Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons. We find that truncating mutation results in SORL1 haploinsufficiency and enlarged endosomes in human neurons. Analysis of isogenic SORL1 wild-type, heterozygous, and homozygous null neurons demonstrates that, whereas SORL1 haploinsufficiency results in endosome dysfunction, complete loss of SORL1 leads to additional defects in lysosome function and autophagy. Neuronal endolysosomal dysfunction caused by loss of SORL1 is relieved by extracellular antisense oligonucleotide-mediated reduction of APP protein, demonstrating that PSEN1, APP, and SORL1 act in a common pathway regulating the endolysosome system, which becomes dysfunctional in AD.@en

BACKGROUND: Dementia in families can be caused by one genetic variant. Identifying these so-called monogenic causes of dementia is important, because it explains the origin of dementia in families and raises the possibility of predictive testing for relatives. Still, we do not know how frequent these monogenic causes are, due to strict selection criteria for DNA testing based on age at onset and a positive family history. We aimed to identify the mutation frequency of monogenetic dementia by screening a large, unselected cohort of patients from a memory clinic specialized in early onset dementia. METHOD: Between 1-1-2010 and 1-7-2012, 1,138 patients visited the Alzheimer Center Amsterdam and all patients underwent the same diagnostic trajectory (van der Flier et al 2018). Of these, 1,093 (96%) consented to research and donated blood. An additional 73 patients (7%) were excluded because suboptimal DNA quality. Whole exome sequencing and C9orf72-repeat length analysis was performed in the remaining 1,020 patients (90% of all patients). All variants in 54 dementia related genes were analysed and classified. C9orf72 repeat length >30 repeat units was considered pathogenic. Variants classified as likely pathogenic and pathogenic were considered a monogenic cause of dementia. RESULT: The average age at presentation was 62(±6SD) years and 419(41%) were female. We found a monogenic cause of dementia in 34 (3.4%) patients. The most frequently occurring (likely) pathogenic variants were found in the genes C9orf72, PSEN1, NOTCH3 and MAPT. These genes explained 65% of the (likely) pathogenic variants. The clinical characteristics of the patients screened positive; 50% were diagnosed with dementia and 50% had a first degree relative with dementia; and 40% had an age at presentation of <60 years and 44% was between 60 to 70 years, the remainder was older. Surprisingly, only 47% of the patients with a (likely) pathogenic variant fulfilled our current criteria (based on diagnosis, age and familial history) for offering diagnostic genetic testing (21% of patients). CONCLUSION: In our large unselected cohort of patients from a memory clinic specialized in early onset dementia, the majority of the patients with a monogenetic predisposition for dementia did not fulfill our current criteria for genetic testing.@en