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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.<\/jats:p><jats:p>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.<\/jats:p><jats:p>Multiple independent studies have now shown associations of rare variants in <jats:italic>NOTCH3<\/jats:italic>, <jats:italic>TREM2<\/jats:italic>, <jats:italic>SORL1<\/jats:italic>, <jats:italic>ABCA7<\/jats:italic>, <jats:italic>BIN1<\/jats:italic>, <jats:italic>CLU<\/jats:italic>, <jats:italic>NCK2<\/jats:italic>, <jats:italic>AKAP9<\/jats:italic>, <jats:italic>UNC5C<\/jats:italic>, <jats:italic>PLCG2,<\/jats:italic> and <jats:italic>ABI3<\/jats:italic> 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 A\u03b2 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.<\/jats:p><jats:p>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\u00a0and put us on the correct path for the development of successful drugs.<\/jats:p>","DOI":"10.1186\/s13024-021-00505-9","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T19:02:38Z","timestamp":1641754958000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Challenge accepted: uncovering the role of rare genetic variants in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"17","author":[{"given":"Marzieh","family":"Khani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Gibbons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Bras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5879-3486","authenticated-orcid":false,"given":"Rita","family":"Guerreiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,9]]},"reference":[{"key":"505_CR1","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nrg.2017.101","volume":"19","author":"NJ Timpson","year":"2018","unstructured":"Timpson NJ, Greenwood CMT, Soranzo N, Lawson DJ, Richards JB. 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