Alzheimer disease and Down syndrome: factors in pathogenesis
Introduction
Down syndrome (DS) is caused by the triplication of chromosome 21, which includes the genes SOD-1, BACE-2, APP and S100β, along with other genes that have been identified with the recent publication of the human genome [7]. Virtually all individuals with DS develop sufficient neuropathology for a diagnosis of Alzheimer disease (AD) by the age of 40 years [48]. Hallmarks of AD observed in brain tissue from individuals with DS include β-amyloid (Aβ) plaques and neurofibrillary tangles. Aβ pathology begins to accumulate in childhood (as young as 8 years) and appears to rise progressively with increasing age [43]. However, between the ages of 35 and 45 years, the rate of AD pathology accumulation appears to accelerate [74]. During this time period, other types of pathology either begin to appear or are exacerbated including the accumulation of neurofibrillary tangles and markers of neuroinflammation.
There is evidence to suggest that certain shared features exist in the pathogenesis of vascular disease and AD [14]. In DS inflammatory factors and abnormalities in cholesterol metabolism (both of which are involved with the development of atheromas) may contribute to the development of AD, and in turn may be influenced by Apo E genotype. The purpose of this review is to discuss factors associated with the development of dementia and Alzheimer disease pathology in DS and when possible, to discuss how these events may also contribute to vascular disease.
Section snippets
Decreased incidence of atherosclerosis in Down syndrome
In the general population, the prodromal stages of atherosclerotic lesions arise in early life [55]. Individuals with DS appear to present a disparate model for the ontogeny of atheromas compared to the general population. Individuals with DS have been shown to have a lower incidence of atherosclerosis in comparison to a population of mentally retarded individuals without DS living in the same institution, a finding that led Murdoch et al. to conclude that DS may represent an atheroma free
Cholesterol and brain aging in DS
Cholesterol is a key contributor to atheroma development and statins can be used to slow atherogenesis [40]. Recent epidemiological evidence [37], [76] and work using animal models [58], [59] all suggest that changes in cholesterol concentration can significantly affect markers of pathological brain aging. The mechanism by which cholesterol reduction may reduce the risk for AD is thought to be through a reduction in Aβ production [13]. Aβ is cleaved from the longer Aβ precursor protein (APP)
Aβ pathogenesis in DS
Aβ pathology in the DS brain has been well-characterized [31], [44], [46], [47], [48], [73], [74]. Typically, in younger individuals (under 30 years), Aβ accumulation is manifested by diffuse deposits that are not associated with neuritic degeneration. These diffuse plaques are thioflavine-S negative, indicating the absence of fibrillar amyloid. The primary Aβ species in these diffuse deposits consist of the toxic and less soluble Aβ1–42 peptide. Aβ1–40 deposits develop after the appearance of
Aβ degradation and clearance
In DS, despite life-long over expression of APP leading to excess Aβ production, extracellular Aβ does not begin to show extensive or an accelerated rate of accumulation until individuals are over the age of 30 years [48]. Thus, for a long period of time, the excess Aβ produced in the DS brain may be cleared or degraded by the activity of Aβ degrading enzymes. Several enzymes are thought to be important for Aβ clearance and include insulin degrading enzyme, neprilysin, and tissue plasminogen
The role of inflammatory processes in development of AD in adults with DS
Aβ deposits are associated with similar neuroinflammatory components as observed in atheromas of blood vessels. In addition, non-steroidal anti-inflammatory agents are protective for both atheroma and for AD. In adults with DS, several markers of inflammation are present at higher levels than in younger individuals, particularly in association with Aβ and this may be due in part to gene over expression. Inflammation may be a major contributor to the acceleration phase of AD pathogenesis in DS
Apolipoprotein E as a risk factor for dementia in DS and influence on AD pathogenesis
Apo E4 has been confirmed as a susceptibility factor for AD in the general population [60] and as a risk factor for vascular dysfunction. Apo E plays an important role in regulating cholesterol levels in the brain and as discussed previously may directly mediate Aβ production. Observations in DS have yielded inconsistent results. Deb et al. carried out a meta-analysis of all previously published studies of the association between Apo E and DS and found that individuals with DS showed a
Clinical correlations
There is an age-associated decline in adaptive functioning in DS with age that may be associated with risk factors common to both vascular and Alzheimer's disease. Cumulative incidence of significant decline for adults with DS increases from less than 0.04 at age 50 to 0.67 by age 72, whereas cumulative incidence of significant decline for adults with mental retardation without DS increased from less than 0.02 at age 50 to 0.52 at age 88 [79]. A higher level of baseline cognitive functioning
Summary
There are several shared pathological features of vascular disease (atheromas) and AD pathology in DS including a role for cholesterol, Apo E and inflammation in both conditions suggesting common disease mechanisms. However, in DS, reduced atheroma development is associated with the accelerated development of AD. Of all the mechanisms discussed including a role for cholesterol and inflammation in both vascular and AD, there appears to be a paradox. Abnormal cholesterol metabolism in DS is
Acknowledgments
Funded by NIA P50 AG16573 and NIA RO1 AG21912. The authors would like to thank Drs. Glabe and Kayed at the University of California at Irvine for the anti-oligomer antibody used to reveal oligomers in DS brain.
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2022, NeuronCitation Excerpt :Genetic overexpression of the APP gene explains the substantial cortical amyloidosis observed in aging adults with DS. APP overexpression may also precipitate downstream proteopathies (i.e., neuritic Aβ plaques and neurofibrillary tangles), neurodegeneration, and cognitive deficits in these adults as they age (Doran et al., 2017; Head et al., 2012; Lott and Head, 2005; Teller et al., 1996). Supporting the importance of APP gene dosage in DSAD, two case studies have reported cognitive sparing in aging adults with DS who possessed an otherwise euploid copy number for APP (Doran et al., 2017; Prasher et al., 1998).