Background: As human longevity increases and Alzheimer’s disease (AD) increasingly becomes a significant societal burden, finding pathways or protective factors that facilitate exceptional brain aging without AD pathophysiologies (ADP) will be critical. The goal of this viewpoint is two-fold: 1) to present evidence for “exceptional brain aging” without ADP; and 2) to bring together ideas and observations from the literature and present them as testable hypotheses for biomarker studies to discover protective factors for “exceptional brain aging” without ADP and AD dementia. Discovering pathways to exceptional aging: There are three testable hypotheses. First, discovering and quantifying links between risk factor(s) and early ADP changes in midlife using longitudinal biomarker studies will be fundamental to understanding why the majority of individuals deviate from normal aging to the AD pathway. Second, a risk factor may have quantifiably greater impact as a trigger and/or accelerator on a specific component of the biomarker cascade (amyloid, tau, neurodegeneration). Finally, and most importantly, while each risk factor may have a different mechanism of action on AD biomarkers, “exceptional aging” and protection against AD dementia will come from “net sum” protection against all components of the biomarker cascade. The knowledge of the mechanism of action of risk factor(s) from hypotheses 1 and 2 will aid in better characterization of their effect on outcomes, identification of subpopulations that would benefit, and the timing at which the risk factor(s) would have the maximal impact. Additionally, hypothesis 3 highlights the importance of multifactorial or multi-domain approaches to “exceptional aging” as well as prevention of AD dementia. Conclusion: While important strides have been made in identifying risk factors for AD dementia incidence, further efforts are needed to translate these into effective preventive strategies. Using biomarker studies for understanding the mechanism of action, effect size estimation, selection of appropriate end-points, and better subject recruitment based on subpopulation effects are fundamental for better design and success of prevention trials. Keywords: Exceptional Aging, AD prevention, Biomarker cascade Background (ADP) are critical. Currently, much of the research has The two primary histopathological changes to the brain been focused on resilience or cognitive reserve , wherein due to Alzheimer’s disease (AD) are the deposition of the focus has been on discovering how and why individuals amyloid and tau . These two AD-related brain changes are able to remain clinically unimpaired or cognitively are the primary underlying causes of neurodegeneration normal despite ADP. However, it is important to inves- and cognitive dysfunction which ultimately leads to tigate, using surrogates of amyloid and tau pathologies dementia. As human longevity increases, and AD dementia via cerebrospinal fluid (CSF) and positron emission increasingly becomes a major societal burden, finding tomography (PET), why majority of individuals develop pathways that lead to brain aging without AD pathologies ADP as they age and how some oldest old individuals are able to age without significant ADP. The latter individuals are called “exceptional agers” without ADP. While the Correspondence: firstname.lastname@example.org absence of ADP can be defined using various thresholds, Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, we refer to the absence of ADP as not reaching the Rochester, MN 55905, USA © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vemuri Alzheimer's Research & Therapy (2018) 10:53 Page 2 of 8 neuropathological definition of AD in pathology studies on optimal or successful aging without cognitive decline and the imaging cutoffs of amyloid and tau positivity in [6–8] in the oldest old. In addition, specific evidence for imaging studies. Amyloid and tau PET scans of an excep- “exceptional brain aging” without ADP comes from these tional ager in comparison to a clinically unimpaired indi- three different lines of investigation. vidual and an AD dementia individual are shown in Fig. 1. In this view point, the main goal is to bring together Prevalence of AD pathologies ideas and observations from the literature and present Nelson et al.  published an amalgamation of neuropatho- them as testable hypotheses or frameworks that can be logical literature showing that each added year of life does employed in biomarker studies to discover protective not lead to an increased prevalence of AD pathologies, factors or pathways to “exceptional brain aging”. In the unlike hippocampal sclerosis and cerebrovascular disease. context of the terminology we recently proposed, for Neuroimaging studies in the Mayo Clinic Study of Aging hypotheses 1 and 2 the focus is on “resistance to ADP” (MCSA) have also found non-monotonicity in the  and for hypothesis 3 the focus is on both resistance frequency of amyloid positivity in clinically unimpaired to ADP and prevention of AD dementia. individuals [10, 11]. Thedatafromour previous work  These concepts are presented in the context of the pri- were consolidated to plot the prevalence of elevated amyloid mary AD pathophysiological processes in the biomarker versus excess cerebrovascular disease burden in clinically cascade (amyloid, tau, and neurodegeneration due to AD unimpaired individuals (Fig. 2a). These curves are reminis- pathologies). The focus is on primary prevention in midlife, cent of two types of growth curve models in population designing effective trials by understanding the mechanisms ecology: exponential, or J-shaped, and logistic, or S-shaped, of action on the biomarker cascade, and looking at the net models. While exponential models have uninhibited growth sum protection against all components of the biomarker in numbers, logistic growth models exhibit a slowing in cascade. Although additional AD processes are not explicitly growth as the population reaches its carrying capacity. Vas- addressed, such as inflammation, synaptic and microglial cular pathologies show a steady increase in the prevalence dysfunction that are relevant to aging and AD dementia, the or rate of growth representing an exponential model over concepts here can also be extended to other measurable an age range of 50–100 years. On the contrary, the amyloid biomarkers that are mechanistically relevant to AD. elevation curves exhibit a slow saturation alluding to the fact that there may be a proportion of the population that will “Exceptional brain aging” without ADP: is it really never develop elevated levels of amyloid, supported by evi- possible? dence from Khachaturian et al. . Amyloid data collected Several pathology and observational studies have provided from 55 studies by Jansen et al. also showed that a logistic evidence for aging without ADP [4, 5] and have focused model was the best fit for amyloid prevalence . Fig. 1 Tau and amyloid positron emission tomography (PET) scans in a typical clinically unimpaired, typical AD, and an exceptional ager (> 85-year-old APOE4 carrier) Vemuri Alzheimer's Research & Therapy (2018) 10:53 Page 3 of 8 Fig. 2 a Prevalence of elevated amyloid levels (A+) versus vascular disease (V+) in clinically unimpaired individuals based on data from Vemuri and Knopman . Vascular pathologies show a steady increase in the prevalence (exponential growth curve models) but the amyloid positivity curves exhibit a slow saturation similar to logistic growth curve models. b Data from our previous study  illustrates the slow longitudinal cognitive decline seen in a clinically unimpaired 80-year-old male without amyloid and cerebrovascular pathologies (in blue) in comparison with significantly greater decline seen in a clinically unimpaired individual of the same age with both elevated amyloid and cerebrovascular pathologies(in red) Declining AD incidence and amyloid levels While the observed evidence can be attributed to excess Recent evidence of age-specific decline in both incidence mortality early in life in those at risk (for example, for of dementia [14, 15] and amyloid levels  in aging APOE4 carriers), it is important to study and understand brains provides compelling evidence for the possibility of how some individuals are able to age without ADP. aging without AD pathologies. With the strong possibility that better medical care and increasing education levels Discovering pathways to “exceptional aging” may have contributed to these declining trends , Given the possibility of “exceptional aging”,how does investigation into the underlying mechanisms may lead us one discover the important protective factors. Three closer to understanding the differences between normal inter-related ideas or hypotheses are presented here aging and developing ADP. that, when taken together, can aid in discovering pro- tective pathways and help design effective preventive strategies. APOE4 carriers without AD dementia and AD pathologies in the oldest old Hypothesis 1 (primary prevention in midlife) Age and the apolipoprotein (APO)E4 genotype are the Discovering and quantifying links between risk factors two well-established risk factors for AD . Therefore, and early ADP changes in midlife using longitudinal one would expect that, as people age, the odds of an biomarker studies is fundamental to understanding why APOE4 individual developing AD dementia would increase the majority of individuals deviate from normal aging to with age. However, there have been several observations the AD pathway. showing that the association between APOE4 genotype and development of AD dementia is weak in the oldest Normal aging versus pathological aging old, i.e., there are some APOE4 carriers who live into their Aging acts through a number of biological mechanisms at 90s without AD dementia [12, 18–20]. While these studies the cellular or tissue level that lead to loss of reserve and have proven the presence of very old APOE4 carriers with- function . Prominent aging-related changes occur in the out AD dementia, one may argue that protection against brain during midlife, and more so in the sixth to seventh AD dementia primarily comes from “resilience to ADP, i.e., decades. Midlife also represents the time during which coping with pathology”. However, the presence of amyloid- (neurodegenerative and cerebrovascular) pathologies are negative APOE4 cognitively normal individuals at 85 years observed in brain autopsies . Even in the absence of of age (~ 25%) in a large meta-analysis  supports pathologies, individuals suffer from age-related neural theideaof “resistance to ADP” in the oldest old APOE4 structure alterations [22, 23] and alterations in gene expres- carriers. sion  starting in midlife. However, in the presence of Vemuri Alzheimer's Research & Therapy (2018) 10:53 Page 4 of 8 neurodegenerative and cerebrovascular pathologies, the protective factors can be employed for primary prevention structural and functional deterioration of the brain has [38, 39]. While significant focus has been placed on amyl- been observed to be greater. This accelerated decline in oid imaging since it has been available from the mid- brain health due to neurodegenerative and cerebrovascular 2000s, the same concepts can be extended to tau-related pathologies is the primary observed cause of dementia. By studies as longitudinal tau data become available . age 80, > 60% of clinically unimpaired individuals have either ADP or cerebrovascular disease. Figure 2b based on Hypothesis 2 (designing effective trials) data from our previous study  illustrates the slow lon- A specific risk factor may have quantifiably greater impact gitudinal cognitive decline seen in a clinically unimpaired as a trigger and/or accelerator on a specific component of the 80-year-old male without amyloid and cerebrovascular biomarker cascade (amyloid, tau, or neurodegeneration). pathologies (in blue) in comparison with a significantly greater decline in a clinically unimpaired individual of the The biomarker cascade framework and quantifying the same age with both amyloid and cerebrovascular patholo- impact of each risk/protective factor gies (in red). There is also consensus about the significant Although amyloid and tau deposition can be initiated heterogeneity in the cognitive aging process . All these independently, there is sufficient recent evidence sup- studies taken together provide evidence that normal aging porting the hypothesis that amyloid deposition accelerates is different from pathological aging and late midlife tau deposition which, in turn, is closely associated with represents a critical time period during which we observe cognitive decline [41–44]. Autosomal dominant AD noticeable divergence of these two pathways. Given that studies that represent younger-onset pure AD cases slowing of age-related changes in midlife can be observed have confirmed the sequence of amyloid followed by with better lifestyle factors such as physical activity and tau, followed by cognitive decline [45, 46]. The biomarker ideal levels of cardiovascular health [26–28], our focus model presented and refined based on the literature by should be on primary prevention during midlife and early Jack et al.  synthesized AD processes into a set of adulthood. testable hypotheses. Amyloid, tau, neurodegeneration, and There is well-established literature supporting that cognitive decline form the biomarker cascade and this midlife conditions have a significant impact on late-life framework has helped significantly improve our under- dementia, especially cardiorespiratory fitness and standing of disease onset and progression [41, 47–49]. vascular risk factors . The relationship between The presence of suspected non-AD pathophysiology several risk factors (obesity, hypertension, dyslipidemia) (SNAP; neurodegeneration in the absence of amyloid) and dementia incidence has been observed to be U-shaped  and primary age-related tauopathy (PART) in the in nature with the greatest association during midlife absence of amyloid  illustrate the heterogeneity in [31–33]. Additionally, the prevalence of amyloid curves the age-related neurodegenerative processes and share (as mentioned above) follows a logistic growth curve some pathophysiological aspects (neurodegeneration or model with the greatest rate of amyloid accumulation in tau) of the AD biomarker cascade. Since each of these the population during late midlife. The first hypothesis pathophysiologies plays a role in the development of AD proposes that greater focus needs to be placed on longitu- dementia, as discussed further in hypothesis 3 below, dinal biomarker studies that can discover and quantify studying independent triggers and accelerators for each links between risk factors in midlife and increased ADP component of the AD biomarker cascade will be important. accumulation in late midlife to understand why individuals In the second hypothesis, it is proposed that looking at deviate from the normal aging process. each individual component of the biomarker cascade One may argue that there has been extensive literature (amyloid, tau, neurodegeneration) to explore the impact already supporting the hypothesis that midlife risk factors of the risk factor of interest will aid in understanding such as vascular risk factors increase late life dementia the mechanisms through which the specific risk factor incidence. However, the results from intervention stud- impacts AD processes. ies based on a reduction of vascular risk factors  highlights the need for longitudinal biomarker studies Importance of knowing the mechanisms in midlife that focus on understanding the mechanisms Although a vast amount of literature has provided evidence of action of the suggested risk factors as early ADP for the impact of risk factors on dementia incidence, less changes evolve. This is especially important for risk or has been published on the impact of each individual risk protective factors that are highly debated in the literature factor on the primary disease mechanisms. Discerning the [35–37]. Understanding how the risk factors or combin- disease stage at which the reduction of a specific risk factor ation of risk factors impact early ADP changes (whether it would be helpful will be important for designing effective is amyloid, tau, or neurodegeneration) using longitudinal preventive strategies. A recent example was the failure studies will facilitate a better understanding of how of the TOMORROW trial, which targeted diabetes Vemuri Alzheimer's Research & Therapy (2018) 10:53 Page 5 of 8 medications for reduction of dementia . While there health was quantifiably greater on neurodegeneration than has been substantial evidence that diabetes is associated on amyloid deposition supporting the second hypothesis with AD dementia incidence, the primary mechanism of . If one were to consider that vascular risk factors cause action may be through neurodegeneration (discussed fur- significantly greater neurodegeneration and cognitive decline ther below) . Therefore, with diabetes as a preventive compared with their effect on early amyloid deposition, it strategy, the focus should be on measuring the reduction strongly supports the epidemiological findings that vascular in neurodegeneration and not on reduction in amyloid risk factors lower the threshold of dementia detection and deposition. Another example is that of sleep as a prevent- are related to a higher incidence of dementia . ive strategy. While poor sleep has been shown to impact amyloid deposition through poor clearance of amyloid Hypothesis 3 (net sum game) [53, 54], and thus could mechanistically be linked to “Exceptional aging” as well as protection against AD de- greater dementia incidence and brainatrophy , mentia will come from “net sum” protection against all improving sleep quality as a preventive strategy for AD the components of the AD biomarker cascade. dementia may fail in individuals who have high levels of If protection against AD pathology in each individual amyloid. Therefore, quantifying the effect size of risk were viewed as a “net sum” of effects from all triggers factors on each component of the biomarker cascade will and accelerators (lifestyle, midlife risk factors, chronic aid in choosing appropriate outcomes and the sample sizes conditions, net difference between protective and risk genes) required. In addition, determining the effect modifiers as well as additive and interactive non-AD processes, then (main biological and disease-related factors that may influ- “exceptional aging” without ADP and ultimately without ence the treatment response such as additional interactions AD dementia would be possible if a large positive “net sum” of the risk factors with age and APOE4 status) will aid in were present. This hypothesis highlights the importance for better enrichment strategies and intervention optimization. multifactorial or multidomain approaches to “exceptional Figure 3 illustrates well-established triggers and accelera- aging” without ADP and AD dementia. tors for some of the components of the biomarker cascade. The support for “net sum” against AD dementia A specific example of vascular health and neurodegenera- primarily comes from dementia risk score studies [59, 60] tion is discussed here. Poor vascular health and vascular risk that have shown that a combination of several risk factors factors are clearly related to higher incidence of dementia are best at predicting dementia risk compared with indi-  as well as causing significant brain changes independent vidual risk factors. The large positive “net sum” against of amyloid and tau . While there has been no doubt that ADP was also observed in our recent study where we vascular risk factors, specifically diabetes and hypertension, found that, irrespective of the impact of a risk factor on increase neurodegeneration (cortical thinning and hip- amyloid or neurodegeneration, several protective factors pocampal atrophy), there has been considerable debate (absence of midlife risk factors, lower chronic conditions) about the impact of vascular risk on amyloid deposition. had moderate effect sizes in predicting those who were In a recent study, we found that the impact of vascular greater than or equal to 85 years of age without abnormal Fig. 3 Framework for the second hypothesis and examples of triggers and accelerators of some of the components of the biomarker cascade. AD, Alzheimer’s disease; APOE, apolipoprotein E Vemuri Alzheimer's Research & Therapy (2018) 10:53 Page 6 of 8 Fig. 4 Impact of intellectual enrichment (e.g., education, occupation, cognitive activity) and Other neurodegenerative processes on the Alzheimer’s disease (AD) trajectories. Cognition curves are superimposed on the ADP curves (amyloid or tau) shown in blue. The horizontal line indicates the cognitive impairment threshold. The time at which cognitive function meets the threshold allows us to deduce the ADP levels at the same time point on the superimposed ADP curves. a Illustration of individuals with high (green curve) and low (red dashed line) intellectual enrichment and the ADP levels (shown by the circles) at which cognitive impairment would be observed in both groups of individuals. b Illustration of individuals with only AD path (green curve) and AD path in addition to other neurodegenerative pathologies (red dashed line) and the ADP levels (shown by the circles) at which cognitive impairment would be observed in both groups of individuals amyloid and neurodegeneration levels compared with those Conclusions who had significant amyloid and neurodegeneration . While important strides have been made in identifying In addition, greater intellectual enrichment can further aid risk factors for AD dementia incidence, future efforts in delaying the onset of impairment through its impact on need to be directed towards discovering the timing and cognition, as illustrated by Fig. 4a [61–63]. mechanism of action of each of these risk factors on The presence of non-AD processes such as cerebrovas- AD processes. In this work, three inter-related ideas are cular disease, TDP-43, Lewy bodies (often alongside AD presented that are important to consider while studying processes) and their contribution to cognitive impairment risk factors and may help us move towards developing are important to consider in this context since non-AD effective preventive strategies to maneuver individuals neurodegenerative pathologies reduce the threshold to away from the AD pathway towards the pathway of AD dementia when present along with ADP [57, 64]. This “exceptional brain aging” without ADP. concept can be observed in Fig. 4b, which illustrates two Acknowledgements subsets of individuals: the first have cognitive decline or The author would like to thank David S. Knopman, MD, Eider M. Arenaza-Urquijo, neurodegeneration only due to ADP, and the second have PhD, and the reviewers for their excellent comments, as well as Heather Wiste a greater rate of neurodegeneration or cognitive decline and Timothy Lesnick for their help generating Fig. 2. For the images used, we would like to thank AVID Radiopharmaceuticals for the provision of AV-1451 due to other non-AD neurodegenerative processes along precursor, chemistry production advice and oversight, and FDA regulatory with ADP. A clear difference can be observed in the levels cross-filing permission and documentation. of ADP at which the same level of cognitive impairment would be expected for both groups. The second group Funding The author was funded by NIH grants (R01 NS097495 and R01 AG056366). would need a much lower level of amyloid to experience the same level of cognitive impairment as the first group. Authors’ contributions This figure illustrates the importance of viewing protection The author read and approved the final manuscript. against AD dementia as protection against all components of the AD biomarker cascade. Ethics approval and consent to participate A major limitation of this work was limiting the scope The data reported here are from Mayo Clinic Study of Aging and from publications by the author. These studies were approved by the Mayo Clinic to the three main AD biomarkers for simplicity. However and Olmsted Medical Center institutional review board. Informed consent the concepts illustrated in Figs. 3 and 4 can be extended was obtained from all participants or their surrogates. after inclusion of additional measurable AD-specific pro- cesses such as inflammation as well as non-AD processes Competing interests and pathologies. The author declares that they have no competing interests. Vemuri Alzheimer's Research & Therapy (2018) 10:53 Page 7 of 8 Publisher’sNote 28. Okonkwo OC, et al. Physical activity attenuates age-related biomarker Springer Nature remains neutral with regard to jurisdictional claims in alterations in preclinical AD. Neurology. 2014;83(19):1753–60. published maps and institutional affiliations. 29. Defina LF, et al. The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study. Ann Intern Med. 2013;158(3):162–8. 30. Gottesman RF, et al. 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Published: Jun 1, 2018
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