Van Der Lee SJ, Hulsman M, Van Spaendonk R, Van Der Schaar J, Dijkstra J, Tesi N, van Ruissen F, Elting M, Reinders M, De Rojas I, Verschuuren-Bemelmans CC, Van Der Flier WM, van Haelst MM, de Geus C, Pijnenburg Y, Holstege H. Prevalence of Pathogenic Variants and Eligibility Criteria for Genetic Testing in Patients Who Visit a Memory Clinic. Neurology. 2025 Feb 25;104(4):e210273. Epub 2025 Jan 27 PubMed.
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UCL Institute of Prion Diseases
LMU
New Focused Referral Criteria for Dementia Gene Panel Testing Significantly Improve Detection of Pathogenic Variants
Van der Lee et al. looked into monogenetic causes of dementia at the Alzheimer Center Amsterdam and refined the criteria for genetic testing. A review of all patients who had given research consent between 2010 and 2012 showed that 3.3 percent carried a pathogenic genetic variant. When refined criteria were applied prospectively (2021–2022), the detection rate jumped from 44 percent to 76 percent. Interestingly, 53 percent of the carriers were older than 60, and 20 percent had psychiatric or subjective complaints.
While monogenic forms of dementia are relatively uncommon, they provide valuable insight. Identifying a pathogenic variant also allows for presymptomatic testing in family members, improves accuracy of diagnosis, and can affect reproductive choices amongst several possibilities. However, pinpointing the right gene isn’t straightforward due to clinical overlap and genetic complexity. This makes next-generation sequencing panels the preferred choice, sometimes supplemented by specific tests, such as repeat expansion analysis (Koriath et al., 2021). Yet, genetic testing is underused in memory clinics. Strict eligibility criteria often exclude pathogenic variant carriers, especially in cases with later onset, atypical symptoms, or unclear family histories. This highlights the need for broader, standardized testing strategies.
Van der Lee et al. analyzed patients to refine genetic testing referral criteria. In the retrospective study (2010–2012), they tested stored DNA from 1,022 patients and found 3.3 percent had pathogenic variants. Based on clinical diagnosis, age, and family history, they developed updated referral criteria. These new criteria significantly improved detection rates compared to traditional guidelines. In a prospective study (2021–2022), 515 patients consented to genetic testing, with 148 meeting eligibility criteria at diagnosis. Testing in 90 patients identified 13 pathogenic variants, leading to a genetic dementia prevalence of 2.5 percent. The improved criteria boosted detection rates from 44 to 76 percent, particularly benefiting those over 60 or presenting with psychiatric symptoms. The study suggests that in similar clinical settings, one in five patients under 70 would qualify for testing, while eligibility drops for older groups.
Our paper, Koriath et al. (Koriath et al., 2018) is the only other large-scale study to assess genetic dementia prevalence by gene panel. Our study identified pathogenic variants in 12.6 percent of cases using a 17-gene panel, but the referral criteria and patient mix were substantially different from Van der Lee, which can explain most of the difference in prevalence. Traditional testing criteria have largely focused on early onset and family history, often using complex disease-specific diagrams (Goldman, 2015; Goldman et al., 2011; Goldman et al., 2018; Barker et al., 2021; Nicolas et al., 2015; Hensman et al., 2014; Bonvicini et al., 2019). Van der Lee’s approach aligns with criteria we proposed (Koriath et al., 2021) but emphasizes age at presentation over age at onset, aiming to reduce recall bias and streamline clinical use. The study also places less weight on early onset cases, as 53 percent of identified carriers in the retrospective cohort were over 60—consistent with findings from similar research (Koriath et al., 2018; Mehta et al., 2022).
Given challenges, such as missing family history or uncertain causes of dementia in deceased relatives (Koriath et al., 2021), Van der Lee recommend prioritizing first-degree relatives for assessment. A referral to a geneticist is suggested for cases involving multigenerational cognitive complaints, amyotrophic lateral sclerosis, or late-onset psychiatric conditions (Koriath et al., 2018; Goldman et al., 2018; Bonvicini et al., 2019).
In healthcare systems where genetic testing is covered, standardized guidelines help prevent unnecessary testing while ensuring appropriate evaluations. The new criteria, which focus on age at presentation rather than age at onset, simplify family history assessments, allow for routine testing in eligible patients, and improve detection rates—particularly in those over 60—without excessive costs.
The Van der Lee et al. findings highlight how updated referral guidelines can significantly enhance diagnostic rates, particularly for individuals with later-onset symptoms who might otherwise be overlooked. The work reinforces the need for broader access to genetic testing and standardized eligibility criteria, ensuring more equitable and effective dementia diagnostics. Future research should focus on integrating and evaluating these improved strategies into routine clinical practice, maximizing their benefits for patient care and genetic counseling.
References:
Koriath CA, Kenny J, Ryan NS, Rohrer JD, Schott JM, Houlden H, Fox NC, Tabrizi SJ, Mead S. Genetic testing in dementia - utility and clinical strategies. Nat Rev Neurol. 2021 Jan;17(1):23-36. Epub 2020 Nov 9 PubMed.
Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
Goldman JS. Genetic testing and counseling in the diagnosis and management of young-onset dementias. Psychiatr Clin North Am. 2015 Jun;38(2):295-308. Epub 2015 Mar 18 PubMed.
Goldman JS, Rademakers R, Huey ED, Boxer AL, Mayeux R, Miller BL, Boeve BF. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology. 2011 Feb 1;76(5):475-83. PubMed.
Goldman JS, Van Deerlin VM. Alzheimer's Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing. Mol Diagn Ther. 2018 Oct;22(5):505-513. PubMed.
Barker MS, Manoochehri M, Rizer SJ, Appleby BS, Brushaber D, Dev SI, Devick KL, Dickerson BC, Fields JA, Foroud TM, Forsberg LK, Galasko DR, Ghoshal N, Graff-Radford NR, Grossman M, Heuer HW, Hsiung GY, Kornak J, Litvan I, Mackenzie IR, Mendez MF, Pascual B, Rankin KP, Rascovsky K, Staffaroni AM, Tartaglia MC, Weintraub S, Wong B, Boeve BF, Boxer AL, Rosen HJ, Goldman J, Huey ED, Cosentino S, ALLFTD consortium. Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia. Cortex. 2021 Jun;139:99-115. Epub 2021 Mar 19 PubMed.
Nicolas G, Wallon D, Charbonnier C, Quenez O, Rousseau S, Richard AC, Rovelet-Lecrux A, Coutant S, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Munter HM, Bourque G, Auld D, Montpetit A, Lathrop M, Guyant-Maréchal L, Martinaud O, Pariente J, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Sauvée M, Moreaud O, Gabelle A, Sellal F, Ceccaldi M, Chamard L, Blanc F, Frebourg T, Campion D, Hannequin D. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, Adamson G, Mudanohwo E, McColgan P, Haworth A, Wild EJ, Sweeney MG, Houlden H, Mead S, Tabrizi SJ. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2014 Jan 28;82(4):292-9. Epub 2013 Dec 20 PubMed.
Bonvicini C, Scassellati C, Benussi L, Di Maria E, Maj C, Ciani M, Fostinelli S, Mega A, Bocchetta M, Lanzi G, Giacopuzzi E, Ferraboli S, Pievani M, Fedi V, Defanti CA, Giliani S, Alzheimer’s Disease Neuroimaging Initiative, Frisoni GB, Ghidoni R, Gennarelli M. Next Generation Sequencing Analysis in Early Onset Dementia Patients. J Alzheimers Dis. 2019;67(1):243-256. PubMed.
Mehta PR, Iacoangeli A, Opie-Martin S, van Vugt JJ, Al Khleifat A, Bredin A, Ossher L, Andersen PM, Hardiman O, Mehta AR, Fratta P, Talbot K, Project MinE ALS Sequencing Consortium, Al-Chalabi A. The impact of age on genetic testing decisions in amyotrophic lateral sclerosis. Brain. 2022 Dec 19;145(12):4440-4447. PubMed.
UCSF
Identifying genetic causes of dementia is becoming increasingly important, as clinical trials targeting specific genetic variants are being developed and made available. Individuals carrying pathogenic variants may have treatment options that would not otherwise be accessible to them. Moreover, understanding a genetic cause for dementia can help family members assess their own risk and plan for the future, considering options such as insurance and reproductive choices.
Advancements in genetic testing technologies have made it easier for patients to access genetic testing. In fact, a buccal kit can be mailed directly to a patient’s home, and results can be shared via a simple video call with a medical provider. However, challenges remain from the provider’s perspective in identifying the best candidates for testing. Additionally, genetic counseling for families affected by dementia can be complex due to the psychosocial implications of the variants for family members.
Currently, there is limited guidance on who should be offered genetic testing. Developing clear eligibility criteria for such testing is therefore crucial. Dr. Van Der Lee and their team have proposed new genetic testing criteria for a clinical cohort at their memory clinic in Amsterdam. These criteria are better suited to identifying patients with a genetic cause for their cognitive symptoms, offering significant value to the patient population they serve.
The authors wisely note that these criteria may not be directly applicable to other countries with different genetic ancestry groups. Therefore, similar criteria must be developed independently for other populations. For instance, in the U.S., where genetic heterogeneity is significant, developing tailored criteria is essential to effectively identify individuals with hereditary dementia.
Van Der Lee and colleagues provide an excellent framework for identifying patients who may benefit from genetic testing in their region. Given the critical importance of identifying genetic causes of dementia for both treatment and family planning, this study will hopefully inspire similar research in other populations.
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