Genetic Testing in Patients with Dementia: A Data-Driven Clinical Decision Tree for Memory Clinics

Importance Identifying 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. Objective Optimizing the patient-selection criteria for offering genetic counselling in patients visiting memory clinics. Design Clinical 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). Setting The Alzheimer Center Amsterdam, a specialized memory clinic in the Netherlands. Participants A 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. Exposure none Main Outcome(s) Presence of a PGVs and eligibility of carriers for genetic testing based on previous and new clinical selection criteria. Results We 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 Relevance Our decision tree improved the identification of patients with genetic dementias. Question Do current clinical criteria for selecting dementia patients identify those with pathogenic genetic variants (PGVs) in dementia-related genes? Findings In 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%. Meaning Our decision tree enhances genetic dementia patient identification, offering an improved approach to identify families with familial dementia. ### Competing Interest Statement Research programs of Wiesje van der Flier have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. WF has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. All funding is paid to her institution. WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. WF is member of steering cie of NovoNordisk evoke/evoke+. All funding is paid to her institution. WF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. WF is member of the steering committee of PAVE, and Think Brain Health. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. Research programs of SvdL have been funded by Vigil Neuroscience and Prevail. All funding is paid to his institution. ### Funding Statement Funding details in the acknowledgement section of the paper. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Medisch Ethische Toetsingscommissie (METC) Amsterdam UMC I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors