Recent Advances in Alzheimer Research

This chapter explores the entangled histories of Down syndrome and Alzheimer’s disease, advocacy endeavors, parental experimentation with cognitive therapies, and uneasy relationships between parents, medicine, and science. The goal is to raise questions to elicit discussion for parent advocates, who may find themselves at the crossroads of new possibilities for people with Down syndrome. It is drawn from anthropological ethnographic research centered on social advocacy for both Down syndrome and Alzheimer’s disease, conducted from 2006-2010. The author also utilizes historical analysis to enhance understanding of contemporary concerns, and to illuminate the unique position of parents in the treatment of their young and adult children with Down syndrome.

Longevity has increased rapidly in the Down syndrome (DS) population since around 1970 with many individuals surviving into the late 50s and 60s. There has been a notable increase in the number of aging adults between 35-60 years (born 1947- 1972) who now require expert medical care. By the time individuals with DS reach their 40s several age-related medical conditions are usually evident and maybe expected to progress over time. As aging and medical complexity increases, this places further demands on aging caretakers and family members. In elderly adults experiencing sudden changes in behavior or adaptive status it is essential to consider the contributory role of several high impact medical conditions including sensory (hearing, vision) impairment, sleep apnea, seizures, hypothyroidism, chronic pain or congestive heart failure. Deterioration in gait and motor function can have multiple causes unrelated to dementia including cervical spondylosis with neural canal stenosis, cervical spine subluxation, lumbar disc herniation, and stroke. A high level of vigilance, routine monitoring and timely evaluation is required to detect and treat occult medical conditions early in their course.

There are difficulties in making an early and accurate diagnosis of dementia in individuals with DS; in screening instruments such as the Mini Mental Status Examination that are used in the general population often show floor effects when used for individuals with Down syndrome (DS) because of their pre-existing cognitive impairment, the level of which varies depending on the severity of intellectual disability (ID). Both informant-rated scales and direct neuropsychological tests have been used for the case detection of dementia for individuals with DS. However, direct neuropsychological tests cannot be used for those who have severe ID and their validity could still be questionable in a number of cases of mild to moderate ID. Therefore, use of informant-rated scales is desirable for screening purposes.

There are many similarities and some differences in the clinical expression of dementia in individuals with DS and the general population who do not have ID. Impaired recent memory and confusion in the context of relatively intact distant memory is likely to be an early symptom in individuals with DS who have mild ID, whereas loss of skills and behavior changes are likely to be an early feature for those with more severe ID. Many symptoms, including features of ‘frontal lobe dysfunction’ that tend to appear late in the dementing process in the general population, may appear early in individuals with DS. An important early sign is any change in behavior or functioning, and dementia must always be considered as a possible cause for the change.

Ideally, individuals with DS should be screened for signs of dementia from before the age of 30-35. A multi-disciplinary approach should be taken for diagnosis of dementia in individuals with DS using a combination of informant-rated scales and neuropsychological tests in a longitudinal fashion over time. Important differential diagnoses include hypothyroidism, depression, and sensory impairment. Assessment should include physical, psychological, and social aspects, including appropriate physical examinations and investigations.

Behavioral and psychological symptoms of Alzheimer’s disease and other dementias may create a considerable burden of care in the general population, yet relatively little research has been carried out in this area. Although problem behaviors may be relatively less frequent in people with Down syndrome who develop Alzheimer’s dementia, nevertheless they cause additional caregiver burden. Both pharmacological and non-pharmacological interventions are used for the management of problem behaviors in people with intellectual disability in general. Similarly, both pharmacological and non-pharmacological interventions are used to manage symptoms of dementia including behavioral symptoms in the general population. Treatment approaches used in both these groups could equally be used to manage problem behaviors in people with Down syndrome who develop dementia. Extrapolated evidence from studies on children with autism spectrum disorder and intellectual disability possibly supports use of risperidone for management of problem behavior in adults with Down syndrome and dementia. RCT-based evidence exists to support use of antipsychotics, mood stabilizers, and cholinesterase inhibitors for the management of behavioral and psychological symptoms of dementia in the general population but no specific evidence for Down syndrome exists. Clinicians have to be mindful of potential serious central nervous system adverse effects of antipsychotics in people with dementia. Similarly, evidence for efficacy of non-pharmacological interventions for problem behaviors both in the general population with dementia and people with intellectual disability in general is too equivocal to make any definitive recommendation at this stage for people with Down syndrome and dementia. Recently there has been an emphasis on providing person-centered service specifically designed for people with dementia. Another important aspect of management is training and support for caregivers and care staff to help people with dementia to live a better quality of life and reduce behavioral and psychological problems.

Historically, sleep has been seen as a passive state, and yet more recent research demonstrates that sleep is a time for the brain and body to actively fulfill functions pertaining to cognition, metabolism, and cellular maintenance. Clinical studies of sleep using polysomnography have demonstrated profound sleep disturbances in Down syndrome and Alzheimer disease. Deriving from these basic studies is a better understanding of the networks, neurotransmitters systems, and physiological and genetic factors that regulate the daily organization of sleep and wake cycles. Currently, physiological and pharmacological means for manipulating sleep are being developed. Therefore, it seems plausible that sleep and EEG studies may soon be used to develop new biomarkers for Down syndrome and Alzheimer’s disease and, in turn, improve quality of life.

The most common genetic cause of intellectual disability is Down syndrome (DS). Alzheimer’s disease (AD), characterized pathologically by neuritic plaques composed of Aβ amyloid protein and neurofibrillary tangles made up of τ protein, represents the prototype senile onset dementia. A significant proportion of DS patients develop AD in later life with risk factors described for those particularly predisposed. Seizure disorders are described in both, with diverse as well as common underlying pathogenic mechanism, that have significant clinical and therapeutic implications.

In DS, seizures are seen mainly in infancy and beyond 40 years. Overall, the predominant seizure types are infantile spasm, generalized tonic clonic (GTCS), and focal. In the older age group, a specific seizure type called late-onset myoclonic epilepsy (LOMEDS) is seen, which clinically simulates a progressive myoclonic epilepsy phenotype. Various mechanisms, like abnormal shape of the brain, impaired membrane excitability, altered neurotransmitter circuitry, and overexpression of genes because of a triplicate 21st chromosome, contribute to the causation of seizure in DS. Moreover, with advancing age, AD-like changes in the brain also contribute to the pathogenesis of LOMEDS.

There is increased risk of seizures in AD compared to age-matched healthy individuals. The commonest seizure types are focal and generalized and occasionally myoclonic. Underlying pathogenic mechanisms include formation of Aβ plaques and neurofibrillary tangles, selective hippocampal injury, neurotransmitter imbalance, and channelopathies. Studies have shown that temporal lobe epilepsy and AD have similarities in pathology as well as clinical implications.

In both these disorders, seizures play an important role in pathophysiology and clinical manifestations. Early recognition and appropriate diagnosis and management are imperative as this has significant treatment and overall outcome related implications.

Neuroimaging provides noninvasive in vivo information regarding brain structure and function, which is associated with few if any adverse events, and can serve as a diagnostic and research tool. In Alzheimer’s disease (AD), there is a rich literature of studies using various imaging techniques to understand early changes with disease, disease progression and prodromal changes signaling transition to dementia. In this chapter, we describe different imaging approaches used in Down syndrome (DS) including structural and functional magnetic resonance imaging (MRI), MR spectroscopy (MRS), fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), diffusion tensor imaging (DTI), positron emission tomography (PET), both glucose metabolism and imaging with ligands that can bind to AD plaques and neurofibrillary tangles. In DS, there are several structural MR studies showing neurobiological features of the DS brain that are unique to this cohort. When comparing AD in DS, there are significant overlaps in neuroimaging outcomes that distinguish those with and without dementia. However, there are significant gaps in our knowledge of the aging and AD processes in DS. Neuroimaging approaches will help identify a therapeutic window for intervention (e.g., best age for prevention of disease) as well as provide us with new outcome measures that can be used in clinical trials for DS and AD in the general population.

Alzheimer’s disease (AD) is characterized by progressive pathological changes in the brain, including accumulation of protein aggregates such as amyloid plaques and neurofibrillary tangles (NFTs). Deposition of these proteins leads to widespread neuronal loss and subsequent cognitive decline. AD-associated pathology also develops in individuals with Down syndrome (DS) and is generally found to precede onset of dementia symptoms. In this chapter, we discuss progressive development of AD pathology, including plaques, NFTs, synaptic dysfunction, neuronal loss, and brain atrophy. Furthermore, we examine similarities and differences in these pathologies between AD and AD/DS. Finally, we review several genetic factors that may contribute to the development of AD.

Down syndrome is the most frequent cause of cognitive dysfunction that results from the triplication of chromosome 21. Along with a number of developmental disabilities that occur in early childhood, Down syndrome is also associated with age-related Alzheimer’s disease neuropathology, leading to 50-70% of persons with Down syndrome showing dementia by 6th to 7th decade of life. Recent evidence has strongly implicated inflammatory processes in the pathogenesis of Alzheimer’s disease. However, little is known about the genetic impact of Down syndrome on neuroinflammation. Accordingly, the central aim of this chapter is to explicate our current knowledge of inflammation in Alzheimer’s disease and to discern how it may be extrapolated to understand better the inflammatory processes that affect Down syndrome neuropathology.

Down syndrome (DS) is characterized by several structural and functional anomalies present from prenatal stages that lead to intellectual disabilities. In later life stages, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer’s disease (AD) neuropathology (i.e., β-amyloid [Aβ] plaques, neurofibrillary tangles [NFTs], neurodegeneration, synaptic pathology, neuroinflammation, and increased oxidative stress). Different mouse models of DS have been created based on the homology of human chromosome 21 (Hsa21) and on several syntenic regions of murine chromosomes 16, 10 and 17. In addition, a transchromosomic model (Tc1) bearing a triplication of most Hsa21 genes has been developed. Although DS models display agerelated neurodegeneration and many hallmarks of AD neuropathology DS models do not develop Aβ plaques or NFTs; however, increases in soluble and insoluble Aβ species and hyperphosphorylated tau are present in many of these models. In addition, many murine models of AD have also been created. Because the triplication of the App gene in mice does not lead to Aβ plaque development, numerous transgenic models bearing APP gene mutations found in familial AD have been developed. These mice display Aβ peptide aggregation and other AD-like neuropathological markers; however, these mice do not develop NFTs and neurodegeneration is absent in most of these mice. A second generation of AD models was created by crossing different APP transgenic mice with animals bearing mutations in the presenilin (PS) 1 or PS2 genes. Most of these models display NFTs, an earlier appearance of Aβ plaques and neurodegenerative processes. Finally, triple transgenic mice, bearing mutations in the APP, PS1, and tau genes have been developed, leading to a model that displays most of the AD neuropathological alterations and an earlier onset of the cognitive deficit. The AD models differ in many phenotypes due to variations in the mutations carried by each model, the promoters used and the background strain. However, the similarities between these models have provided extremely valuable insights into AD etiopathology. This chapter analyzes the similarities and differences between the most commonly used DS and AD mouse models, supporting the hypothesis that some pathological processes appearing earlier than Aβ plaques and NFTs, such as synaptic alterations, oxidative stress, and neuroinflammation, could be increasing the soluble and insoluble Aβ species that could exacerbate tau pathology and neurodegeneration. In summary, both DS and AD mouse models are extremely valuable tools for understanding the etiology or neuropathological anomalies responsible for the cognitive deterioration found in both conditions.

Trisomy of chromosome 21 (Ts21), with duplication of one copy of all its genes to increase its copy number by 0.5-fold, is well tolerated, allowing the birth of live children. However, subjects with Ts21 suffer a spectrum of problems, including intellectual disability, skeletal deformity, and a number of secondary conditions such as defects in the visual system, hearing loss, cardiovascular disease, and a progressive dementia similar to Alzheimer’s disease (AD). In this chapter, we discuss the genotypephenotype relationships and identify the role played by individual genes. We also detail the role of the amyloid β (A4) precursor protein causing AD in Ts21 individuals.

A multitude of neuropathological studies has established a robust link between Down syndrome and Alzheimer’s disease. Through massive projections to the entire cortex and hippocampus, the monoaminergic-systems exert a powerful modulatory effect on brain regions vitally important for cognition. Nevertheless, substantial evidence demonstrates these systems are inherently vulnerable to neurodegeneration, particularly in Down syndrome and Alzheimer’s disease. Accordingly, abnormalities in the structure and function of subcortical monoaminergic systems constitute a common characteristic of both disorders. Underlying these deficits are neuropathological changes in the locus coeruleus, ventral tegmental area, substantia nigra and raphe and tuberomamillary nuclei. Fortunately, preclinical and clinical studies suggest that pharmacotherapies targeting of these systems may provide symptomatic relief along with disease modifying effects in Down syndrome and Alzheimer’s disease.

Down syndrome (DS) is a genetic disorder that results from the triplication of chromosome 21. Accompanying this disorder are a number of medical conditions including intellectual disability and early- onset Alzheimer’s disease (AD). Our understanding of the molecular basis for these has expanded substantially in the past decade, both in patients and relevant animal models. In particular, exciting advances in therapies that modulate neurotransmitters to improve cognitive function have reached clinical trials. Moreover, increased insight into the pathogenesis of AD in DS has motivated clinical trials for AD in DS. Below, therapeutic strategies that have been deployed in clinical trials in DS will be discussed as well as their underlying scientific rational.