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Individuals with Down syndrome are at increased risk of developing Alzheimer's disease due to increase gene dosage resulting from chromosome 21 triplication. Although virtually all adults with Down syndrome will exhibit the major neuropathological hallmarks that define Alzheimer's disease, not all of them will develop the clinical symptoms associated with this disorder (i.e. dementia). Therefore, a good understanding of the pathophysiology of Alzheimer's disease in Down syndrome will be crucial for the identification of novel pharmacological targets to develop disease-modifying therapies for the benefit of Down syndrome individuals and for Alzheimer's sufferers alike. The study of biomarkers will also be essential for the development of better screening tools to identify dementia at its incipient stages. This review discusses the best-validated pharmacological targets for the treatment of cognitive impairment and Alzheimer's disease in Down syndrome. We further examine the relevance of newly discovered biological markers for earlier dementia diagnosis in this population., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Introduction: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need., Methods: We investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline., Results: Aβ40 and Aβ42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aβ correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aβ42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aβ and inflammatory molecules was a strong predictor of prospective cognitive deterioration., Conclusions: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

In Alzheimer's disease and Down syndrome, cholinergic neurons of the basal forebrain progressively degenerate. This neurotransmitter system is the main source of acetylcholine to the cortex and hippocampus. In the mature and fully differentiated central nervous system, the phenotype of forebrain cholinergic neurons and their nerve terminals in cortex and hippocampus depend on the continuous endogenous supply of nerve growth factor (NGF). It has been recently demonstrated that NGF is secreted from cortical neurons in an activity-dependent manner as a precursor molecule, proNGF. Individuals with Alzheimer's disease and Down syndrome exhibit proNGF accumulation in cortex, yet cholinergic neurons become atrophic in both diseases, despite the apparent abundance of the NGF precursor. This review illustrates the recent evidence that NGF metabolism is affected both in Alzheimer's disease and in Down syndrome brains and also discusses a role for amyloid-β peptides and central nervous system inflammation in unleashing such deficits. It further considers the potential of the NGF metabolic pathway as a new pharmacological target to slow down the neurodegenerative process both in Alzheimer's disease and in individuals with Down syndrome.

Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.

Contradictory findings have been recently published on the evaluation of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C-->T) and methionine synthase reductase (MTRR 66 A-->G) as risk factors for having a child with Down syndrome (DS); however, the influence of polymorphisms of methionine synthase (MTR 2756 A-->G) and of MTHFR 1298 A-->C has never been evaluated. In this study, the risk of being a DS case or having a DS child (case mother) was studied by multiple logistic regression analysis of the independent and combined genotypes and of plasma homocysteine, folates, and vitamin B12 in 92 DS cases and 140 control subjects as well as in 63 case mothers and 72 age-matched control mothers from Sicily. (The MTHFR 677 T allele frequency was not different in DS cases and case mothers, compared to the respective control groups). After adjustment for age, total homocysteine (t-Hcys) and MTR 2756 AG/GG genotype were significant risk factors for having a DS child, with odds ratio (OR) of 6.7 (95% CI: 1.4-32.0, P = 0.016) and of 3.5 (95% CI: 1.2-10.9, P = 0.028), respectively. By comparison, MTR 2756 AG/GG genotype increased significantly the risk of being a DS case, with an OR of 3.8 (95% CI: 1.4-10.5, P = 0.009). The double heterozygosity MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a DS child, with an OR estimated at 5.0 (95% CI: 1.1-24.1), after adjustment for t-Hcys. In conclusion, our results provide evidences that homocysteine and MTR genetic polymorphism are two potent risk factors for mothers to have a DS child in Sicily., (Copyright 2003 Wiley-Liss, Inc.)