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. 2025 Feb 25;104(4):e210273.
doi: 10.1212/WNL.0000000000210273. Epub 2025 Jan 27.

Prevalence of Pathogenic Variants and Eligibility Criteria for Genetic Testing in Patients Who Visit a Memory Clinic

Sven J Van Der Lee  1   2   3 , Marc Hulsman  1   2   3 , Rosalina Van Spaendonk  4 , Jetske Van Der Schaar  1   2   3 , Janna Dijkstra  1   2   3 , Niccoló Tesi  1   5 , Fred van Ruissen  4 , Mariet Elting  6 , Marcel Reinders  5 , Itziar De Rojas  7   8 , Corien C Verschuuren-Bemelmans  9 , Wiesje M Van Der Flier  2   3   10 , Mieke M van Haelst  6   11   12 , Christa de Geus  6 , Yolande Pijnenburg  2   3 , Henne Holstege  1   2   3
Affiliations

Prevalence of Pathogenic Variants and Eligibility Criteria for Genetic Testing in Patients Who Visit a Memory Clinic

Sven J Van Der Lee et al. Neurology. .

Abstract

Background and objectives: Identifying genetic causes of dementia in patients visiting memory clinics is important for patient care and family planning. Traditional clinical selection criteria for genetic testing may miss carriers of pathogenic variants in dementia-related genes. This study aimed identify how many carriers we are missing and to optimize criteria for selecting patients for genetic counseling in memory clinics.

Methods: In this clinical cohort study, we retrospectively genetically tested patients during 2.5 years (2010-2012) visiting the Alzheimer Center Amsterdam, a specialized memory clinic. Genetic tests consisted of a 54-gene dementia panel, focusing on Class IV/V variants per American College of Medical Genetics and Genomics guidelines, including APP duplications and the C9ORF72 repeat expansion. We determined the prevalence of pathogenic variants and propose new eligibility criteria for genetic testing in memory clinics. The eligibility criteria were prospectively applied for 1 year (2021-2022), and results were compared with the retrospective cohort.

Results: Genetic tests were retrospectively performed in in 1,022 of 1,138 patients (90%) who consecutively visited the memory clinic. Among these, 1,022 patients analyzed (mean age 62.1 ± 8.9 years; 40.4% were female), 34 pathogenic variant carriers were identified (3.3%), with 24 being symptomatic. Previous clinical criteria would have identified only 15 carriers (44% of all carriers, 65% of symptomatic carriers). The proposed criteria increased identification to 22 carriers (62.5% of all carriers, 91% of symptomatic carriers). In the prospective cohort, 148 (28.7%) of 515 patients were eligible for testing under the new criteria. Of the 90 eligible patients who consented to testing, 13 pathogenic carriers were identified, representing a 73% increase compared with the previous criteria.

Discussion: We found that patients who visit a memory clinic and carry a pathogenic genetic variant are often not eligible for genetic testing. The proposed new criteria improve the identification of patients with a genetic cause for their cognitive complaints. In systems without practical or financial barriers to genetic testing, the new criteria can enhance personalized care. In other countries where the health care systems differs and in other genetic ancestry groups, the performance of the criteria may be different.

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Conflict of interest statement

S.J. Van Der Lee, M. Hulsman, and R. Van Spaendonk report no disclosures relevant to the manuscript. J. Van Der Schaar wrote a book for a layman's audience about the personal impact of dominantly inherited AD, for which she received grants or contracts from Aegon Nederland and Alzheimer Nederland and royalties from Uitgeverij Prometheus. She is a member of the advisory board for the National Dementia Strategy of the Dutch Ministry of Health, Welfare and Sport. J. Dijkstra, N. Tesi, F. van Ruissen, M. Elting, M. Reinders, I. De Rojas, and C.C. Verschuuren-Bemelmans report no disclosures relevant to the manuscript. W.M. Van Der Flier has research programs that 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, and Combinostics; she 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; she 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; she is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc., and Eisai; all funding is paid to her institution; she participated in advisory boards of Biogen MA Inc., Roche, and Eli Lilly; she is a member of the steering committee of EVOKE/EVOKE+ (NovoNordisk); all funding is paid to her institution; she is member of the steering committee of PAVE, and Think Brain Health; she was associate editor of Alzheimer, Research & Therapy in 2020/2021; and she is an associate editor for Brain. M.M. van Haelst, C. de Geus, and Y. Pijnenburg report no disclosures relevant to the manuscript. H. Holstege received consultancy fees from Retromer Therapeutics and Muna Therapeutics; all funding is paid to her institution. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Old and Newly Proposed Clinical Practice Around Genetic Testing in Memory Clinics
The left block shows the clinical practice in most memory clinics. Eligibility criteria for genetic testing (if present) are sporadically applied to patients who visit a memory clinic. Based on current finding, we propose a different clinical workflow. In this workflow, the clinician assesses the eligibility using the proposed criteria for genetic testing for all patients at time of the initial diagnosis in the multidisciplinary meeting that precedes diagnosis in most memory clinics. Based on this assessment, the patients are eligible or not. Only patients with a strong positive family history were referred to a clinical geneticist. If this strong suspicion was not present, the neurologist could counsel and, if indicated, order the test directly or refrain from testing.
Figure 2
Figure 2. Main Results of the Analysis of the Retrospective and Prospective Cohort
Patients are eligible for testing in retrospective and prospective cohort (A), percentage of PGV carriers of all patients in retrospective and prospective cohort (B), number of PGV carriers that were eligible for genetic testing in retrospective cohort. PGV = pathogenic genetic variant.
Figure 3
Figure 3. Proposed Criteria to Determine Eligibility for Genetic Testing in a Memory Clinic Setting
The dementia gene panel consists of 54 dementia related genes, the APP duplication, and the C9ORF72 repeat expansion. First-degree relatives are parents, siblings, and children. *Means symptomatic as determined by a neuropsychological investigation. The outcomes of the criteria are numbered and correspond to the rows of Table 2. The chance to find a pathogenic variant based on the retrospective cohort is shown on the right of the figure. In addition to family history of dementia a family history of severe late-onset psychiatry, amyotrophic lateral sclerosis and Parkinson disease dementia should be considered as well. MCI = mild cognitive impairment; PPA = primary progressive aphasia; PPD = primary psychiatric diagnosis.
Figure 4
Figure 4. Results of 1-Year Prospective Implementation in Clinical Care
Green = those eligible for genetic testing. Yellow = those not eligible for genetic testing. PGV = pathogenic genetic variant; VUS = variant of unknown significance.
See this image and copyright information in PMC

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