Alzheimer's Disease in Down Syndrome

Abstract

A key challenge to adults with Down syndrome (DS) as they age is an increased risk for cognitive decline, dementia, and Alzheimer disease (AD). In DS persons ranging from 40-49 years of age, 5.7-55% may be clinically demented and between 50-59 years, dementia prevalence ranges from 4-55% (reviewed in [1]). Despite the wide ranges reported for dementia prevalence, a consistent feature of aging in DS is the progressive accumulation of AD brain pathologies. By the age of 40 years, virtually all have sufficient senile plaques and neurofibrillary tangles for a neuropathological diagnosis of AD [2]. Thus, there is dissociation between the age of onset of AD neuropathology (40 years) and increasing signs of clinical dementia. We discuss the hypothesis that frontal impairments are a critical factor affecting cognitive function and are associated with white matter (WM) and AD neuropathology. While these may be an early sign of conversion to dementia, we also review several other clinical comorbidities that may also contribute to dementia onset.

Keywords: Trisomy 21; beta-amyloid; dementia; neurofibrillary tangles; oxidative damage.

Figure 1

Hypothetical progression of events associated with the development of Alzheimer's disease neuropathology in Down syndrome as a function of age. A. A timeline is proposed from birth to over 60 years that may begin with B. Intracellular Aβ (green) and early endosomes (green) appear to be co-localized (yellow) in younger individuals with DS. As adults approach ~30 years of age, extracellular deposits of Aβ can be observed*. By age 40 years, both extracellular Aβ and NFTs are present in sufficient quantities for a neuropathological diagnosis of AD. As DS individuals progressively age to over 50 years, AD neuropathology increases in severity*. C. Early mitochondrial dysfunction (green) can be distinguished from functional mitochondria (red) within astrocytes and increased generation of reactive oxygen species (ROS) occurs as early as in fetal brain. D. Brain inflammation may begin as early as in the late teens with the presence of activated microglial cells (blue), which later in age are associated with Aβ plaques (brown). E. Plasma Aβ appears to rise after the age of 40 years and may reflect brain pathology although F., clinical signs of dementia may not become frequent until after the age of 50 years.

1. Reproduced with permission from Schupf et al., 2010 [51]: Figure 2.

2. Reproduced with permission from Schupf et al., 2002 [97]: Figure 1.

3. Modified with permission from Cataldo et al., 2004: Figure 7.

4. Modified with permission from Busciglio et al., 2002: Figure 4

5. Image kindly provided by Dr. Donna Wilcock at the University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY.

*Additional images from E. Head, University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY.

Figure 2

Imaging in Down syndrome as a function of dementia. A. An axial, nonlinearly registered, fractional anisotropy image generated from diffusion tensor imaging data taken from 20 middle aged and older individuals with DS. The green skeleton depicts the white matter fibers common to all 20 participants who are in our study. Sagittal (left) and coronal (right) T1 (MPRAGE) magnetic resonance images from a 48 year old DS individual (B) and a 47 year old person with DS and dementia (C). Note the relative sizes of the hippocampi. A single voxel short echo proton spectroscopy (TE 35ms) taken from the posterior cingulate gyrus of a 48 year old nondemented person with DS (D) and a 47 year old person with DS and dementia (E). Note the decreased N-Acetyl Aspartate (NAA) peak and increased My inositol (Ins) peak.