Undersökningar av den nyfunna Uppsalamutationen, som orsakar tidigt debuterande ärftlig Alzheimers sjukdom

Tidsperiod: 2016-01-01 till 2019-12-31

Projektledare: Lars Lannfelt

Medarbetare: Lars Nilsson, Martin Ingelsson, Anna Erlandsson, Dag Sehlin, Greta Hultqvist, Vilmantas Giedraitis

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 4 000 000 SEK

Mutations in the genes for the amyloid precursor protein (APP) and the presenilins cause early-onset, inherited forms of Alzheimer’s disease (AD). We have previously identified and characterized two different APP mutations, the Swedish and the Arctic mutations. Analyses of these mutations have proven very important for the understanding of the disease process. Recently, we discovered a new APP mutation, which we have dubbed the “Uppsala” mutation, as the family originates from this city. It is a deletion of six consecutive amino acids in amyloid-β (Aβ). Deletions like this have never previously been described for AD. We will investigate the pathophysiological effects of the mutation with a multitude of different techniques: genetics, biochemistry, cell biology and in transgenic mice. Clinical studies on members from the family are ongoing, where age of onset among mutation carriers is around 43 years. We have CSF biomarker data from two affected mutation carriers, which both displayed elevated levels of Aβ42 (930 pg/ml and 740 pg/ml, respectively). CSF levels of Aβ42 are usually below 550 pg/ml in AD and investigations are underway to understand the molecular background to this unexpected and intriguing finding. Previous studies of AD mutations have generated extremely valuable knowledge about the disease processes, giving hope for future treatments, and we now have confidence to extend this knowledge.