Research press release


Nature Medicine

Medical research: Rare mutation linked with protection from Alzheimer’s disease in one individual



今回報告された女性の脳にはアルツハイマー病の特徴であるアミロイドの高度な蓄積が見られたが、この病気に伴う種々の症状は観察されていなかった。Y Quiroz、J Arboleda-Velasquezたちはこの女性のゲノムを調べ、病気の原因となるプレセニリン1遺伝子の変異の他に、Christchurchと呼ばれるAPOE遺伝子の珍しいバリアントが存在することを見いだした。この変異が加わったためにプレセニリン1変異の有害な作用が弱められ、脳に高レベルのアミロイド病変が存在したのにもかかわらず、アルツハイマー病の発症から守られた可能性があると著者たちは考えている。この女性は、70代になっても認知機能は健全なままだった。いくつかの実験で、アルツハイマー病に関わるとされる糖の1つへのAPOEの結合をこの変異が妨げることが示され、これが保護的作用をもたらしたのではないかと著者たちは考えている。


The presence of a rare mutation in the APOE3 gene may have protected a woman from the development of symptoms associated with Alzheimer’s disease, reports a case study published in Nature Medicine. This individual was discovered in a study of 1,200 individuals in Colombia for whom Alzheimer’s disease is extremely likely to develop owing to genetic predisposition.

The causes of the majority of cases of Alzheimer’s disease are unknown. However, a small subset of individuals who carry a specific mutation in the gene for the protein presenilin 1 are predisposed to developing Alzheimer’s disease, and almost invariably experience cognitive problems and dementia at an unusually young age, typically starting in their 40s.

Examination revealed that the woman had a high degree of brain amyloid pathology, a hallmark of Alzheimer’s disease. However, she did not present with symptoms associated with the disease. When Yakeel Quiroz, Joseph Arboleda-Velasquez and colleagues studied her genome, they found that in addition to the disease-causing mutation, she had a rare variant of the APOE gene, called Christchurch. The authors suggest that this additional mutation may have counteracted the detrimental effects of the presenilin 1 mutation, which could have protected the individual against the disease despite the presence of high levels of amyloid pathology in her brain. She remained cognitively healthy into her 70s. In several experiments, they suggested mechanisms by which this mutation may exert its protective effects by impairing binding of APOE to a type of sugar implicated in Alzheimer’ disease.

The authors conclude that this case study provides new insights about the mechanisms involved in the development, treatment, and potential prevention of Alzheimer’s disease. It also offers the first known candidate for a gene that could potentially be used to develop interventions to halt the progression of the disease. They note that further research with larger samples is required to establish a definitive causal relationship between the APOE3 Christchurch mutation and protection from disease, and they underscore the importance of developing APOE-related gene and drug therapies for the disease.

doi: 10.1038/s41591-019-0611-3


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