Trends in the public health significance, definitions of disease, and implications for prevention of Alzheimer’s disease

Abstract

Purpose:

Although Alzheimer’s disease (AD) was described over a century ago, there remains no cure, and with the global demographic shift to older ages, the impact is increasing rapidly. This article summarizes how the conceptualization of AD has evolved in response to research advances. Current challenges, including the impact of multimorbidity are outlined and potential targets for prevention are discussed.

Recent Findings:

The ability to study AD neuropathology in vivo and results from longitudinal epidemiologic studies have led to a consensus that AD has a long preclinical course spanning decades. This view is driving efforts to identify early markers that will identify individuals at risk for AD dementia.

Summary:

Critical questions remain regarding the pathological mechanisms underlying AD and their relation to clinical symptoms. Nevertheless, evidence suggests that interventions targeting modifiable risk factors may slow or prevent the onset of disease while the search for a cure continues.

The world population over the age of 65 years will nearly double, and the number over the age of 85 is expected to increase more than three-fold by 2050 [1]. With this demographic shift, dementia and Alzheimer’s disease (AD) are consuming an increasing share of resources [2]. This trend is compounded by the fact that decreasing mortality from cardiovascular disease and stroke [3], the growing epidemic of obesity and diabetes [4], and the increasing prevalence of frailty and physical disability with increasing age [5], have led to increased rates of comorbidities among older adults affected by AD and dementia. This review will summarize: 1) trends in the public health impact of dementia with a focus on AD, the leading cause of dementia [6]; 2) challenges for epidemiologic and clinical studies of AD and how they have impacted the evolution of criteria for defining the disease; 3) current challenges including the impact of multimorbidity, and 4) implications for prevention.

Public Health Impact

Dementia is a clinical syndrome characterized by impaired functioning in one or more cognitive domains including memory, language or problem solving, that impacts the ability to perform activities of daily living and may result in behavioral symptoms [7]. There are several subtypes of dementia, with Alzheimer’s disease accounting for approximately two-thirds of cases [6].

Worldwide dementia prevalence is estimated to be between 44 and 47 million with 7 million new cases developing annually [2,7]. Dementia rates increase exponentially with age, doubling every five years between ages 65 and 90 years [8]. Estimates from the US show that 1 in 10 persons aged 65–84 years and over a third over age 85 years is impacted [9]. Therefore, with the demographic shift to older ages, the prevalence of dementia in older adults is expected to double every 20 years, and to reach 135 million by the year 2050 [2,7].

The increasing prevalence of dementia is a global epidemic that is expected to be most pronounced in low and middle income nations. While 58% of those living with dementia were estimated to be in low and middle income countries in 2013, projections suggest that this will increase to 71% by 2050 [10]. Globally, the prevalence of Alzheimer’s disease is expected to reach over 106 million by 2050 [11]. In the United States, a new case develops every 60 seconds, and the current prevalence of 5.8 million cases is expected to increase to 14 million before 2050 [7].

Data from a number of large cohort studies in the US and in Western Europe suggest that incidence of AD or dementia may have begun declining over recent decades in middle and high income nations [12–15]. In the Rotterdam Study cohort, a decrease in dementia incidence rates was accompanied by an increase in total brain volume over the same period [13]. Similarly, a large autopsy series of older adults has reported a temporal trend of declining levels of amyloid deposition between 1972 and 2006 [16]. Some studies have suggested that observed declines in dementia rates are attributable to increased levels of education [14], or to advances in the management and prevention of cardiovascular disease, including reduced rates of heart disease and stroke, and better management of hypertension [13,17]. However, whether declines in incidence can outpace the demographic shift to older ages, and the impact of a growing diabetes epidemic remains to be seen [12]. While declining incidence might, in theory, be expected to reduce prevalence of a condition, the prevalence of AD is expected to increasing given increases in life expectancy and declining mortality from other leading causes of death [18,19]. In contrast, increased incidence of dementia has been reported some areas of the world including China [20] and Japan [21,22], and sub-Saharan Africa [23]. Better characterizing factors, including lifestyle and environmental factors that underlie these geographic differences and temporal trends may provide clues regarding targets for preventive interventions [24].

In addition to the burden of symptoms and disability, AD and dementia comprise the fifth leading cause of death worldwide, up from 14^th in the year 2000 [25]. In the United States, Alzheimer’s disease is currently the 6^th leading cause of death. [7]. While US death rates from leading causes of mortality including heart disease and stroke have declined since 2000, the death rate from Alzheimer’s disease has increased by 145% [7]. These are likely to be underestimates of the contributions of AD to mortality, given that death certificates often do not attribute cause of death to AD [26], and that AD has indirect impact on mortality through effects on other conditions [27].

Finally, AD and dementia are among the costliest conditions to society. These costs include direct costs of medical care as well as costs for informal care, and long-term and hospice care. In 2015, the World Health Organization estimated that total worldwide costs were 818 billion US dollars, and projected that by 2018 it would reach a trillion US dollars [10]. Estimates for the US suggest that total costs of AD care would increase from 290 billion dollars in 2018 to 1.1 trillion dollars by 2050 [7]. In addition to these costs, the large costs of unpaid or informal care must be considered. In 2018 alone, unpaid caregivers were estimated to have provided 18.5 billion hours of care to individuals with AD, and cost of this care was estimated to be 234 billion dollars. In addition to the monetary costs associated with AD and dementia, there is a substantial cost to society in terms of years of life lost due to premature death and years of life spent with disability. As of 2016, AD was ranked sixth among all conditions in terms of disability adjusted life years, which is a sum of these two [28].

In summary, the worldwide demographic shift toward older ages is driving a global increase in the numbers of persons impacted by AD and dementia. The costs associated with AD are growing in terms of mortality, morbidity and societal costs including health care expenditures and years of life lost. It is projected that these costs may be greatest in low and middle income countries, where resources may be most limited. These trends highlight the critical need for strategies to prevent or arrest the progression of AD.

Evolution of the Conceptualization of AD

Age related cognitive decline has been described since ancient times, with one of the first references to cognitive impairment in old age attributed to Pythagoras in the 7^th century B.C. [29]. The neuropathological hallmarks of Alzheimer’s disease, amyloid plaques and tau neurofibrillary tangles, were first described in a 1907 paper by Alois Alzheimer, who described their presence in the brain of a 51 year-old female patient with clinical evidence of cognitive decline and behavioral changes over five years prior to death [30]. Amyloid plaques are extracellular deposits of amyloid beta peptides, (Aβ42 and Aβ40), which are products of amyloid precursor protein, a regulator of synapse formation and function [31,32]. Neurofibrillary tangles are intracellular deposits of phosphorylated tau protein associated with impaired neuronal function [31]. Amyloid plaques and tau neurofibrillary tangles are associated with presence of neurodegeneration, as indicated by cortical atrophy, neuron and synapse loss. To this day, autopsy confirmation of amyloid plaques and tau neurofibrillary tangles remains the gold standard for confirming AD diagnosis, with diagnosis based on the morphology, density and distribution of lesions [32–34]. Although these defining pathologies were described over a hundred years ago, the inability to diagnose and study them in vivo has been the major impediment to identifying disease altering treatments and prevention strategies [35].

In the 1970’s Dr. Lewis Kuller described the limitations of studying heart attacks and strokes rather than atherosclerosis, including inability to focus on preclinical stages of the disease process, and biases stemming from heterogeneity in the extent to which vascular pathology leads to onset of clinical symptoms [36]. These issues, in many ways, parallel those that have historically hampered the field of Alzheimer’s disease research, namely the inability to assess underlying neuropathology in vivo and reliance on case definitions based solely on clinical presentation with confirmation only at autopsy. The earliest studies were based primarily on late stages of disease in those who came to autopsy, and thus were not able to elucidate factors associated with natural history and progression of the underlying pathology or its clinical manifestations. Over the past several decades, advances in AD research have facilitated study of the neuropathological processes in vivo while longitudinal studies of aging cohorts have advanced understanding of the natural history and progression of the cognitive symptoms associated with the disease. As outlined below, these advances have been central to a shift in how AD is conceptualized, and to emphasis on distinguishing between AD neuropathology and clinical AD dementia.

In 1984, the first standard criteria for the clinical diagnosis of AD were established by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) workgroup [37]. These criteria were predicated on the underlying assumption of a close correlation between clinical symptoms and the presence and extent of underlying neuropathology [38], such that presence of AD pathology was synonymous with clinical dementia, and cognitively normal individuals were free of AD pathology [39,40]. Clinical diagnosis was defined by evidence for progressive decline in memory, accompanied by decline in language, perception and motor function not explained by other diseases [37]. Diagnoses were termed possible or probable AD, with definitive confirmation only upon autopsy. This clinical case definition has a high correlation with the gold standard histopathological diagnosis with accuracy ranging from 80–90 percent [41–43], and provided a standardized way for population based studies to describe the incidence and prevalence of clinical AD over time, within demographic subgroups and across geographic areas [24]. The application of these criteria in longitudinal cohort studies of individuals initially free of cognitive impairment have increased understanding of the neuropsychological trajectories that precede clinical AD diagnosis [39], and have identified predictive factors associated with risk for incident AD dementia [44].

Over the past three decades, several lines of evidence have led to revisions of the framework for defining AD. First, mounting evidence has made clear that AD occurs on a continuum [45,46]. Epidemiologic studies have established that subtle cognitive changes are detectable years prior to the emergence of cognitive and functional impairment that meets the diagnostic threshold for AD dementia [45]. Advances in neuroimaging including MRI and PET, and in the development of cerebrospinal fluid (CSF) and blood based biomarkers have facilitated the study of AD neuropathology in vivo [35,47,48] and have documented that accumulation of AD pathology begins 10–20 years before the onset of detectable clinical symptoms [38,45]. Epidemiologic evidence for a prodromal stage of AD led to introduction of the concept of mild cognitive impairment (MCI) defined as loss of cognitive functioning in memory or other domains, that is greater than would be expected for a given age but not meeting criteria for dementia [49]. This led to a bourgeoning of research aimed at characterizing MCI and factors associated with its onset and which predict transition to clinical AD dementia [50].

Second, the application of imaging modalities and AD biomarkers as well as advances in clinical-neuropathological studies have challenged the original assertion of a high correlation between clinical symptoms and extent of AD pathology. It has become clear that a significant proportion of clinically normal individuals meet pathologic criteria for AD [51–53]. A recent meta-analysis examined reports from 17 cohorts which included over 4,700 individuals with longitudinal clinical assessment followed by postmortem examination [54]. While presence of significant AD pathology was associated with a doubling of the risk of clinical AD dementia prior to death, a third of community residing older individuals with intermediate to high level AD pathology were clinically normal at the time of death. In addition, it is also clear that the clinical manifestations of AD pathology may be atypical, with presentation of impairment in cognitive domains other than memory [55,56].

Third, accumulating evidence has demonstrated substantial heterogeneity in the neuropathology present in the brains of older adults, with or without cognitive impairments. Early autopsy studies were based primarily on patients from specialty clinics and thus provided biased estimates of the distributions and co-occurrence of different pathologies, with over-representation of AD pathology and underestimates of the prevalence of vascular and other pathologies [52]. Data from population based neuropathological series have established that multiple pathologies are present concurrently in the brains of older individuals regardless of whether they exhibit clinical dementia symptoms [32,52,57]. It is now established that presence of AD pathology alone is uncommon among those meeting either clinical [57–59] or pathological criteria for the disease [32,60,61]. Up to two-thirds of clinical AD cases have both AD and significant vascular pathology [32,57,59,62,63]. Lewy body disease, TAR DNA-Binding protein (TDP-43) pathology and hippocampal sclerosis also occur frequently in AD brains [32,60,64]. Even among individuals who are cognitively normal, the majority have multiple neuropathologies in addition to AD [65].

The presence of coexisting pathologies has been shown to exacerbate the clinical presentation of AD [60]. In particular, among those with pathologically defined AD, presence of vascular pathology is associated with increased rates of cognitive decline and with increased probability of having been clinically diagnosed with AD [61,66–69]. For example, data from the Nun Study demonstrate that for a given level of tau neurofibrillary tangles, ante-mortem cognitive performance was worse and the chances of a clinical dementia diagnosis was higher in the presence of lacunar infarcts [67]. In addition, the presence of multiple pathologies can further complicate clinical diagnosis, as non-AD pathologies can mimic the classic AD symptoms [70].

Finally, recent shifts in the definitions of AD have been driven by the fact that efforts to develop treatments have been unsuccessful. Since 1984, there have been over a hundred failed AD drug trials [71]. Only five drugs have been approved for treatment of AD and their clinical effects have been modest, while no new therapies have been approved since 2003 [71,72]. It has been theorized that drug trials have failed in part because they have intervened late in the course of AD, at a time when pathological changes may not be reversible [46,73]. Thus, the search for early markers of individuals at elevated risk for AD is central to current research efforts and a major impetus shaping the operational definitions of the disease process.

In response to increased understanding of both the neuropathological and clinical course of AD, and recognition of the need to target drug trials and prevention efforts on early, preclinical stages, the National Institute on Aging and Alzheimer’s Association (NIA-AA) revised diagnostic guidelines for AD in 2011 [33,40], and most recently in 2018 [74]. The first revision considered AD pathology and clinical syndromes as occurring on a continuum, and focused on defining three stages of Alzheimer’s disease: Alzheimer’s dementia, mild cognitive impairment and preclinical. PET or CSF biomarkers of amyloid deposition, and markers of synaptic dysfunction or neurodegeneration (PET glucose uptake, MRI) were included to define the preclinical stage [40,45]. A notable feature of these guidelines is that they explicitly proposed disaggregating the pathological process of AD from the clinical syndrome, highlighting the need to better understand the temporal sequences of each and the mechanisms linking the two. This distinction between the underlying pathology and the clinical syndrome was taken further with the most recently proposed NIA-AA framework which defines Alzheimer’s disease on the basis of biomarkers of amyloid deposition, and cerebral tau pathology, independent of the clinical syndrome [74].

Thus, while the diagnostic hallmarks of AD remain amyloid plaques and tau neurofibrillary tangles as described over a century ago, conceptualization of the disease process has shifted dramatically. While the first, 1984 diagnostic criteria, considered only the clinical syndrome of AD dementia, the current research framework is driven by a conceptualization of AD as occurring on a continuum with disease defined solely on the basis of the neuropathology. This framework is posed as a dynamic one which will evolve as new information accumulates and is intended to facilitate the development of new biomarkers that sensitively and specifically identify individuals at risk for AD dementia prior to the onset of detectable cognitive symptoms. It is important to note that the report acknowledges that the application of biomarkers in a clinical context is not yet warranted, and that further work is needed to understand the natural history of the clinical syndrome [74].

Current Challenges

The numerous advances in AD research over the past several decades have highlighted several challenges for identifying effective treatments. The shift of focus from the late stages of clinical AD dementia to the early preclinical stage has led to consensus regarding the need for early intervention, and has motivated the quest for early biomarkers to identify asymptomatic individuals who have a high probability of developing clinical AD. Neuroimaging techniques, such as PET [75,76] and CSF markers [31,77] have established that cerebral amyloid and tau deposition can be detected years in advance of clinical symptoms [78,79]; yet their application to large scale trials is limited by cost or the need for invasive procedures. Thus, current efforts are directed at developing more widely applicable, reliable and valid blood-based biomarkers of early AD [31,39,77].

Although amyloid plaques and tau neurofibrillary tangles are considered the hallmarks of AD dementia, an overarching challenge is that the fundamental causes of AD dementia have not been established [32,54]. Some have postulated that amyloid and tau are markers of an underlying disease process rather than a causal factor [32,80,81]. Evidence suggests that the onset of clinical symptoms depends upon a constellation of multiple pathological processes rather than amyloid or tau alone [64,81–83]. The mechanistic links among these pathologies and whether they are additive or synergistic is unknown [32,64]. In addition, the temporal sequence of pathological changes in AD also remain a topic of debate [32,39,84]. Ultimately, effective treatment of clinical AD may require therapies that target multiple pathways [32,39,85], and this will require increased clarity regarding disease mechanisms. Meanwhile, it has been noted that known pathology accounts for only half of all dementias [86,87].

Given these gaps in understanding the mechanisms of AD, the most recent NIA-AA research framework has generated controversy over the exclusive focus on biomarkers. Ultimately, it is the clinical disease, AD dementia, that we wish to treat, and opponents caution against narrowing the focus on specific biomarkers before we fully understand how multifactorial pathological processes manifest in clinical disease [39,81]. This point is underscored by a recent analysis which estimated the lifetime and 10-year risk of clinical AD according to presence of preclinical markers, that included amyloidosis, neurodegeneration and MCI [88]. The projections indicated that the majority of individuals with a preclinical marker of AD will not develop clinical disease in their lifetime, and further suggested that presence of clinical symptoms adds significantly to the probability that someone with amyloidosis or neurodegeneration will develop clinical AD prior to death. Others have shown that clinical cognitive symptoms do as well as or better than biomarkers (MRI morphometry, FDG-PET brain metabolism, and CSF markers of amyloid and tau) in predicting who will develop clinical AD [89]. Thus it is critical to continue efforts at improving the sensitivity and specificity of cognitive tests for detecting early cognitive change, and to combine neuropsychological assessments with biomarkers to disentangle heterogeneity in the presentation of AD, particularly in the early, prodromal stages [39].

Impact of Multimorbidity

An additional challenge is the increasing impact of multiple co-morbid chronic conditions, or multimorbidity, on the presentation and clinical course of AD [90,91]. Increasing lifespan and advances in prevention of major causes of mortality, including heart and cerebrovascular disease have resulted in increasing prevalence of AD patients with multimorbidity [7]. Medicare data demonstrate that multimorbidity is more common among those with AD or other dementias, with five or more conditions present in 25% of those with dementia compared to 4% of those without [7]. Medicare data show that, among dementia patients coronary artery disease or diabetes is present in over a third, 29% have chronic kidney disease, 28% have congestive heart failure, and a quarter have chronic obstructive pulmonary disease [7]. Multimorbidity has also been associated with increased risk of incident MCI [92]. A systematic review has summarized evidence for the relationship of multimorbidity with progression of cognitive, functional and neuropsychiatric symptoms in AD patients [93]. Most cross-sectional studies showed that multimorbidity is associated with worse status for each of these outcomes. Longitudinal studies showed mixed results regarding the association of baseline co-morbidities with subsequent disease progression [93–95], and one suggested that the relation of co-morbidities with clinical manifestations of AD may be dynamic, with function at any point in time dependent on the number and severity of concomitant conditions [94].

Whether multimorbidity is causally associated with AD remains unclear. Cross-sectional analyses have shown associations between multimorbidity and imaging indices of neurodegeneration, but not with amyloid deposition [96–98]. Yet, evidence strongly supports that the presence of multiple underlying conditions, particularly vascular conditions, may lower the threshold for clinical presentation of dementia syndromes, and may be related to faster rates of clinical disease progression. Better understanding the impact of multimorbidity on the clinical course of AD might improve the ability to predict individual prognosis [93]. Conversely, in terms of managing chronic conditions, the relation of multimorbidity to AD dementia is likely bi-directional. Multimorbidity is associated with use of multiple drug therapies [99] such that cognitively impaired patients may face challenges associated with management of complex drug regimens which result in poor compliance [100,101]. Few studies have addressed ways to optimize management of chronic disease states in persons with cognitive impairment or dementia, particularly among community residing individuals [102]. Cognitive dysfunction may pose a particular challenge for the management of diabetes [103]. The ability to engage in non-pharmacologic health behaviors, such as physical activity and maintenance of a healthy diet may also be impacted by cognitive dysfunction [104]. Finally, there is a need for increased consideration of multimorbidity in the design of therapeutic clinical trials in order to ensure generalizability [90].

Implications for Prevention

Several of the aforementioned challenges to elucidating the root causes of AD and to finding an effective cure may also be viewed as potential avenues for prevention. While no disease modifying therapies have been found, it may be possible to impact the clinical course of AD dementia without directly impacting AD pathology. The lack of correspondence between definitive AD neuropathology and clinical symptoms [54] and the fact that known pathologies do not account for the majority of dementia cases [86,87] suggest the need to identify individual characteristics that determine resilience to the cognitive effects of AD pathology [44,54,82]. For example, some data suggest that declining dementia incidence in recent decades may be related to improvements in education across successive birth cohorts [14,15], while health behaviors and medical history may also be linked to cognitive resilience [44].

The association of multimorbidity with cognitive impairment and AD dementia suggests that improved management of co-morbidities may provide a means of improving disease prognosis in those with mild cognitive impairment or AD dementia [93,95]. Both treatment of existing conditions and routine monitoring for onset of new co-morbidities may be important for impacting the progression of AD symptoms [93]. This may be true regardless of whether common chronic conditions have additive or synergistic effect on AD pathology.

Similarly, while we do not know how mixed pathologies interact to impact clinical AD, the fact that the majority of AD cases also have other significant neuropathology, particularly the frequent co-occurrence of vascular pathology, suggests a window for prevention. Whether vascular and AD pathology have additive or synergistic effects remains to be established [64]. However, the presence of vascular pathology clearly impacts the clinical threshold for emergence of cognitive dysfunction as well as the progression of cognitive decline. Decades of research in cardiovascular disease prevention have shown the beneficial effects of risk factor interventions.[105,106]. Some studies have suggested that positive secular trends in cardiovascular risk may explain observed declines in dementia incidence in Western nations [13,17], and a number of modifiable vascular risk factors, including diabetes, obesity, hypertension, and sedentary behavior have been associated with risk for AD [107]. Estimates of population attributable risk show that worldwide, 10% to 20% reductions in risk factors would result in an 8.3% to 15.3% reduction in the projected number of AD cases in the year 2050. This equates to a reduction of between 8 and 16 million new cases over the next three decades [108].

Long term cohort studies have shown that midlife may be a critical period for intervening on vascular risk factors to prevent later life cognitive decline [109,110]. However, there is also evidence that interventions at later ages may prevent or slow cognitive decline or dementia [107]. The fact that AD dementia is a multifactorial condition paired with limited efficacy in interventions that have targeted single risk factors has led to the development of multi-domain behavioral interventions [107,111]. The first of these, the FINGER trial, tested a two-year intervention targeting diet, exercise, cognitive training, social engagement and management of co-morbid chronic conditions in a population based sample of older adults at high risk for cognitive decline [112], The trial demonstrated beneficial effects on rates of decline in multiple domains of cognition and on non-cognitive outcomes such as quality of life, diet and body mass index [112]. Two subsequent multi-intervention trials in older adults yielded negative results in the primary cognitive endpoints, but showed benefit in post-hoc analyses [107]. Currently, the world-wide FINGERS network has been formed to test modifications of the FINGERS intervention model in diverse geographical settings [113].

Summary:

The public health impact of AD continues to grow, and there remain many challenges to finding a cure. Advances in the field have shifted the conception of disease to that of a continuum with a long preclinical phase and have demonstrated great heterogeneity in both the neuropathology and clinical manifestations of the disease. Improved understanding of AD mechanisms and how they impact clinical AD dementia will be critical to the development of effective therapies. However, until such therapies are found, current evidence suggests that identifying ways to modify factors associated with cognitive resilience and developing behavioral interventions targeting comorbidities and vascular risk may impact the clinical presentation and progression of AD dementia. Projections of the global burden of AD have indicated that delaying onset or progression of AD by only one year would result in over 9 million fewer AD cases, or a 10% reduction in projected prevalence by the year 2050 [11].