth D, Scambray K, Corrada MM, Kawas CH, Sajjadi AS, manuscript under review) noted a lack of imaging studies in this age group. In general, studies found greater global, medial temporal, or hippocampal atrophy to be related to dementia risk [35], cognitive performance [18▪,36▪▪,37▪▪] and faster rates of cognitive decline [37▪▪,38▪]. High burden of white matter lesions was also a common finding and was associated with worse baseline scores and faster decline in measures of global cognition [18▪,37▪▪]. Amyloid burden assessed through PET, is usually high in the oldest-old and associated with dementia risk [35], worse cognitive performance [18▪,38▪], and faster cognitive decline [38▪,39]. However, many oldest-old can maintain normal cognition in the presence of a high amyloid burden [35,40].
The utility of biomarkers to estimate risk of dementia due to AD, changes with age and in the oldest-old is low compared to younger elderly, mostly due to a lower life expectancy. A study estimating the risk of AD dementia noted that in 90+ year olds with normal cognition, the lifetime-risk is <10% if either amyloid positivity or neurodegeneration were present and <20% when both were present [41]. The risk was significantly higher and reached 47% in the oldest-old only if mild cognitive impairment was also present (Fig. 4). This finding suggests that due to lower life expectancy, using biomarkers to predict dementia in the oldest-old may have limited utility [42▪] and is helpful only if cognitive impairment is already present.
FIGURE 4: Lifetime risk of Alzheimer's dementia for women and men based on screening for amyloidosis, neurodegeneration, and mild cognitive impairment (MCI). Created from data published in
[41].
Resistance and resilience
Although the presence of cerebral amyloid is strongly age-related, the prevalence of amyloid deposits levels off in advanced age, and approximately 20% of individuals over age 90 do not have significant amyloid in their brain at autopsy (CERAD stage 0) [43]. Absence of amyloid at younger ages does not preclude the eventual deposition later in life but at very advanced ages, it raises the possibility that these individuals may be resistant to the deposition of amyloid. Although we do not yet know factors related to absence of amyloid, these studies can provide important clues for understanding AD dementia, which is defined by evidence of amyloid. It is interesting to note that, unlike amyloid, low levels of tau are virtually always present in 90+ year olds (Braak stages I & II) [23,44▪], even in the absence of amyloid deposition.
A growing body of research has been focused on so-called ‘resilience’ [45▪▪] where individuals with normal cognition have significant dementia-related neuropathologic changes in their brains, particularly AD [43,44▪]. Until recently, we were not able to identify these individuals until autopsy, if indeed an autopsy occurred. However, recent advances in imaging, spinal fluid and blood biomarkers have paved the way for identifying individuals with AD pathology while still alive, greatly enhancing our ability to study them. Biomarker development for most of the other pathologies associated with dementia is underway but at less advanced stages. These biomarkers will be crucial for our understanding of resilience because increasing evidence from autopsy studies in the oldest-old suggests that resilience to AD may in large part reflect the absence of other, non-AD pathologies including cerebrovascular disease, HS and TDP-43 [43,44▪].
CONCLUSION
The oldest-old are the fastest growing segment of the population in most of the world and have the highest risk of dementia. Clinical and neuropathological investigations of cognition in these individuals have revealed surprising findings and given new insights into the expression of dementia in aging. Factors generally associated with dementia risk are not always relevant to this age group (e.g., APOEε4) and in some cases may even be protective against the development of dementia (e.g., hypertension developing after age 85). At least half of dementia in this age group is attributable to causes other than AD which deserve more intensive study. Conversely, some individuals in this age group with AD or other neuropathologies appear to be resilient to the effects of these pathologies. Investigations in the oldest-old provide an important platform for investigating cognitive loss and dementia, as well as resistance and resilience, and will inform our understanding of dementia at all ages.
Acknowledgements
None.
Financial support and sponsorship
This work was supported by a grant from the National Institutes of Health (R01AG021055).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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