Regular articleCandidate gene analysis for Alzheimer's disease in adults with Down syndrome
Introduction
Adults with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD) (Schupf, 2002, Zigman, 2013, Zigman and Lott, 2007), and many, but not all, will develop dementia by the end of their seventh decade of life (Lai and Williams, 1989, Zigman, 2013). The neuropathological manifestations of AD in DS have been attributed, at least in part, to triplication and overexpression of the gene for amyloid precursor protein (APP) located on chromosome 21 (Rumble et al., 1989), leading to an increased substrate for production of amyloid β (Aβ) peptides (Mehta et al., 1998, Schupf et al., 2001, Tokuda et al., 1997). Of the two major species of Aβ peptides—Aβ40 and Aβ42—generated by sequential proteolytic cleavage by β and γ secretases of the APP (Selkoe, 2001), lower levels of Aβ42 or the Aβ42/Aβ40 ratio in cerebrospinal fluid along with high levels of tau are associated with high risk of AD (Blennow and Hampel, 2003, Jack et al., 2013). However, even among individuals with full trisomy 21, age at onset of AD varies widely, and levels of Aβ40 and Aβ42 and Aβ42/Aβ40 ratio also vary widely even among individuals who are of comparable age (Coppus et al., 2008, Head et al., 2012, Holland et al., 2000, Lai and Williams, 1989, Schupf, 2002, Zigman et al., 2007).
Genetic as well as environmental factors may contribute to the observed variation in age at onset. Multiple genome-wide association studies (GWAS) and meta-analyses have identified at least 20 genes that are significantly associated with AD in the general population (Bertram et al., 2007, Hollingworth et al., 2011, Lambert et al., 2009, Lambert et al., 2013, Lee et al., 2011, Naj et al., 2011, Wijsman et al., 2011). To date, however, only 1 genome-wide study of age at the onset of AD in DS based 67 autopsy samples has been reported (Jones et al., 2013). Several studies have examined the relation between single nucleotide polymorphisms (SNPs) and dementia in adults with DS using a candidate gene approach (Jones et al., 2013, Lee et al., 2007b, Liu et al., 2008, Margallo-Lana et al., 2004, Mok et al., 2014, Patel et al., 2011). In addition, mouse models of DS have identified genes that are differentially expressed between AD and controls (Chrast et al., 2000, Cook et al., 2005, Lyle et al., 2004, Prandini et al., 2007). Compared with individuals without DS, triplication and overexpression of genes that are located on chromosome 21, including APP and others, may contribute to AD risk or more general atypical aging in adults with DS. Some of these genes have also been implicated in AD pathogenesis. These include beta amyloid converting enzyme-2 (BACE2), superoxide dismutase (SOD1), and the astrocyte-derived neurotrophic factor S100 beta (S100β). In the present study, we examined SNPs in candidate genes on chromosome 21 as well as a subset of autosomes and chromosome X to determine their contribution to variation in risk for dementia due to AD in a large longitudinal cohort of adults with DS (refer to Supplement Table 1 for a complete list of candidate genes).
Section snippets
Study participants
We examined 93 individuals with dementia and 227 without dementia for a total of 320 community-residing adults with confirmed DS (Table 1). All individuals were 30 years of age and older at the time of their study enrollment (range 31–78) and resided in New York, Connecticut, New Jersey, or eastern Pennsylvania. Participants were recruited with the help of state and voluntary service provider agencies and were eligible for inclusion in the present study if: (1) a family member or correspondent
Demographic and clinical characteristics
The average age of the 320 study participants at the time of baseline was 49.9 year old (SD = 7.6), and the mean age of adults at the baseline for adults with dementia was 7 years older than those without (Table 1). The majority of the individuals had mild to moderate intellectual disability. Ethnicity for over 90% of the study participants was reported in the medical charts as non-Hispanic White, and the allele frequency of the APOE ε4 (11.6%) was comparable to other populations of Caucasian
Discussion
The present study confirmed that SNPs in APP and CST3 were significantly associated with AD risk for adults with DS, whereas those in MARK4 were suggestively associated; further, 2 SNPs in APP and 1 SNP in MARK4 were also found to be associated with AD in a large-scale GWAS of adults without DS. Our results extend previous findings of a relationship between SNPs in candidate genes located on chromosome 21 and chromosomes other than 21 and risk of AD in adults with DS (Jones et al., 2013, Lee
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
This study is supported by grants R01AG014673 (Schupf) and P01HD035897 and U54 HD079123 (Silverman) from NIA and NICHD, respectively, and by NYS through its Office for People with Developmental Disabilities. The authors thank the study participants and participating agencies from the tri-state area that made this study possible.
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2020, Progress in Brain ResearchCitation Excerpt :Alternatively, increased APP gene dosage might be acting in concert with bona fide early aging to accelerate the onset of this disease (Devenny et al., 2005; Head et al., 2012). According to this hypothesis, the age-at-onset of AD in DS is dictated by multiple modifier genes, including some that are not located on Hsa21 but have biological roles in AD pathology and are genetically polymorphic in human populations (Lee et al., 2017; Schupf et al., 2015, 2018), and others, aside from APP, that reside on Hsa21 and might affect the aging process per se. Moreover, early aging of other organs might rather be due to the triplications of other Hsa21 gene orthologs, some of which might directly influence the aging process.
Down syndrome: Neurobiological alterations and therapeutic targets
2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :APP gene product encoded by Hsa21 represents a prominent component of the amyloid cascade hypothesis of early manifestation of AD in the DS population. APP gene expression in the DS brain was found to be 1.6 fold higher than in the euploid brain and thought to be responsible of the accumulation of the plaques containing fibrillar β-amyloid (Aβ) peptide (Lee et al., 2017; Mao et al., 2003). The neurotoxicity of Aβ has been attributed to microglia activation and increased oxidative stress production (Zana et al., 2007).
Exosomal biomarkers in Down syndrome and Alzheimer's disease
2018, Free Radical Biology and MedicineCitation Excerpt :Taken together, these data demonstrated that neuron-derived exosome levels of Aβ1–42 and P-Tau follow different trajectories in adults with DS with symptoms of dementia, suggesting that these differences may be useful for the diagnosis and prognosis of AD dementia. It is not surprising that Aβ1–42 levels were elevated early in DS because the APP gene resides on Hsa21 [34,67], and previous studies have shown elevated levels of amyloid peptides in plasma from children and young adults with DS [85]. Interestingly, findings from the Dominantly Inherited Alzheimer Network (DIAN) study (e.g., [29]), an international registry of individuals at certain risk for developing autosomal dominant AD, suggest that early biomarkers predict the onset and trajectory of dementia in vulnerable non-DS populations.