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                <term xml:lang="en">Risk variant</term>
                <term xml:lang="en">clinical utility</term>
                <term xml:lang="en">exome</term>
                <term xml:lang="en">pathogenic variant</term>
                <term xml:lang="en">risk variant</term>
                <term xml:lang="en">Alzheimer disease</term>
                <term xml:lang="en">Clinical utility</term>
                <term xml:lang="en">Exome</term>
                <term xml:lang="en">Pathogenic variant</term>
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              <classCode scheme="mesh">Humans</classCode>
              <classCode scheme="mesh">Alzheimer Disease</classCode>
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              <classCode scheme="mesh">Presenilin-1</classCode>
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              <p>Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 &amp;lt; AOO &amp;lt; 75, n = 92).Results: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees.Conclusion: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.</p>
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