Two decades ago, if charged with the task of indicating future directions for research into Down syndrome (DS) and Alzheimer’s disease (AD), investigators would have had difficulty in imagining the current scope of the field. The chapters in this volume reflect our current understanding of the many factors involved in the pathogenesis, evaluation, and treatment of AD in people with DS. However, the field is advancing quickly and will undoubtedly change as new data informs our perceptions. In this chapter, some future directions are suggested. Time will prove if they are correct.
Fluid biomarkers will continue as a major focus for predicting cognitive and functional decline in DS, at a time most suitable for therapeutic intervention trials. Biomarkers, representing molecular mechanisms in the pathogenesis of AD, are likely to become active years before signs of cognitive decline. However, more work will need to be done to determine whether the presence of biomarkers for amyloid and tau, for example, is causally linked to cognitive and functional decline. The development of efficient tools for clinical diagnosis of dementia and the monitoring of disease progression will also require further biomarker discovery. The recent additions of NfL and additional forms of tau (p-Tau- 181 and p-Tau 217) to a biomarker panel are examples. Already changes in the levels of some proteomic and metabolomics markers appear to correlate with MCI in adults with DS. Blood samples from which fluid biomarkers are derived are noninvasive and cost effective. CSF, while challenging to obtain in adults with DS, holds promise for defining the role of core biomarkers of AD and MCI. CSF biomarkers are also a critical link between peripheral markers of AD pathophysiology and the CNS. Future studies are likely to produce a set of emerging biomarkers that will need to be studied in DS. The ATN (amyloid, tau, neurodegeneration) network proposed for AD in the general population holds promise for generating a biomarker risk profile in people with DS even in the absence of clinical symptoms. Given the increasing diversity of biomarkers, standardization of protocols for sample preparation, experimental design and biomarker extraction across national and international sites is likely to be a major focus for collaborative research.
A strength of metabolomics is the capability to provide a snapshot of a plethora of metabolites that define an individual’s metabolic state at a given time. Since the metabolome is the level of systems biology most proximate to the phenotype, it can reflect an individual’s unique profile of genomic, proteomic, and transcriptomic alterations. Future studies may find this analysis to be superior to other approaches in the diagnosis of dementia. Already metabalomic analysis has shown differences between preclinical and clinical signs of dementia in people with DS. Future research is likely to focus on the earliest signs of dementia and whether a specific metabalomic signature is a proxy for mild cognitive impairment. Defining metabolic trajectory across AD trajectories and its relationship to clinical phenotype in people with DS is likely to produce a powerful roadmap for future drug discovery.
Neurovascular integrity and inflammation appear to be drivers of the neuropathological features of dementia in people with DS and are likely to be a major focus for future studies. Neuropathological examination of postmortem brain is still an indispensable part of the diagnosis of AD in DS. However, the pathology in postmortem exams is often end-stage. Future directions will likely include focus on temporal events in the pathogenesis of AD and how they relate to the metabolic signature of biomarkers. One area where anatomic and biomarkers intersect is inflammation. Many of the genes on chromosome 21 have inflammatory and immune functions. Yet detailed research on the role of inflammation in DS is still relatively small compared to the general AD field and future studies are poised to expand this discipline. Of particular note will be the role of glial activation, in part, related to peripheral inflammatory drivers and emergence of antiinflammatory phenotypes which can modulate the course. Periodontitis is a modifiable risk factor for AD and in people with DS who have poor dental hygiene may result in increased oxidative stress as well as direct microbial invasion. Future research is likely to expand understanding of the pathogenesis of periodontitis as well as public health measures to curtail its influence.
Neuroimaging is an active and dynamic biomarker in both DS and AD. Further understanding of the intersection between imaging and neuropathology and its impact on people with DS at risk for AD is likely to emerge as a focus for future studies. Functional connectivity and white matter integrity have been shown to be abnormal in adults with DS and future research is likely to focus on a more complete understanding of the neurobiological bases of these changes. Hypometabolism in certain brain regions as demonstrated by FDG-PET has been demonstrated in AD within the general population and will be the subject of future exploration in DS as an early marker of disease. Now with the advent of advanced molecular, structural, and functional neuroimaging techniques, the aspects of the AT(N) involving amyloid, tau, and neurodegeneration can be explored further. To these observations will be added cerebrovascular, microstructural, and functional abnormalities that have been captured in vivo. The generation of multimodal imaging data to track the transition between baseline functioning and conversion to MCI is likely to be a focus of future research. There will be very large data sets generated and deep (representational) learning algorithms will likely be employed to aid in analysis.
Genomic variants in adults with DS add to the possibility of predicting conversion to dementia through alteration in biomarker levels. A strong potential is seen to link a metabolic signature to the examination of genetic variants to predict disease risk. This is another example of multiomic integration, a likely focus for future research. Decades of research into AD in the general populations has taught us that many genetic and nongenetic factors are likely to be involved. Genomic research in DS may simplify this complexity somewhat since the triplication of APP is a single enduring feature in the pathogenesis of AD in trisomy 21. It is thus possible to explore the involvement of the amyloid pathway through multiple endophenotypes involving intermediate proteins and metabolites. Induced pluripotent stem cell technology offers an in vitro model by which to capture a precise patient genome, the cells of potential interest and the gene expression of these cells. Mouse models of DS, involving trisomy of all or part of human chromosome 21 or orthologous mouse genomic regions, are providing valuable insights into the contribution of triplicated genes or groups of genes to the variable AD trajectories in DS.
Regardless of the underlying pathology, the broad construct of neuropsychology is to correctly identify the cognitive changes associated with AD in DS, to identify the subtle changes associated with early disease progression, and to track progression over time. The neuropsychology of DS is unique due to a cognitive phenotype associated with intellectual disability. The usefulness of neuropsychological testing in the future could be enhanced by the use of measures derived from indices of decline in functioning rather than normative data and the development of functional testing in collaboration with cerebral imaging. For adults with DS more specifically, future directions are likely to include a consensus for a core set of neuropsychological procedures for staging clinical progression tailored to the severity of lifelong impairments. These “best practices” will generate optimal measures for clinical trial outcomes. Future research will hopefully identify the cognitive variables associated with aging per se as separate and independent of dementia. Furthermore, there is a critical need to harmonize standardized neuropsychological instruments in languages other than English and to reduce cultural influences. Medical evaluations will benefit from a clear understanding of the comorbidities associated with aging in DS. These have now been clearly outlined in health care guidelines relevant to adults with DS who are showing declines in adaptive functioning. The neurological evaluation is positioned to provide an independent opinion regarding dementia consensus. One promising area for future studies is gait analysis and its correlation to dementia stage in adults with DS. The neurological examination can also elucidate the many causes of gait impairment in people with DS that are not related to the stages of AD. The COVID19 pandemic has fostered telemedicine and its potential for evaluating those at risk for dementia. However, more research in the use of telemedicine for the neurological examination in DS needs to focus on validation compared to the in-person exam, consistency, acceptance by doctor and patient, cost-effectiveness, and system requirements.
Clinical trials for the primary and secondary prevention of dementia in people with DS have diverse therapeutic targets involving amyloid and tau pathological processes, mitochondria, inflammatory pathways, neuroglia, neurochemicals, and multimodal lifestyle alterations. Common to all of these interventions are outcome measures that will reflect improvement in cognition and adaptive behaviors. An ongoing challenge in people with DS is the large variation in baseline intellectual disability. As research into the age-related cognitive phenotype in DS expands, the diagnosis of early mild cognitive impairment is an important goal for interventional trials. Likewise, having a clinical trial ready cohort of well-characterized adults with DS is imperative. Future studies may focus on an individualized goal scaling tool which can be responsive to therapeutic interventions and which is not confounded by variation in premorbid intellectual disability. There is also a need to understand research attitudes in regard to clinical trial intervention among people with DS and their families. How are these attitudes expressed among potential participants of minority representation? The tools for assessing this have been developed for the general population with AD and now are awaiting application to the community with DS.
In a relatively few years, research into aging and AD in people with DS has taken its place alongside the major initiatives in the field of general AD. Many of the studies described in this monograph have parallel ties to the Alzheimer’s Disease Neuroimaging Initiative and the Dominantly Inherited Alzheimer Network. How “cross-talk” occurs between DS research and these large initiatives is likely to be a major emphasis in the coming years. The history of research involving people with developmental disabilities has had a troubled past. Our emphasis now and in the future must be to primarily understand and assist people with DS. Good science will invariably follow.