Genetic Testing in patients with Dementia: A Data-Driven Clinical Decision Tree for Memory Clinics
Authors: van der Lee Sven J. , Hulsman Marc , van Spaendonk Rosalina M.L. , van der Schaar Jetske , Dijkstra Janna I.R. , Tesi Niccoló , van Ruissen Fred , Elting Mariet W. , Reinders Marcel T. , de Rojas Itziar , Verschuuren Corien , van der Flier Wiesje M. , van Haelst Mieke M. , de Geus Christa M. , Pijnenburg Yolande A.L. , Holstege Henne H. 
Published: January 2024

AbstractImportanceIdentifying genetic causes for dementia in patients who visit a memory clinic is important for patients and family members. However, current clinical selection criteria for genetic analysis may miss carriers of pathogenic genetic variants (PGVs) in dementia-related genes.ObjectiveOptimizing the patient-selection criteria for offering genetic counselling in patients visiting memory clinics.DesignClinical cohort study at the Alzheimer Center Amsterdam, analysing patients from January 2010 to June 2012, and who participated in the Amsterdam Dementia Cohort. A 54-gene dementia panel was used to identify PGVs, class IV/V variants according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Subsequently, we formulated a novel decision tree to determine eligibility for genetic testing, allowing optimal identification of symptomatic PGV carriers. The decision tree was prospectively applied in the same memory clinic for one year (2021-2022).SettingThe Alzheimer Center Amsterdam, a specialized memory clinic in the Netherlands.ParticipantsA total of 1,138 patients visited the memory clinic (2010-2012), of whom 1,022 were genetically analysed [90%]. Of the analysed patients 413 were female [40.4%], mean [SD] age at presentation 62.1 [8.9] years. The decision tree was applied to 517 patients that visited the memory clinic between 2021-2022; 215[41.6%] female, mean [SD] age at presentation 64.1[8.5] years.ExposurenoneMain Outcome(s)Presence of a PGVs and eligibility of carriers for genetic testing based on previous and new clinical selection criteria.ResultsWe identified 34 PGV carriers, corresponding to 3.3% of all patients. Of these, 24 carriers had symptoms of dementia [n=24]. Based on previous clinical criteria, only 15 of all PGV carriers were eligible. Which was 44% of all PGV carriers [15/34] and 65% of symptomatic PGV carriers [15/24]. With the new decision tree, 22 of all PGVs were eligible 62.5% [22/34] and 91% [22/24] of all symptomatic PGV carriers were eligible. In the prospective application, 517 patients were evaluated of which 148[31%] patients were eligible for a genetic test, 103 [20%] were finally tested and 13 patients carried a PGV [2.5% of total]. There were 73% more patients with a PGV identified than anticipated.Conclusions and RelevanceOur decision tree improved the identification of patients with genetic dementias.Key PointsQuestionDo current clinical criteria for selecting dementia patients identify those with pathogenic genetic variants (PGVs) in dementia-related genes?FindingsIn a cohort study at the Alzheimer Center Amsterdam, 34 PGV carriers were identified among 1,022 patients. Previous criteria identified only 44% (15/34) of all carriers and 65% (15/24) of symptomatic carriers. A new decision tree increased this to 62.5% (22/34) and 91% (22/24), respectively. Real-life implementation improved carrier identification by 73%.MeaningOur decision tree enhances genetic dementia patient identification, offering an improved approach to identify families with familial dementia.