Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

Abstract

The search for rare variants in Alzheimer’s disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful.Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs.Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aβ pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions.Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.

Dementia-related genetic variants in an Italian population of early-onset Alzheimer’s disease

“…We also confirmed enrichment of APOE ε4/ε4 homozygosity and rare pathogenic/likely pathogenic variants in SORL1, TREM2, and ABCA7 (Khani et al, 2022). Additionally, we found a substantial proportion of pathogenic variants in several autosomal dominant genes, causal in other dementias or previously identified as risk factors for AD, most often in patients with positive familiarity, providing evidence to the hypothesis that many different rare mutations usually detected only in a single family or in small populations could be causal in familial EOAD.…”

“…To date, four autosomal dominant AD families are known in which rare ABCA7 PTC and missense variants segregated with the disease ( Hoogmartens et al, 2021 ). Although our variants are missense, they may likely act as essential contributors to EOAD susceptibility, albeit with variable penetrance ( Khani et al, 2022 ).…”

“…Still, the genetic factors identified account only for a portion of the genetic basis of the disease. To date, only about 33% of the genetic variance in sporadic AD is accounted for by common variants, and ultra-rare, rare and low-frequency variants that typically have a more harmful impact on protein function may be significant to the ‘missing heritability’ of AD ( Khani et al, 2022 ). A proportion of 35–60% of EOAD patients have at least one affected first-degree relative ( Campion et al, 1999 ; Brickell et al, 2006 ), while in 10–15%, the inheritance is autosomal dominant.…”

Rejection of inappropriate synaptic partners mediated by transcellular FLRT2-UNC5 signaling

“…FLRT and UNC5 proteins are emerging as important contributors to many facets of brain development and disease (Ando et al, 2022; Del Toro et al, 2017; Khani et al, 2022; Klein and Pasterkamp, 2021; Murcia-Belmonte et al, 2019; Yamada et al, 2019). Thus, there has been substantial interest in understanding both the molecular mechanisms by which these proteins function as well as the specific neurodevelopmental events they control.…”

Prediction of Alzheimer’s Disease by a Novel Image-Based Representation of Gene Expression

“…In recent decades, up to 95 new risk genes have been reported [ 7 ], with many involved in cholesterol or fatty acids, metabolism ( CD36 ), or ATP-binding cassette transporter subfamily A member 7 ( ABCA7 ) [ 8 ]. In addition, different variants may display risks or protective effects [ 9 ].…”