Specificity of the fivefold increase in AD in mothers of adults with Down syndrome

Abstract

These findings suggest that the increased risk of AD among mothers who gave birth to children with DS before age 35 appears to represent a specific vulnerability to AD, as opposed to other age-related degenerative disorders.

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

“…Furthermore, women who have a Downs syndrome/ trisomy 21 child before the age of 35 are usually aneuploid for trisomy 21 themselves and have a five-fold increased risk of developing AD later in life [26,37,38]. These findings indicate that overexpression or an extra copy of normal APP, either in Down syndrome, in the duplicated APP families, or because of spontaneous or PS-induced trisomy 21 mosaicism can lead to AD.…”

Chapter 4 Alzheimer's Disease in Adults with Down Syndrome

“…There was no increase in risk of dementia among mothers who were over 35 when their child with Down syndrome was born, and no differential patterns of dementia risk in older versus younger fathers of children with Down syndrome or children with other intellectual disabilities. In a follow-up study of the familial aggregation of Down syndrome and Alzheimer's disease, Schupf (Schupf, Kapell et al, 2001) replicated her previous findings and clearly determined that the increased risk for Alzheimer's disease was not reflected in increased risk for other age-related neurological diseases. This suggests that risk both for Alzheimer's disease and having a child with Down syndrome at a relatively young age is determined, at least in part, by some common underlying mechanism, perhaps controlling some aspect rate of aging.…”

“…The heterogeneity in the clinical expression of Alzheimer's disease observed within the population of adults with Down syndrome may be due to the additive and/or interactive effects of a number of these risk factors, including, but not limited to genotypic variation, sex, age, health activity and diet [e.g., (Chace et al, 2007;Patel et al, 2004;Patel, Seltzer, Wu, & Schupf, 2001;Prasher et al, 2008 in press;Schupf, Kapell, Lee, Ottman, & Mayeux, 1994;Schupf et al, 1996;Schupf, Kapell et al, 2001;Schupf et al, 1998;Schupf et al, 2003;Schupf et al, 2007;Schupf et al, 2006;Zigman, Jenkins, Tycko, Schupf, & Silverman, 2005;]. The search for factors predictive of dementia in people with Down syndrome closely parallels analogous investigations in the typically developing population.…”

“…Shared Genetic Susceptibility-Nondisjunction, or the failure of chromosome pairs to separate properly during meiosis or mitosis, is the principal cause of Down syndrome, and is of maternal origin over 90% of the time (Freeman et al, 2007). Schupf and her associates (Schupf et al, 1994;Schupf, Kapell et al, 2001) therefore postulated that if there was a shared genetic susceptibility for Down syndrome and Alzheimer's disease, it should only be most evident among mothers and maternal relatives of individuals with Down syndrome. They further hypothesized that evidence of shared susceptibility would be strongest in the population of relatively young mothers for whom having child with Down syndrome at a relatively young age might reflect an accelerated aging process in which they were biologically older than their chronological age.…”

Abnormal Folate Metabolism and Maternal Risk for Down Syndrome

“…The mean frequency of binucleatedmicronucleated cells increased significantly with the increasing number of MTHFR 677 T alleles, and MTHFR 1298 AA women have significantly higher binucleated-micronucleated cells frequency than do MTHFR 1298 AC + CC carriers (Coppedè et al, 2007;Coppedè, 2009). In addition, mothers who had a DS child at a young age showed increased frequency (of about 5-fold) of Alzheimer's disease (AD) (Schupf, et al, 2001). A unifying hypothesis trying to relate DS, trisomy 21, and AD has proposed that trisomy 21 mosaicism at the germ cell level or in brain cells could account for the familial aggregation of AD and DS (Potter, 1991).…”