Earlier onset of Alzheimer's disease in men with Down syndrome

Abstract

Both male gender and the presence of an APOE epsilon4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE epsilon2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

“…However, increased incidence of clinical signs of dementia in DS after the age of 50 years [29,54,63,66] appear to be at a later age than the first signs of significant insoluble Aβ accumulation or plaque accumulation and also after the first signs of neurofibrillary tangle pathology [35]. Thus, downstream events that may be directly or indirectly related to Aβ or tangle formation may lead to neuronal dysfunction and cognitive decline.…”

Human brain myelination and amyloid beta deposition in Alzheimer's disease

“…Thus, the peak probability of AD is reached 5 years earlier for men than women: age 78 and 83 years for APOE e4/e4, age 91 and 96 for APOE eX/eX, and age 92 and 97 for APOE e4/eX, respectively [29]. Furthermore, in patients with Down syndrome, who have an elevated risk for developing AD on a genetic basis, men develop AD at an earlier age than women [31]. In women with Down syndrome, an earlier menopause, which increases peripheral iron levels [32], is associated with earlier age at onset of AD [33,34].…”

Human Chorionic Gonadotropin Increases β-Cleavage of Amyloid Precursor Protein in SH-SY5Y Cells

“…Considering that LH levels are maximal during this critical period and HRT suppresses LH production, it is conceivable that any beneficial effects of estrogen administration on reducing AD risk could be mediated in-part through reducing the level of circulating LH. Furthermore, people with Down's syndrome have a high prevalence of AD, develop the disease at younger ages than the general population and also have relatively high levels of LH starting at puberty indicating abnormalities in primary gonadal function that correlate with earlieronset AD (Schupf et al, 1998). I(n summary, the demonstrated dose-dependent increase in β-secretase activity upon treatment of SH-SY5Y cells with the LHR agonist hCG suggests that reported LH/LHR-mediated increases in Aβ levels are due to activation of β-secretase.…”