As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer’s disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3–24.2)], and VNTR length inversely correlated with amyloid β1–42 in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular—which is formed through exon 19 skipping—lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1841-z) contains supplementary material, which is available to authorized users.

Early‐onset Alzheimer's disease (EOAD) is generally known as a dominant disease due to highly penetrant pathogenic mutations in the amyloid precursor protein, presenilin 1 and 2. However, they explain only a fraction of EOAD patients (5% to 10%). Furthermore, only 10% to 15% of EOAD families present with clear autosomal dominant inheritance. Studies showed that only 35% to 60% of EOAD patients have at least one affected first‐degree relative. Parent–offspring concordance in EOAD was estimated to be <10%, indicating that full penetrant dominant alleles are not the sole players in EOAD. We aim to summarize current knowledge of rare variants underlying familial and seemingly sporadic Alzheimer's disease (AD) patients. Genetic findings indicate that in addition to the amyloid beta pathway, other pathways are of importance in AD pathophysiology. We discuss the difficulties in interpreting the influence of rare variants on disease onset and we underline the value of carefully selected ethnicity‐matched cohorts in AD genetic research.