People with Down syndrome (DS) have increased risk of Alzheimer disease (AD), presumably conferred through genetic predispositions arising from trisomy 21. These predispositions necessarily include triplication of the amyloid precursor protein (APP), but also other Ch21 genes that confer risk directly or through interactions with genes on other chromosomes. We discuss evidence that multiple genes on chromosome 21 are associated with metabolic dysfunction in DS. The resulting dysregulated pathways involve the immune system, leading to chronic inflammation; the cerebrovascular system, leading to disruption of the blood brain barrier (BBB); and cellular energy metabolism, promoting increased oxidative stress. In combination, these disruptions may produce a precarious biological milieu that, in the presence of accumulating amyloid, drives the pathophysiological cascade of AD in people with DS. Critically, mechanistic drivers of this dysfunction may be targetable in future clinical trials of pharmaceutical and/or lifestyle interventions.

患有唐氏综合症 (DS) 的人患阿尔茨海默病 (AD) 的风险增加，这可能是由 21 三体性引起的遗传倾向造成的。这些倾向必然包括淀粉样前体蛋白 ( APP ) 的三倍体，但也包括直接导致风险的其他 Ch21 基因或通过与其他染色体上的基因相互作用。我们讨论 21 号染色体上的多个基因与 DS 代谢功能障碍相关的证据。由此产生的失调途径涉及免疫系统，导致慢性炎症；脑血管系统，导致血脑屏障（BBB）破坏；和细胞能量代谢，促进氧化应激增加。综合起来，这些破坏可能会产生不稳定的生物环境，在淀粉样蛋白积累的情况下，会驱动 DS 患者发生 AD 的病理生理级联反应。至关重要的是，这种功能障碍的机械驱动因素可能是未来药物和/或生活方式干预临床试验的目标。