Demographic patterns and consequences of longevity

Life expectancy of individuals with DS has steadily improved over the last 100 years, paralleling the experience of neurotypical populations, but to an even greater extent [4–9]. This increased longevity is an obvious benefit provided by improved medical care and enlightened social policies, but it raises new concerns for older adults with DS, as well as for their caregivers [7, 10]. Aging is accompanied by changes in cognition and health status, increasing risk for neuropsychiatric concerns, physical frailty, and Alzheimer’s disease (AD) [6, 11], all of which will affect their ability to function relatively independently [12–14]. In turn, these age-related changes may substantially increase needs for supports and services. Adding to the complexity is the fact that in comparison with adults without lifelong impairments, adults with DS are more likely to experience these age-related changes at earlier ages, by some estimates as early as in their 40s [15, 16]. Perkins and Moran [17] called this the “synergistic effect of increasing age with concomitant membership in a highly vulnerable population” (p. 91). In neurotypical populations, caring for elderly adults is challenging due to the mixture of increased physical and medical fragility as well as social challenges faced [18, 19], but for individuals with DS these lifelong challenges are further compounded by their preexisting developmental impairments.

The cognitive and behavioral phenotype of DS

An extensive literature on the cognitive and behavioral abilities of individuals with DS has documented a general pattern of relative strengths and weaknesses that is now broadly described as the cognitive phenotype of DS [1, 2, 20, 21]. Its major features include relative weaknesses in the development of language and language-related processes (e.g., verbal working memory [2, 22]). These relative weaknesses cannot be explained by impairments in either hearing or speech or the neurological complications and comorbid factors reviewed by Lott and Diersson [1, 23]. Advancing our understanding of the details of them has attracted considerable interest [24, 25]. While variability across individuals is certainly present, individuals with DS typically demonstrate a consistent pattern during early development that includes stronger receptive language skills compared to expressive language skills and a relative lag in syntactic development (the ability to form well-developed sentences from words or phrases) compared to vocabulary growth [26–28]. Rondal and Comblain [29] and Chapman and Hesketh [27] have provided in-depth reviews of the development of language processes in individuals with DS.

Executive functioning contributes to performance in a broad range of tasks, including those with a primary focus on attention, perceptual speed, reaction time, motor control, set shifting, working memory, inhibition/perseveration, and fluency [30]. In comparison to individuals with intellectual disability (ID) without DS, individuals with DS present with deficits in many aspects of executive functioning (e.g., [20, 31, 32]). For example, Rowe and colleagues [20] compared groups with and without DS matched on age and on a measure of vocabulary proficiency (British Picture Vocabulary Test [33]) and found that the group with DS performed at significantly lower levels on all tests of executive functioning with the exception of spatial span, compared to their peers without DS.

Age-related changes in cognitive functioning

In individuals with DS, aging in adulthood is known to have multiple impacts on cognition, with subtle declines in a broad range of abilities beginning roughly in the mid- to late 20s (see Grieco et al. [1] for a general review). In general, this is an underinvestigated area demanding further research yet, of the studies that have investigated cognition in adults with DS without dementia (e.g., [34]), there is agreement that changes in cognitive abilities and adaptation skills mirror those observed in older adults in neurotypical populations, but appear to occur at an accelerated rate (e.g., [35]).

Das et al. [36] found that the rate of cognitive decline was faster in adults with DS who were 40 years of age and older in comparison to individuals with comparable levels of intellectual functioning but without DS. Differences in the effects of aging on performance were especially evident on tasks requiring planning and attention and language abilities such as speech rate and word series tests; these all became more impaired with age compared to other cognitive processes. Similarly, Ribes and Sanny [37] documented a reduction in short-term and long-term memory, in vocabulary usage, and in expressive and receptive language abilities. (According to these observations, there was already a slight decline in abilities that occurred between 20 and 40 years of age, although aging-related declines were more marked after the age of 40 years.)

Studies in adulthood have also shown evidence of declines in executive functioning and attentional processes ( [38–40] and see [1] for a review). Deficits in attention first observed in early development have been observed to persist through adulthood [20, 41, 42]. These deficits contribute to difficulty prioritizing, staying engaged with a task, and consistently responding in the same manner to certain situations, all of which may affect the ability to function and live independently.

Though studies across the lifespan have consistently demonstrated that auditory working memory is an area of relative weakness for people with DS [43–45] (and see [23] for a review), visuospatial short-term memory remains relatively stable in adulthood. A review by Yang and colleagues [46] noted that, while visuospatial processing can show an uneven profile, many aspects of abilities remain commensurate with general cognitive abilities at younger ages. More recently, Tsao and colleagues [47] examined typical aging in cognition and social adaptation in adults with DS, specifically focusing on the interindividual variability. In adults, aged 20–69 years and dementia free, they observed both interindividual variability and age-related decline in both cognitive and social adaptation skills.

Cross-sectional studies examining language deficits that occur with aging have highlighted differences in linguistic performance between older and younger individuals with DS [48–50]. The largest differences observed were in language comprehension, articulatory precision, and speech rhythm while lexical and morphosyntactic processes seemed to be significantly less affected [36]. Moss et al. [49] reported a significant inverse relation between advancing age and several aspects of auditory linguistic comprehension in individuals with DS between that ages of 32 and 65 years.

Rondal and Comblain [29] showed that no significant changes occur in receptive morphosyntactic abilities between late adolescence and approximately 50 years of age. Das et al. [36] observed little to no change in nonverbal reasoning, memory, receptive and expressive vocabulary, planning and attention, perceptual motor and adaptive skills until individuals reached the age of 60 years.

In general, studies support the view that individuals with DS show specific rather than pervasive declines associated with aging, per se [51].

In a case study, Krinsky-McHale et al. [52] described a man with full trisomy 21 DS who, at 70 years of age, had maintained a longitudinal cognitive and functional profile of performance of clear stability. While they were unable to determine the factors that contributed to his exceptional longevity, this case emphasizes that adult aging can occur without having significant impacts on a broad range of cognitive abilities. Thus it seems clear that the processes regulating adult aging are complex. There is a pressing need for greater insights into the many roles genes on chromosome 21 play in development and brain functioning, the impact of an extra copy of chromosome 21 on the rest of the genome, and the interactive effects on nongenetic factors.

A number of suggestions have been proposed regarding the timing and type of cognitive evaluations that should become standard practice for adults with DS in order to monitor aging-related risks and to distinguish the effects of aging from those associated with dementia. First, a broadly focused assessment at a time during adulthood that precedes risk for AD-related clinical progression is needed in order to establish a personal baseline level of cognitive and adaptive functioning against which future status can be compared [53, 54]. Specific assessment methods need to be tailored to the “premorbid” abilities of each individual to allow him/her to perform high enough above test floor in order to allow quantification of future decline. However, there is no broad agreement on timing specifics, nor is there a consensus among researchers and clinicians regarding the frequency of follow-up. Certainly, retesting should take place if concerns arise, but costs need to be balanced against potential benefits, recognizing that the impacts of adults aging, per se, and AD progression, at least during its early stages, emerge over the course of years rather than months. Assessment frequency should be increased once adults reach ages when they are at risk for dementia and other causes of frailty and be increased even more once indications of AD-related clinical progression are present. However, the relatively small and continuous changes expected with adult aging, per se, should only require reassessment at intervals of 2–4 years [2, 55].

Age-dependent risk for AD and its early effects, best characterized as “insidious,” has to be a major consideration for studies of adults with DS focused on the impacts on cognition of adult aging, per se. Even for neurotypical adults, the earliest stages of AD clinical progression can be difficult to quantify and given the lack of clear diagnostic criteria for adults with DS (discussed in the following section of this chapter), it can be even more difficult to disentangle aging effects from prodromal AD, the prevalence of which will increase exponentially after they are 40 years of age. Therefore, until valid biomarkers of preclinical and prodromal AD are discovered (see Chapters 6–9 in this volume), studies comparing aging adults with and without DS, even when presence of dementia is an exclusion criterion, must be cognizant of the potential confound presented by differential AD risk.

Alzheimer’s disease (AD) and its clinical progression in neurotypical adults

As described in Chapter 2, AD is the most prevalent among the many causes of old age-associated dementia. A definitive diagnosis of AD is based on the presence of significant β-amyloid and neurofibrillary pathology, but it also has an identifiable clinical progression. AD initially affects more complex aspects of cognition and spares more “automatic” functions. Abilities affected include [56]: (a) executive functioning (poor planning, poor judgment, impaired ability to perform complex tasks, disinhibition); (b) learning and memory (i.e., deficits in the ability to learn and retain new information, and loss of semantic knowledge); (c) orientation, more to time and place initially and then to person with further progression; (d) language (anomia, poor speech content, irregular speech rhythm); (e) visual processing (spatial confusion, impaired directed attention, poor object/person recognition); and (f) praxis (inability to perform movement and skilled gestures, making precise movements with an arm or leg).

A “prodromal” stage of clinical progression is now recognized as “mild cognitive impairment (MCI),” reflecting the presence of observable declines in cognition that is greater than expected with advancing adult aging but of insufficient severity to merit a dementia diagnosis. Operationally, identifying MCI in adults from neurotypical populations has relied on performance profiles on norm-referenced cognitive tests, with interpretation of assessments usually resting on a premise of preclinical performance no lower than approximately 1.5 standard deviation below a mean of a reference population [57, 58] and minimal declines in activities of daily living (e.g., [59–68]). Like dementia, MCI has many causes and not all diagnosed individuals will progress to develop frank dementia. In fact, a significant minority of diagnosed individuals will be found to improve at follow-up, indicating that the original diagnosis was either a false positive or was associated with a reversible condition [69]. Nevertheless, this diagnosis increases dementia risk dramatically, with an estimated 5% to 20% of diagnosed cases progressing to frank dementia annually [70]. When MCI is caused by AD, however, eventual development of dementia is inevitable.

Typically, initial symptoms of MCI include mild memory disturbance and the inability to learn and recall new information [71]. In addition, emergent neuropsychiatric concerns can occur [69, 72, 73], but these will be present in a minority of affected adults and, even when present, would not be considered a core definitional feature of MCI. While earlier characterizations of MCI emphasized amnestic processes, nonamnestic forms have been recognized. Regardless of subtype, the core feature of MCI is the same, reflecting a degree of declining abilities intermediate between expectations due to aging and indications of early frank dementia.

In the case of AD, the initial indications of MCI, which can be quite subtle, are invariably followed by more obvious declines and involvement of an expanding number of cognitive domains. Typically, over a period of years, serious impairments in motor function and coordination develop. In its late stages, all functional abilities are lost, including ambulation, language, and recognition of family and friends, with end-stage disease producing a vegetative state followed by death.

Cognitive decline with AD in adults with DS

As previously discussed, there are significant challenges to diagnosing dementia in individuals with DS compared to diagnosing the condition in neurotypical populations. These include their preexisting intellectual impairment which may overshadow subtle declines that occur during early clinical progression [55] as well as individual differences in severity and profiles of developmental impairments. For adults with DS, symptoms of AD throughout its complete progression from prodromal stages to advanced dementia then need to be understood in the context of their lifelong cognitive phenotype [15].

While sensitive and specific biomarkers of AD may eventually avoid these concerns, especially with respect to recognition of the earliest stages of disease progression with an eye on prevention, these are goals for the future (see Chapters 6–9). Presently, the state of the art for a diagnosis of AD in people with DS is an observed decline in cognitive and/or adaptive functioning. Measures of progressive decline should be established through the administration of valid and reliable measures of abilities able to quantify changes over an extended period of time, necessarily taking into account the preclinical impairments of the individual being evaluated. Appropriate assessment methods must allow performance during preclinical periods to be significantly above floor to allow for meaningful decline as AD progresses [34, 55, 74–78].

Episodic memory declines, evaluated with a variety of tasks [79–81], have consistently been found early in the development of dementia for adults with DS, as is the case for neurotypical populations developing MCI [82]. Using a modification of the Selective Reminding Task [83], Krinsky-McHale et al. observed episodic memory declines involving both storage in long-term memory and retrieval from long-term storage in adults with DS. These declines were detected several years preceding a clinical diagnosis of dementia [79]. Further, using another list learning task, the Cued Recall Task [84], converging results have been found.

The specific sequence of declines across cognitive domains with AD progression in adults with DS has not yet been established [85], although progressive and broadening recruitment of cognitive domains has been found consistently [86]. Our research group found [86] that a sample of adults with DS followed over a 10-year period of time showed significant memory declines prior to receiving a diagnosis of dementia and showed concomitant declines on tasks that require perception of abstract stimuli, visual organization, and visuo-motor coordination (e.g., the Wechsler Intelligence Scale for Children-Revised [87] Block Design and Coding subtests). With progression from early to the middle stages of AD, further deficits in language comprehension, measures of visuospatial organization, and vocabulary were observed. Therefore, with advancing clinical progression of AD, both severity of impairments and a broadening of affected domains are to be expected.

The question arises as to how similar the profiles of AD-related impairments are in adults with and without DS. Dick and colleagues [88] found that the neuropsychological profiles of AD for higher functioning individuals with DS were very similar to those of neurotypical adults, as represented by mean scores on multiple measures derived from performance on the Severe Impairment Battery [89].

A case study of Françoise, a woman with “standard Trisomy 21” first evaluated when she was in her early 30s, offers an interesting profile of decline in language and cognitive abilities associated with AD. When Rondal and colleagues [90] first met Françoise, they noted that she had exceptionally good language abilities. In a follow-up evaluation conducted when she was 47 years of age, she showed a marked deterioration in receptive language, although it was still relatively well preserved in comparison to her peers. In terms of her expressive language, she had word finding difficulties, and speech rate and mean length of utterance was reduced to 50% of the level observed at the initial observation. Grammatical complexity also had declined significantly. This was in contrast to her articulatory skills and basic productive morphosyntax, which seemed to be less affected. Ylieff [91] examined Françoise’s cognitive functions and confirmed that there was a marked deterioration in episodic memory and concluded that the observed linguistic deficits suggested attentional and working memory difficulties rather than articulation limitations per se.

While the notion of MCI as a transitional state between “normal” cognitive aging and dementia is intuitively easy to grasp, development of an operational definition sufficiently precise to delineate a unique and useful diagnostic entity in adults with DS has proven challenging. Needless to say, the developmental impairments typical of people with DS limit the utility of norm-referenced tests, which were never intended to distinguish between developmental and AD-related impairment. Thus, the task of distinguishing the relatively subtle symptoms of MCI from those associated with adult aging, per se, rests on the development of empirically validated methods able to take significant preexisting impairments into account while also having the sensitivity needed to detect this prodromal stage of AD [92].

While establishing a consensus on the key characteristics of MCI for adults with DS remains a challenge, progress is being made. Findings from recent long-term longitudinal studies have shown that measures examining various cognitive and functional domains can be sensitive to declines indicative of MCI in adults with DS when they are scaled appropriately. These domains include memory, orientation, verbal fluency, adaptive behavior, and perception [93, 94].

Several early studies focused on MCI in adults with DS at ages of risk, though the condition was defined idiosyncratically and was not labeled as such. Terms used have included, “early dementia,” “preclinical dementia,” “prodromal AD,” and even “questionable” decline, while more recent studies have adopted the term “mild cognitive impairment in DS (MCI-DS).” For example, Devenny et al. [86] described 10 individuals with DS who showed “questionable” profiles, operationally defined by declines that were of insufficient severity to justify a diagnosis of dementia. In addition to declines in tests of episodic memory, this group of individuals had relatively poor performance on tests of visuospatial organization and new learning. Devenny et al. [81] additionally examined longitudinal data of adults with DS who developed dementia and who were evaluated 2 years prior to receiving that diagnosis. They found that a test of episodic memory, the Cued Recall Test [84], was able to identify early memory decline in most of these individuals [81]. Krinsky-McHale et al. [79] found converging results administering a different test of episodic memory, a modified version of the Selective Reminding Test, suggesting that “amnestic” MCI is a likely prodromal feature of AD in adults with DS, as it is in late onset AD affecting neurotypical adults.

Krinsky-McHale et al. [95] examined declines in visuospatial working memory associated with MCI-DS. Using the Visual Sequential Memory Test from the Illinois Test of Psycholinguistic abilities [96] to measure the visual component and the forward span of the Corsi Block-Tapping Test [97] to measure the spatial component of visuospatial working memory, they found that individuals with MCI-DS only showed impaired spatial spans but relatively preserved visual spans. They hypothesized that in MCI-DS, the dorsal cortical stream (responsible for processing spatial characteristics of stimuli) may be more compromised relative to the ventral cortical stream (responsible for processing visual characteristics) [98]. (Note that, as expected, both the visual and spatial components of visuospatial working memory were impaired in individuals with dementia.) In another study, this same group described converging results, with adults with DS and MCI-DS showing relatively poor performance on a task requiring attention to visually presented stimuli but in this case with minimal memory demands [99].

A series of three studies by our group [93] evaluated a battery of tests developed explicitly for determining the dementia status of adults with DS (and by extension, any adult with a lifelong history of significant cognitive impairments). Analyses focused on testability for individuals ranging in the severity of ID, the sensitivity of objective measures of performance to the onset of MCI-DS, and the ability of these measures to quantify subsequent decline indicative of dementia [93]. As expected, this was the case for most, but not all, of the measures examined, which included a modified version of the Selective Reminding Test [79], assessments of mental status [100, 101], and the Dementia Questionnaire for Persons with Learning Disabilities (DLD) [102, 103], an informant questionnaire developed explicitly for determining dementia status of adults with developmental disabilities. Testing of category fluency [104] and visuospatial organization (Beery-Buktenica Visual Motor Integration Test [105]), as well as informant measures tapping social (DLD-SOS) rather than cognitive abilities, showed changes only with dementia.

A recent study by the Alzheimer’s Disease in DS (ADDS) program [106], a component of the Alzheimer’s Biomarkers Consortium-DS (ABC-DS), evaluated the accuracy of The National Task Group Early Detection Screen for Dementia (NTG-EDSD) [107] for detecting MCI-DS in a large sample of adults with DS. Results indicated that sections of the NTG-EDSD were sensitive to MCI-DS, with one or more concerns within the “Memory” or “Language and Communication” domains combined being most informative (sensitivity and specificity in the range of 0.8.) Thus the NTG-EDSD showed considerable value for informing diagnosis of MCI-DS when used in conjunction with other methods of evaluation. However, these analyses also showed that overall sensitivity and specificity for detecting even frank dementia was substantially lower than the near perfect findings described in an earlier report [108]. These findings are especially important given the attractive features of the NTG-EDSD and its broad availability on-line, but users need to recognize that using the original classification criteria as a screen will risk substantial numbers of false negative findings, a risk that is especially high during early clinical progression of AD.

While there is considerable convergence of findings regarding the early indications of AD-related clinical progression for adults with DS, some differences in findings across research groups are evident. Rather than difficulties with memory processes, some have argued that frontal lobe-related dysfunction occur earlier, affecting planning, attention, articulation, and neuropsychiatric status (including apathy, depression, indifference, and uncooperativeness).

In one study of DS, informant-reported personality/behavior changes were a significant predictor of subsequent declines in executive functioning [109, 110]. Ball et al. [110] examined the relationship between executive dysfunction and the clinical and preclinical/prodromal features of AD. A version of the Cambridge Cognition Examination (CAMCOG; a computer-based neuropsychological test battery) modified for use with people with DS was used to quantify performance longitudinally. They found that informant-reported changes in personality/behavior were significant predictors of performance on tasks measuring executive function, arguing that these findings are evidence of a specific impairment associated with frontal-lobe functioning during the prodromal stage of AD in adults with DS. They found that a measure derived from their results, labeled “Executive Function and Attention,” was the earliest manifestation of AD-related clinical progression in adults with DS and was evidence that the functions of the frontal lobes are compromised prior to memory-related declines. However, findings described by Urv et al. [73, 111, 112] suggest a more complicated relationship, with risk for emergent neuropsychiatric/behavioral concerns increased during early clinical progression of AD but only occurring in a minority of affected adults with DS. Another study found that the most affected areas, while including working memory, could also include agnosia, aphasia, and apraxia [113].

Given that these groups have adopted different sampling methods, employed different procedures, and had different classification criteria, some divergence in findings is to be expected. One possible explanation might be that tasks employed to target different cognitive domains have varied in their relative difficulty across assessment batteries, and it is those tasks that place the greatest demands on cognitive processing that are observed to show the earliest declines. This points to the importance of appropriate “difficulty scaling” in developing assessment methods, with selection of specific procedures tailored to the relative strengths and weaknesses of the individual under examination. This also points to the need to develop consensus among researchers and clinicians regarding the structure of a core set of assessment methods as well as objective criteria for staging clinical progression. These should be high priority considerations for future research.

Due to the difficulties in assessing decline in this population, relying on any single test or source of information for diagnosis or case classification is inherently risky. This risk can be reduced substantially by employing multiple assessment methods that include both informant reports such as the DLD [114–116] and the NTG-EDSD [117], as well as direct assessments of cognitive and neuropsychological functioning. Additionally, any evaluation of dementia status must consider the individual’s baseline level of functioning and conditions unrelated to neuropathology that may present clinically as a “pseudo-dementia” (e.g., sensory loss, medication side effects).

Clearly, empirically validated measures sensitive to MCI-DS can inform clinical diagnosis and can be used to track progression of underlying disease. It is critically important to acknowledge that currently available and empirically supported best practices, even for late onset AD in neurotypical adults, have less than perfect validity and some individuals identified as having MCI-DS (or MCI more generally) will be found to have been false positives at follow-up. In addition, some positive cases will be missed until their disease progresses further. Even accepting the limitations in current best practices, we can now identify MCI-DS with high, if not perfect, accuracy. This group of individuals represents an obvious target for inclusion in clinical trials for treatment with promising disease-modifying drugs once they become available, and some of the measures evaluated in research to date have strong empirical support for their use as outcome measures in these clinical trials. Finally, these measures can serve as critically important tools in longitudinal discovery studies targeting biomarkers of preclinical AD, prior to MCI-DS onset, with the goal of preventing clinical progression altogether [118]. In-vitro biomarker technology is rapidly developing and prospective studies with clear relationships of future clinical progression are needed for validation.

The relation between cognitive functioning and biomarkers in individuals with DS

This chapter has reviewed progress in developing methods useful for informing diagnosis of dementia status for adults with DS, including MCI-DS that, in most cases within this high-risk population, reflects prodromal AD. In addition to clarifying the features of early clinical progression of AD in adults with DS, recent studies have focused on fluid and neuroimaging biomarkers of clinical status and risk (e.g., [119–126]), and these efforts have been reviewed in Chapters 3–9. Of course, these studies rely on valid classification of clinical status, and the methods we have reviewed herein, especially when used longitudinally, provide that critically important contribution to those efforts.

Hartley et al. [127] provide one example of the power of complementing biomarker studies with neuropsychological assessments. Their focus was on preclinical AD in adults with DS, comparing individuals with and without evidence of brain amyloid deposition who initially were without indications of clinical progression. They found that an increase in global deposition of amyloid was related to declines in a variety of cognitive domains. These findings bring us one step closer to validating biomarkers of early AD.

Discussion and future directions

Understanding “old-age” in people with DS presents many significant challenges, with a breadth and scope of complexities that we are only beginning to understand. Fortunately, interest in advancing relevant knowledge in this area has increased dramatically in recent decades, recognizing the importance of a rapidly growing population of elderly adults and the concerns of all individuals with DS and their families. Currently, substantial investments in basic and translational research are beginning to pay important dividends. In this chapter we have presented research to date examining changes in cognition and functioning that occur naturally with advancing adult aging and with the clinical progression of AD. It is important to bear in mind that these things do not occur in isolation but rather against a backdrop of other consequences of aging, such as changes in health, sensory declines, and increasing fragility risk.

Despite advances over the last 25 years, consensus has yet to emerge regarding best practices for assessing the dementia status of adults with DS, and groups of researchers and clinicians vary, sometimes substantially, in their selection of diagnostic procedures and criteria for determining presence/absence of MCI and even frank dementia. There is an obvious need for consensus regarding at a minimum a core set of procedures that all groups can use to promote comparability in case definitions. This will facilitate the determination of the types and magnitude of declines that occur, both as a natural consequence of adult aging and throughout the full-range of AD progression, increase understanding of the factors that contribute to individual differences in AD risk, and variability in the rate of disease progression. There is still work that needs to be done to validate quantitative measures for identifying MCI-DS, to clarify the sequence of earliest changes as AD progresses from its preclinical to prodromal state, to understand how these changes are related to lifelong impairments, and to discover biomarkers that are predictive of this progression.

The identification of sensitive and specific biomarkers of AD in adults with DS during its earliest stages of progression is the current goal of our and other research efforts. Screening tools such as blood-based biomarkers (see Chapters 6 and 7) have been attracting increasing interest, as they are minimally invasive, relatively low in cost, and show considerable promise for tracking AD progression and predicting risk prior to symptom onset [123]. Jack and colleagues [128] asserted that they, “envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment associated with AD, as well as the multifactorial etiology of dementia” (p.536). Prospective longitudinal studies, such as the ABC-DS [129] and the European Horizon21 DS Consortium, offer great promise for achieving this goal for adults with DS, as well as for late onset AD more generally. These studies of adults with DS will provide key insights for improving the quality of life for this high-risk population but, can provide invaluable insights into AD as it affects all populations of elderly adults. Thus progress to date provides the foundation for advances in diagnosis, treatment, and prevention that seem likely to occur in the foreseeable future.