Logotyp: till Uppsala universitets webbplats

Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed.

Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD).

Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations.

Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations.

Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.