Dementia in Down syndrome: unique insights for Alzheimer disease research

Abstract

Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. Amyloid-β accumulates in the brain across the lifespan of people with DS, which provides a unique opportunity to understand the temporal progression of AD and the epigenetic factors that contribute to the age of dementia onset. This age dependency in the development of AD in DS can inform research into the presentation of AD in the general population, in whom a longitudinal perspective of the disease is not often available. Comparison of the risk profiles, biomarker profiles and genetic profiles of adults with DS with those of individuals with AD in the general population can help to determine common and distinct pathways as well as mechanisms underlying increased risk of dementia. This Review evaluates the similarities and differences between the pathological cascades and genetics underpinning DS and AD with the aim of providing a platform for common exploration of these disorders.

Figure 1 ∣. Amyloid plaques in Down syndrome.

Representative example of Aβ plaques (Aβ1-42; brown staining; arrowheads) and neurofibrillary tangles (PHF-1 antibody; blue staining; arrow) in the frontal cortex of a 46 year old person with DS and endstage AD.

Figure 2 ∣. Brain structural changes in Down syndrome.

Structural differences shown in coronal and sagittal sections from an MRI between a 46 year old person with DS without dementia (parts A and C ) and a person without DS ( parts b and d) highlighting structural differences in frontal cortex (arrowhead in parts a and b), cerebellum (arrow in parts a and b) and hippocampus (arrow in parts c and d).

Figure 3 ∣. Amyloid PET in Down syndrome.

Representative examples of Pittsburgh Compound B (PiB) PET neuroimaging for amyloid in people with DS. The pattern of PiB binding highlights striatal PiB uptake (arrows). Three patterns of PiB update are highlighted in this figure from Lao and colleagues (2016) showing nonspecific white matter binding in the top row, striatal only PiB uptake in the middle row and striatal with cortical PiB update on the bottom row. SUVR, standard uptake value ratio.

Figure 4 ∣. Cerebrovascular pathology in Down syndrome.

a ∣ Aβ1-42 immunolabeling in a 67 year old man with DS defines plaques clearly but also shows substantial accumulation on blood vessel walls (arrows). b ∣ Aβ1-40 labeling clearly defines vascular pathology but plaque labeling is less than that observed with Aβ1-42. c ∣ panel shows the possible consequences of CAA in a 58 year old man with DS — microhemorrhages, illustrated with a Prussian blue stain as deposits (white arrows) that are blue adjacent to blood vessels (black arrowheads). d ∣ cerebrovascular pathology identified by T2* MR imaging in a 60 year old man. Progressive worsening of bleeds can be seen, particularly in the occipital cortex (arrows). Modified with permission from Wilcock et al., 2016 .

Figure 5 ∣. Hypothetical model of biomarker and clinical outcomes.

Ballard and colleagues developed a hypothetical model of different biomarker and clinical outcomes reflecting the progression of AD in DS. Amyloid changes are thought to be detectable after 20 years of age whereas tau pathology might not be detectable until 30 years of age. In vivo neuroimaging suggests that changes in brain volume and glucose metabolism (FDG-PET) can develop after 30 years of age, not long after tau pathology develops. Clinical changes are delayed and may not be detectable until after 35 years of age. Each of these biomarkers is thought to get progressively more abnormal as people with DS age. Ages are estimated on the basis of published studies. Reproduced with permission from Ballard et al., 2016 .

Figure 6.. Hypothetical progression of Alzheimer disease neuropathology in Down syndrome.

A proposed timeline from birth to over 60 years of age of Alzheimer disease (AD) pathology in individuals with Down syndrome (DS). Mitochondrial dysfunction and increased generation of reactive oxygen species (ROS) occurs as early as in fetal brain. Brain inflammation can begin as early as in the late teens with the presence of activated microglial cells, which are associated with Aβ plaques later in the disease. By age 40 years, both extracellular Aβ and NFTs are present in sufficient quantities for a neuropathological diagnosis of AD. As individuals with DS age to over 50 years, AD neuropathology increases in severity and clinical signs of dementia become frequent.