The Neurobiology of Aging and Alzheimer Disease in Down Syndrome

The Neurobiology of Aging and Alzheimer Disease in Down Syndrome provides a multidisciplinary approach to the understanding of aging and Alzheimer disease in Down syndrome that is synergistic and focused on efforts to understand the neurobiology as it pertains to interventions that will slow or prevent disease. The book provides detailed knowledge of key molecular aspects of aging and neurodegeneration in Down Syndrome by bringing together different models of the diseases and highlighting multiple techniques. Additionally, it includes case studies and coverage of neuroimaging, neuropathological and biomarker changes associated with these cohorts. This is a must-have resource for researchers who work with or study aging and Alzheimer disease either in the general population or in people with Down syndrome, for academic and general physicians who interact with sporadic dementia patients and need more information about Down syndrome, and for new investigators to the aging and Alzheimer/Down syndrome arena.

• Discusses the complexities involved with aging and Alzheimer’s disease in Down syndrome
• Summarizes the neurobiology of aging that requires management in adults with DS and leads to healthier aging and better quality of life into old age
• Serves as learning tool to orient researchers to the key challenges and offers insights to help establish critical areas of need for further research

• Language: English
• Publisher: Academic Press
• Release date: Aug 31, 2021
• ISBN: 9780128188460

Book preview

Chapter 1: Introduction

Elizabeth Heada,*; Mark Mapstoneb; Ira T. Lottb,c    a Department of Pathology & Laboratory Medicine, University of California, Irvine, CA, United States

b Department of Neurology, University of California, Irvine, CA, United States

c Department of Pediatrics, School of Medicine, University of California, Irvine, Orange, CA, United States

* Corresponding author: [e-mail]

Abstract

Introduction to the book that provides a brief history of Down syndrome, provides information on the link between Down syndrome and Alzheimer's disease, and briefly describes each upcoming chapter.

Keywords

Alzheimer's disease; Beta-amyloid; Down syndrome; History; Trisomy 21

Our goal for this book is to provide an overview of key topics related to aging and the development of Alzheimer's disease (AD) in people with Down syndrome (DS). We envision that this book will be useful to students, researchers and physicians, healthcare professionals, and to interested family members. We have assembled leaders in the field to provide chapters in their areas of expertise representing the cutting edge of research both nationally and internationally. In this introduction, we will review some background information that will set the stage for the chapters and provide context.

History

The clinical features of Down syndrome (DS) were initially described by J. Langdon Down in 1866 [1, 2] (Fig. 1) but it was not until 1959 when the most common cause of DS was identified as a chromosome 21 trisomy by Drs. Lejeune, Gautier, and Turpin in 1959 [3] (Fig. 2). An extra copy of chromosome 21 is due to meiotic nondisjunction or the abnormal segregation of the chromosomes during gamete formation (reviewed in Ref. [4]) and accounts for 95% of the people with DS. Interestingly, there are two additional causes of DS that includes partial trisomy 21 (~ 4%) and somatic mosaicism (less than 1%) [4, 5].

Fig. 1

Fig. 1 Image of Dr. J. Langdon Down and one of his publications describing the features of Down syndrome [1].

Fig. 2

Fig. 2 Image of Dr. LeJeune (left) and an image of a Down syndrome karyotype (right) highlighting the extra copy of chromosome 21. Image of Dr. LeJeune from https://lejeunefoundation.org/.

Of course what has become known as Down syndrome existed before these seminal descriptions, much less is known about the early history of the condition prior to the 19th century. It is interesting to note that there is evidence of children with DS dating back to the 5–6th century AD based upon a study of the Saint-Jean-des-Vignes child, in the painting titled The Adoration of the Christ Child (c. AD 1515) [6, 7] (Fig. 3), which was found in a burial site. Children with DS were have been depicted in several art pieces with a thorough discussion of several paintings described by John M. Starbuck (https://docs.lib.purdue.edu/cgi/viewcontent.cgi?article=1019&context=jca).

Fig. 3

Fig. 3 The Adoration of Christ Child painting from Saint-Jean-des-Vignes, a painting from the 5–6th century, which appears to depict children with Down syndrome. Reproduced from Levitas AS, Reid CS. An angel with Down syndrome in a sixteenth century Flemish Nativity painting. Am J Med Genet A 2003;116A(4):399–405.

Prevalence of DS and phenotype

DS or trisomy 21 is one of the most common causes of intellectual disability and recent national prevalence estimates suggest that 1 in 790 babies are born with DS [8]. This gives us an estimate of approximately 206,366 people with DS in the United States [8], a substantial increase in the population from 1950 of 49,923 people. In Europe, recent estimates suggest that from 2011 to 2015 there were 8031 annual live births of children with DS and a total population of people with DS estimated at 572,000. Of note, selective terminations after prenatal testing have decreased the numbers of children born with DS on average, 54%, leading to an overall 27% reduction in the population [9].

DS is associated with characteristic facial features, deficits in the immune and endocrine systems, and delayed cognitive development (Fig. 4). A full discussion of these conditions, and contribution to aging, are described in Chapters 11 and 13.

Fig. 4

Fig. 4 Individuals with trisomy 21 (the presence of a supernumerary chromosome 21; also known as Down syndrome (DS)) present with a distinct collection of symptoms and manifestations that affect multiple body systems, although variation exists between individuals. Reproduced with permission from Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, et al. Down syndrome. Nat Rev Dis Primers 2020;6(1):9.

People with DS are living longer

Improvements in medical care for children and adults with DS, along with more enriched lifestyles, have led to significant extensions in lifespan and enhanced quality of life [10, 11]. As a consequence, up to age 35 years, mortality rates are comparable in adults with DS to individuals with intellectual disability from other causes [12]. Studies in the late 1990s suggested that after age 35, mortality rates doubled every 6.4 years in people with DS as compared to every 9.6 years for people without DS [12]. These statistics are still improving with estimates from 2010 suggesting that 28% of people with DS are living past 40 years of age, as compared with 4% in the 1950s [8]. Indeed, the number of people with DS over the age of 40 years is rapidly rising (Fig. 5). Thus, in the coming decades there will be an increasing need to address age-associated health issues and the development of dementia in this vulnerable population.

Fig. 5

Fig. 5 The number of people with Down syndrome over the age of 40 years is one of the most rapidly rising aging segments. Estimates (1950–2010) are shown by age for (A) all persons, (B) non-Hispanic whites, (C) non-Hispanic blacks, (D) Hispanics, (E) Asians/Pacific Islanders, and (F) American Indians/American Natives. Reproduced with permission de Graaf G, Buckley F, Skotko BG. Estimation of the number of people with Down syndrome in the United States. Genet Med 2017 19(4):439–47.

The link between Alzheimer's disease and Down syndrome

Alzheimer's disease (AD) is the major cause of dementia in our elderly non-DS population with age being the biggest risk factor. AD was first described by Alois Alzheimer in 1906 based upon a case study of one of his patients (for a comprehensive review, see Ref. [13]) [14]. Auguste D was a 50-year-old woman whose husband noted untreatable paranoid symptomatology in his wife and then - in fast progression and with increasing intensity - sleep disorders, disturbances of memory, aggressiveness, crying, and progressive confusion. At autopsy, Dr. Alzheimer noted the presence of plaques and neurofibrillary tangles (Fig. 6). Auguste D had a much earlier age of onset than is typically observed, and interestingly, was later determined to have a genetic mutation that led to her dementia [15]. A later breakthrough in the field identified beta-amyloid protein as a culprit in the disease (the amyloid hypothesis—[16]), and subsequently, the genetic locus of the amyloid precursor protein (from which beta-amyloid is cleaved) was found to be on chromosome 21, present in triplicate in people with DS [17]. Thus we believe that one of the strongest reasons for the link between AD and AD in DS is the overexpression of the beta-amyloid protein.

Fig. 6

Fig. 6 (A) Photographs of Dr. Alzheimer and (B) his first patient, Auguste Deter. (C) Image of the original postmortem histological slides showing silver impregnated neuritic plaques (D) and a neurofibrillary tangle (E) in the brain of Auguste Deter. Photos A, B, and D were obtained from the Internet. Images C and E were reproduced from an internet article posted Friday, November 3, 2006 by Mo Costandi under Alzheimer's Disease, History of Neuroscience, 100 years of Alzheimer's disease. Mufson EJ, Mahady L, Waters D, Counts SE, Perez SE, DeKosky ST, et al. Hippocampal plasticity during the progression of Alzheimer's disease. Neuroscience 2015;309:51–67.

Based upon neurobiological studies initiated in the late 1970s by Henry Wisniewski's laboratory (United States) and in parallel with work by David Mann (United Kingdom), a clear link was established between AD and AD in DS. Thus research has focused on amyloid precursor protein (APP) processing and the temporal events in beta-amyloid pathogenesis [18, 19]. As a consequence of overexpression of APP and enhanced production of the beta-amyloid protein, virtually all adults with DS over the age of 40 years have sufficient neuritic plaques and neurofibrillary tangles for a neuropathologically based diagnosis of AD [18–20]. Extracellular beta-amyloid accumulation in diffuse plaques does not typically begin until after the age of 30 years [20]. Between the ages of 30 and 40 years, neuropathology rapidly accumulates until it reaches levels sufficient for a diagnosis of AD by 40 years [19]. Since these original observations, there has been a slow but steady increase in studies of AD in people with DS, with the past 5 years showing an exciting increase in research focus on this important topic (Fig. 7).

Fig. 7

Fig. 7 There is an increasing number of publications describing studies of Alzheimer's disease in Down syndrome (PubMed search, January 2021).

Overview of the chapters

Conceptually, this book is designed to take the reader from the neurobiology of DS up to a discussion of clinical trials in the future. Chapter 2 provides an overview of the neuropathology of the aging DS brain and a description of AD neuropathology (Mufson et al.). Additional features of the aging DS brain that contribute to AD neuropathology include neuroinflammation (Chapter 3, Martini et al.), cerebrovascular pathology (Chapter 4, Rizvi et al.), and oxidative stress (Chapter 5, Butterfield et al.). Next we describe biomarkers of AD in DS that includes those measurable in blood and cerebrospinal fluid (Chapter 6, Iulita et al.), with a focus on proteomics and metabolomics (Chapter 7, Petersen et al.), by magnetic resonance imaging (Chapter 8, Yassa et al.), and by positron emission tomography or PET (Chapter 9, Christian et al.). The genetics of AD in DS are also a rapidly rising area of interest and suggests that genes both on chromosome 21 and on other chromosomes may contribute to age of onset or risk of dementia (Chapter 10, Lee et al.). In the next chapters, we describe co-occurring illnesses that may happen as a person with DS ages (Chapter 11, Capone and Chicoine) including a role for sleep in the development of cognitive decline (Chapter 12, Hartley and Esbensen). Chapter 13 by Lott describes the features of the neurological examination for clinicians and families and its importance for diagnosis of dementia. In parallel with health changes, there is an increasing appreciation for psychiatric issues that may also occur with older adults with DS (Chapter 14, Pape et al.). The assessment of learning and memory through the neuropsychological examination is thoroughly discussed in Chapter 15 (Krinsky-McHale et al.). Much of the work many of the investigators who provided chapters for this book, we hope, contributes to the development of clinical trials dedicated to people with DS (Chapter 16, Rafii). Last, in Chapter 17 (Lott, Mapstone, Head), we pull our current knowledge together and outline some gaps and needs for future studies.

Two notes that we would like to add. First, we were unable to capture the entirety of the exciting, innovative, and cutting edge research that is currently ongoing. We hope that others will continue this process and prepare more books on dedicated topics relevant for DS. Second, we had another goal of this book to encourage more researchers to this critical field of study.

We are at the very beginning in our quest to understand aging in DS. There remains much to do and many problems for the next generation of young researchers to solve. Our responsibility, reflected physicist Richard Feynman of all scientists, is to do what we can, learn what we can, improve the solutions and pass them on.

References

[1] Down J.L.H. Observations on ethnic classification of idiots. Lond Hosp Rep. 1866;3:259–262.

[2] Van Robays J. John Langdon Down (1828-1896). Facts Views Vis Obgyn. 2016;8(2):131–136.

[3] Lejeune J., Gautier M., Turpin R. Etude des chromosomes somatiques de neuf enfants mongoliens. C R Hebd Seances Acad Sci. 1959;248:1721–1722.

[4] Sherman S.L., Allen E.G., Bean L.H., Freeman S.B. Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev. 2007;13(3):221–227.

[5] Shin M., Siffel C., Correa A. Survival of children with mosaic Down syndrome. Am J Med Genet A. 2010;152A(3):800–801.

[6] Levitas A.S., Reid C.S. An angel with Down syndrome in a sixteenth century Flemish Nativity painting. Am J Med Genet A. 2003;116A(4):399–405.

[7] Rivollat M., Castex D., Hauret L., Tillier A.M. Ancient Down syndrome: an osteological case from Saint-Jean-des-Vignes, northeastern France, from the 5-6th century AD. Int J Paleopathol. 2014;7:8–14.

[8] de Graaf G., Buckley F., Skotko B.G. Estimation of the number of people with Down syndrome in the United States. Genet Med. 2017;19(4):439–447.

[9] de Graaf G., Buckley F., Skotko B.G. Estimation of the number of people with Down syndrome in Europe. Eur J Hum Genet. 2021;29(3):402–410.

[10] Glasson E.J., Sullivan S.G., Hussain R., Petterson B.A., Montgomery P.D., Bittles A.H. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clin Genet. 2002;62(5):390–393.

[11] Bittles A.H., Bower C., Hussain R., Glasson E.J. The four ages of Down syndrome. Eur J Pub Health. 2007;17(2):221–225.

[12] Strauss D., Eyman R.K. Mortality of people with mental retardation in California with and without Down syndrome, 1986-1991. Am J Ment Retard. 1996;100(6):643–653.

[13] Hippius H., Neundorfer G. The discovery of Alzheimer's disease. Dialogues Clin Neurosci. 2003;5(1):101–108.

[14] Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allg Z Psychiat Psych-Gericht Med. 1907;64:146–148.

[15] Muller U., Winter P., Graeber M.B. A presenilin 1 mutation in the first case of Alzheimer's disease. Lancet Neurol. 2013;12(2):129–130.

[16] Hardy J.A., Higgins G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–185.

[17] Korenberg J.R., Pulst S.M., Neve R.L., West R. The Alzheimer amyloid precursor protein maps to human chromosome 21 bands q21.105-q21.05. Genomics. 1989;5(1):124–127.

[18] Wisniewski K., Howe J., Williams D.G., Wisniewski H.M. Precocious aging and dementia in patients with Down's syndrome. Biol Psychiatry. 1978;13(5):619–627.

[19] Wisniewski K.E., Wisniewski H.M., Wen G.Y. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol. 1985;17(3):278–282.

[20] Mann D.M.A., Esiri M.M. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci. 1989;89:169–179.

Chapter 2: Alzheimer's neuropathology in Down syndrome: From gestation to old age

Elliott J. Mufsona,b,*; Jennifer C. Miguela; Sylvia E. Pereza    a Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States

b Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States

* Corresponding author [e-mail]

Abstract

The brains of people with Down syndrome (DS) are structurally and biochemically unique both pre and postnatally. Fetal cortical sulcal development is delayed, cholinergic basal forebrain is compromised, the cerebellar cortex displays phosphorylated tau, synaptic integrity is disrupted, and AD pathology is virtually absent. The adult cortical poles appear blunted, the cerebellum is shrunken and displays diffuse amyloid accumulation, the ventricles are enlarged, neocortex and limbic regions are reduced in size. Striatal cholinergic interneurons display normal morphology despite containing neurofibrillary tangles (NFTs), amyloid plaque deposition occurs prior to NFT pathology, cholinergic neurons within the nucleus basalis degenerate and contain globose NFT pathology, cortical amyloid plaque load is similar in demented and nondemented DS but NFT pathology is greater and more advanced in cases with dementia. Transcript profiling of brain homogenates and single frontal cortex layer V–VI neuron gene array analysis reveals dysregulated classes of transcripts between DS vs control and demented vs nondemented DS cases, respectively, suggesting distinctive genetic signatures that may contribute to dementia in DS.

Keywords

Aging; Alzheimer's disease; Amyloid; Cholinergic; Development; Down syndrome; Fetal; Genetics; Synuclein; Tau; Trisomy

Acknowledgments

Support by NIH P01AG14449, R01AG043375, R01AG061566, AZADC Consortium and the Bright Focus Foundation CA2018010. We thank Laura Mahady for editing the manuscript.

Introduction

At the turn of the twentieth century, Dr. Alois Alzheimer described a form of progressive presenile dementia in a female patient named Auguste Deter, who developed memory loss and died at the age of 56 [1]. Postmortem neuropathology revealed extensive brain shrinkage and accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) [2], now considered the defining lesions of the disease bearing his name. SPs accumulate in the extracellular matrix and contain insoluble fibrils of amyloid beta (Aβ) protein fragments, which are derived from the larger transmembrane amyloid precursor protein (APP) through serial cleavage by beta-site APP cleaving enzyme 1 (BACE1) and the γ-secretase complex [3–5]. NFTs are composed of argyrophilic aggregates of several hyperphosphorylated epitopes of the protein tau [6, 7]. These pathological protein aggregates display a β-pleated sheet conformation and are thought to interfere with cytoskeletal integrity, which disrupts synaptic and neuronal function. In over 99% of individuals, the onset of Alzheimer's disease (AD) occurs in late adulthood, usually after the age of 65 [8]. In a small portion of people (< 1%), the disease displays an autosomal dominant pattern of inheritance (familial AD, FAD), resulting from one of three different gene mutations, APP, presenilin 1 (PS1), or presenilin 2 (PS2) and manifests much earlier [8]. Interestingly, genetic analysis of tissue from the brain of Auguste Deter revealed a PSEN1 mutation [1, 9], which was consistent with her early age of disease onset. Genotyping for APOE ɛ4, a major risk factor for AD, revealed that Augusta Deter was an ɛ3/ɛ3 carrier [1].

Although late onset sporadic AD is the leading cause of dementia in the United States, affecting an estimated 5.4 million people and is predicted to afflict 13 million people in the USA by 2050 [8], the field lacks a true animal model that fully recapitulates the pathobiology underlying the disease. Currently, premortem clinically and postmortem neuropathologically well-characterized human brain tissue provides the gold standard for defining the pathophysiology of AD. Although similar to AD, individuals with Down syndrome (DS) develop SP and NFT pathology and, dementia as they age, there is a discrepancy between the prevalence of AD pathology (about 100% by age 40) and the prevalence of dementia (about 2%–5% by age 40 and 70% by age 70) in adults with DS [10–12] (see Chapters 1, 13, and 15). This population provides a unique resource for the investigation of the location, temporal course, and clinical association of the cellular and molecular neuropathology related to the development of AD.

As described in Chapter 1, in 1866, the Cornish physician John L. Down published an article entitled Mental affections of childhood and youth, which described the external and innate characteristics of people referred to as a mongoloid idiot. Down's grandson was born with this condition and displayed a phenotype (described by Dr. Down) that included a round face, oblique eyes, flat nape, thin eyebrows, a small pug nose, and thick cleaved tongue [13]. In 1965 the World Health Organization officially confirmed the eponym for this disorder as Down syndrome (DS). Although Down assumed that parental tuberculosis was the cause of this disorder [14], genetic analysis revealed that DS was due to an extra copy of chromosome 21 (Ch21) [15]. This chromosome harbors the gene encoding APP, that results in an overproduction of the Aβ peptide and is associated with the onset of FAD (< 50 years of age) [16–18]. Several groups linked the gene for the APP to a locus on the proximal portion of the long arm of Ch21 [19–21], which then narrowed the location of APP to Ch21 [19, 20]. Behaviorally, DS is characterized by intellectual disability attributed to a full or partial extra copy of human Ch21 (HSA21) [15] that accounts for 95% of the chromosomal anomalies in this disorder, or lesser frequent genotypes associated with a translocation of Ch21 onto another chromosome (4%) and mosaicism where some cells exhibit an extra copy of Ch21 (1%). DS occurs in 1 in 800 births in the United States and affects approximately 6 million people worldwide. The extra copy of Ch21 results in developmental alterations that distinguishes DS from the neurotypical brain.

Prenatal brain pathology in DS

During gestation, the DS brain appears smaller than its neurotypical counterpart (Fig. 1). In the neurotypical cortex the lateral sulcus (Sylvian fissure), which first appears on the superolateral surface as a minor indentation, is observed as early as gestational weeks 13.5 in DS (Fig. 1E). At these early developmental ages, the corpus callosum and callosal sulcus appear on the medial surface of the hemisphere, although these structures are more evident in the neurotypical brain (Fig. 1A′ and E′). During normal brain embryology, the lateral sulcus gradually becomes deeper, at the same time as the frontal, parietal, and temporal opercula are rapidly expanding (Fig. 1C and D) compared to a less well-developed narrow lateral fissure seen in DS gestational weeks 20 and 26 (Fig. 1F and G). At about week 21 of gestation, the central sulcus appears as a small groove in the dorsal region of the normal cortex (Fig. 1C), which was not evident in DS (Fig. 1F). However, the central sulcus was clearly visible in the dorsolateral cortex at gestational week 26 in DS (Fig. 1G). At 24 weeks’ gestation, the neurotypical cortex displays a pre- and postcentral sulci as well as a developing superior temporal sulcus (Fig. 1D) that are not clearly visible at embryonic week 26 in DS (Fig. 1G). At fetal week 17 the medial surface of the neurotypical brain displayed cortical invagination indicative of the callosal fissure and the developing corpus callosum (Fig. 1A′), which was less well defined at gestational week 13.5 in DS (Fig. 1F′). The medial surface of the neurotypical cortex also revealed indentations indicative of a developing calcarine and parietooccipital sulcus (Fig. 1B) similar to that seen at 26 weeks in the DS brain (Fig. 1G′) [22]. We were able to identify the cerebellum at DS fetal week 13.5 (Fig. 1E, E') and 26 (Fig. 1G, G'). The developmentally altered trisomy brain indicated by delayed central nervous system maturation associated with prenatal arrest of neuro and synaptogenesis [23, 24] may be partially a consequence of delayed cortical development. It is important to note these developmental differences in the brains of people with DS, since these regions are similar to those later affected by aging and AD.

Fig. 1

Fig. 1 (A–G) Photographs of the lateral and medial cerebral surface showing development of the Sylvian/lateral fissure (A, C, D, E, F, G), central (C, D, G), callosal (A′, E), cingulate (B, G′), and superior temporal (D, G) sulci in the neurotypical fetal brain at 17 (A, A′), 18 (B), 21 (C), and 24 (D) weeks compared to Down syndrome (DS) 13.5 (E, E′), 20 (F), and 26 (G, G′) gestational weeks. Note the delayed and less visible central sulcus (CS) (B, G) and Sylvian fissure (SyF) (A, C, D, F, G) between the neurotypical and DS fetus. Panel G′ shows the calcarine fissure (CaF), posterior occipital sulci (POS), the corpus callosum (CC), fornix (fx), diencephalon (Di), and cerebellum (Cb). (H–K) Images showing diffuse APP/Aβ immunoreactivity (H), absence of Aβ 40 (I), Aβ 42 (J), and AT8 tau (K) reactivity in the frontal cortex of a 1-year-old female DS case. Abbreviations: CaS , callosal sulcus; CiS , cingulate sulcus; IHF , interhemispheric fissure (longitudinal cerebral fissure); Ins , insula; POCS , postcentral sulcus; PreCS , precentral sulcus. Sections in panels I and J were counterstained with cresyl violet. Scale bar in G′ equals to 5 mm in E, 7 mm in E′ and G, 8 mm in F and, the scale bar in K = 25 μm, 15 μm in I and 100 μm in H.

Adult brain pathology in DS

Gross evaluation of the adult DS brain revealed abnormalities that include a reduction in brain weight, altered configuration, less numbers of gyri and depth of cerebral sulci, stumpy/shortened appearance of the frontal and temporal lobes, hypoplasia of the brainstem and cerebellum (Fig. 2). Coronal sections of the DS brain revealed ventricular enlargement (Fig. 2), cortical and hippocampal shrinkage (Fig. 2) [25–28], as well as alterations of cortical lamination. Increased cortical thickness has been reported in sensory (Brodmann areas in 1, 3b), middle frontal, and orbital cortex [29] in DS. Although these changes may play a role in defects in somatic, memory, and olfactory responses in people with DS, there is variability in these alterations across cortical regions. In 1948 George Jervis reported that individuals with DS displayed dementia premortem and a postmortem neuropathological phenotype that included SP and NFT similar to that described 60 years earlier by Dr. Alzheimer [2, 30]. Other studies confirmed these pathological findings and showed a similar topography of these lesions between DS and euploid AD cases [31]. Individuals with DS also exhibit characteristics of premature aging and are at a higher risk for developing dementia of the AD type several decades earlier than patients with sporadic AD [10, 32–34] (see Chapters 1, 13, and 15). Despite parallels between AD and DS, current transgenic mouse models do not truly replicate these disorders and the consequence of trisomy in nonhuman species is not consistent with the genotype or phenotype of DS [35]. Therefore this chapter will provide an overview of the similarities and differences in the cellular and molecular pathobiology of the human DS brain from gestation to older ages in contrast to AD.

Fig. 2

Fig. 2 Lateral view of the cerebral hemisphere from an aged healthy control (HC) subject (A), Alzheimer's disease (AD) (B) and Down syndrome (DS) (C) brain. Note the widening of sulci and the narrowing of gyri in AD compared to the aged healthy control and DS case and the shrinkage of the DS cerebellum (C) compared to the control (A) and AD (B) brains. (D–J) Rostral to caudal coronal hemibrain slabs from a 59-year-old female DS case with dementia showing ventricular hypertrophy and gray matter reduction. (K) Coronal slab showing a reduction in the size of the hippocampal formation, entorhinal cortex, and an enlarged lateral ventricle in this 59-year-old female with DS and dementia. Abbreviations: Cd , caudate; Ent , entorhinal cortex; fi , fimbria; fx , fornix; HP , hippocampus; LV , lateral ventricle; Pt , putamen; SN , substantia nigra; Th , thalamus.

Cortical amyloid in AD and DS

Although all cases of DS display AD pathology, only about two-thirds develop dementia [10] (see Chapters 1, 13, and 15). The biology underlying this disconnect between the presence of AD neuropathology and presence of dementia is an underinvestigated area, primarily due to the lack of autopsy cases that are clinically well characterized. In AD and DS, an increase in soluble Aβ species precedes plaque deposition [34, 36, 37], and occurs as early as 21 gestational weeks in DS [36, 37]. In a recent study, amyloid plaques were not seen at 0.01, 1.6, and 3 months of age in the frontal and temporal cortex or brainstem in DS [38]. In our ongoing developmental investigations, we were not able to immunohistochemically visualize Aβ40, Aβ42, or Aβ plaques-like structures in the frontal cortex at 6 months, 1 year (Fig. 1H–K), and in a 3-year-old DS case. However, an occasional diffuse starburst deposit displaying immunoreactivity against the 6E10 antibody, which recognizes amyloid precursor protein (APP) and Aβ was found in these same cases (Fig. 1H). Interestingly, there is one other case report showing a similar starburst pattern [39]. By contrast, no amyloid-like staining was seen in a 5-year-old neurotypical case. These observations suggest that APP and not Aβ is an early event in the developing DS cortex, which may be related to altered axonal pruning and neuronal culling [40]. Although diffuse deposits of Aβ42 have been reported in people with DS between 8 and 27 years of age [38, 41, 42], an earlier time point than seen in AD [41–43], they appear to have negligible effects upon neurons and their deposition is not associated with clinical symptoms [44]. In DS cases aged 40–50 years, levels of cortical Aβ deposition are similar to those observed in sporadic, late onset AD [11, 42, 45–49]. In addition to diffuse plaques, a few cored plaques associated with dystrophic neurites (neuritic plaques) have been reported at age 19 and in a 30-year-old DS case [38], which are of neuropathological diagnostic significance in AD. By age 40, people with DS exhibit Aβ plaque density and morphology similar to that seen in AD [38].

Cerebellar amyloid in AD and DS

Although neuropathological reports suggest that the reduced size of the DS cerebellum leads to a delay in fine motor development [25, 50], studies of AD neuropathology in this structure during gestation are minimal. We found scattered diffuse amyloid-like plaques, some containing a dense central core immunoreactive for APP/Aβ1–16 (6E10) in the white matter and granular cell layer of the cerebellum at postnatal day 10 and between 4 and 20 weeks of age in DS. Another study reported virtually no amyloid plaque pathology between 0 and 53 years of age using the 4G8 antibody (APP/Aβ17–24), but beyond this age all cases displayed various levels of Aβ pathology in DS [38]. The difference between earlier and a more current study [38] may be related to the sequence specificity of the 4G8 antibody [51]. However, in both the adult AD and DS cerebellum, amyloid deposition visualized using an antibody against the Aβ peptide (Aβ4) appears as amorphous patches, which often occur perpendicular or parallel to the pial surface within the molecular layer (ML) [52]. We recently investigated the deposition of amyloid using antibodies that detect different epitopes of the Aβ sequence in cerebellar cortex obtained from demented (average age 51.2; range 45–59) and nondemented (average age 50.3; range 44–60) individuals with DS (average age 81.7; range 71–98) and healthy aged controls (average age 70.9; 51–85). Cerebellar tissue reacted with an antibody that recognizes both APP and Aβ (6E10), revealed patches of APP/Aβ in the ML that was greater in both DS groups compared to AD and nondemented healthy subjects (Fig. 3A–D). Since the elevation of levels of the long form of Aβ, Aβ42, compared to the short form, Aβ40, plays a role in the early events underlying the pathogenesis of AD, we evaluated Aβ42 and Aβ40 immunoreactivity within cerebellar tissue from these same adult cases. Aβ42, but not Aβ40 immunoreactivity, was found in the cerebellum of both DS groups but to a lesser extent in AD (Fig. 3E–H). In DS, Aβ42 appeared as bands perpendicular to the pial surface within the ML (Fig. 3F and G). Interestingly, only scattered patches of APP/Aβ and Aβ42 were seen in the cerebellar ML in AD (Fig. 3D and H). Both demented and nondemented individuals with DS had significantly higher Aβ42 plaque loads in the ML compared to nondemented controls. Cerebellar Aβ42 loads in demented individuals with DS were significantly increased compared to AD [53].

Fig. 3

Fig. 3 Photomicrographs showing APP/Aβ (A–D) and Aβ42 (E–H) immunolabeling in molecular layer (ML) of the cerebellar cortex in aged healthy control (HC) (A, E), nondemented Down syndrome (DS) (B, F), demented DS (G, C), and Alzheimer's disease (AD) (D, H) subjects. Note the deposits of APP/Aβ in DS without (DSD −, B), with dementia (DSD +, C), and AD (D), while Aβ 42 immunoreactivity appeared as parallel bands reaching the pial surface within the ML in DSD − compared to wider patches of immunoreactivity in DSD + and the limited patches in AD. APP/Aβ and Aβ 42 immunostaining was not detected in HC subjects. Abbreviations: GL , granular cell layer; ML , molecular layer. Scale