Jetske van der Schaar
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Background and ObjectivesIdentifying 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.MethodsIn 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.ResultsGenetic 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.DiscussionWe 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.
Genetic testing of common and rare variants in dementia patients from a memory clinic
Dementia-related genetic testing in memory clinic
Many types of dementia have high heritability, which creates opportunities for DNA diagnostics. Clinicians sporadically test for causal genetic variants. However, in addition to causal genetic mutations, an increasing number of both common and rare risk factors are being identified, especially for Alzheimer’s disease (AD). Here, we describe and evaluate diagnostic performance of combining genetic risk factors for AD to assist memory clinic clinicians.
Methods
A retrospective analysis of 998 consecutive patients (mean age 62.1, 40.3% females, 63.3% dementia) was conducted over 2.5 years in a Dutch memory clinic. The patients underwent a complete genetic risk assessment, including whole-exome sequencing and array genotyping. We examined known pathogenic genetic variants for all dementia types and their correlation with clinical diagnoses. We evaluated a combined genetic score (GS) based on all genetic risk factors for AD - namely APOE genotypes, candidate risk rare variants in 11 genes, and a polygenic risk score (PRS) based on 82 common variants. Then, we analyzed the discriminatory characteristics of the GS.
Results
Causal pathogenic variants were rare, present in 3.4% of individuals, but genetic testing would have altered the diagnosis in over half of the carriers. Candidate rare risk variants were more common, identified in 31.6% of patients. Both APOE genotypes and the PRS were independently associated with AD, and gene-specific interaction was found between TREM2 and AD-PRS (β = -1.16, p = 0.015). Patients with a high GS were 7 times more likely receive an AD diagnosis compared to those with a low GS (p = 2.5E-07).
Conclusion
Overall, this study highlights the potential of integrating genetic risk factors into clinical practice to enhance AD diagnosis, though the improvement in diagnostic accuracy was moderate. The findings underscore the importance of genetic testing in diagnosis while also recognizing its limitations. ...
Many types of dementia have high heritability, which creates opportunities for DNA diagnostics. Clinicians sporadically test for causal genetic variants. However, in addition to causal genetic mutations, an increasing number of both common and rare risk factors are being identified, especially for Alzheimer’s disease (AD). Here, we describe and evaluate diagnostic performance of combining genetic risk factors for AD to assist memory clinic clinicians.
Methods
A retrospective analysis of 998 consecutive patients (mean age 62.1, 40.3% females, 63.3% dementia) was conducted over 2.5 years in a Dutch memory clinic. The patients underwent a complete genetic risk assessment, including whole-exome sequencing and array genotyping. We examined known pathogenic genetic variants for all dementia types and their correlation with clinical diagnoses. We evaluated a combined genetic score (GS) based on all genetic risk factors for AD - namely APOE genotypes, candidate risk rare variants in 11 genes, and a polygenic risk score (PRS) based on 82 common variants. Then, we analyzed the discriminatory characteristics of the GS.
Results
Causal pathogenic variants were rare, present in 3.4% of individuals, but genetic testing would have altered the diagnosis in over half of the carriers. Candidate rare risk variants were more common, identified in 31.6% of patients. Both APOE genotypes and the PRS were independently associated with AD, and gene-specific interaction was found between TREM2 and AD-PRS (β = -1.16, p = 0.015). Patients with a high GS were 7 times more likely receive an AD diagnosis compared to those with a low GS (p = 2.5E-07).
Conclusion
Overall, this study highlights the potential of integrating genetic risk factors into clinical practice to enhance AD diagnosis, though the improvement in diagnostic accuracy was moderate. The findings underscore the importance of genetic testing in diagnosis while also recognizing its limitations.