Guo MH, Lee WP, Vardarajan B, Schellenberg GD, Phillips-Cremins JE.
Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease.
Nat Commun. 2025 Jan 28;16(1):1126.
PubMed.
To some extent, repeat expansions have been the dark matter of human disease. They are generally missed by SNP arrays and by short-read sequencing technologies and it is only with long-read sequencing we can see them and also appreciate their high mutation rates and perhaps appreciate also their roles as risk loci. What is not yet clear is what pathologies they are associated with: Is it plaque and tangle disease or (like C9orf72 and PGRN genes) is it more with TDP-43 pathology?
This study examined the relationship between short tandem repeat (STR) expansions, a frequently overlooked type of genetic variation, and the risk of AD. While one STR was significantly associated with AD risk, its association could be almost fully accounted for by the APOE-e4 genotype. This lack of single STR association is likely explained by a lack of power due to small sample size (~ 1,500 cases and 1,500 controls).
However, aggregating all STRs into a burden test yielded exciting results. Individuals with more than 30 STR expansions had more than a three-fold risk of AD. An odds ratio of this magnitude is similar to that of the largest genetic effect for late-onset AD, namely APOE4. Current odds-ratio GWAS estimates of this locus range between 2-5. Reassuringly, and in contrast to the single STR association, the authors show this STR burden effect is independent of APOE4.
It remains unclear how well common-variant, SNP-based GWASs tag STR expansions. If SNPs tag STR expansions well, then they would be unable to explain much of the missing heritability, which is part of the study's motivation. To address this, an analysis that adjusts the STR burden effect for a polygenic risk score (PRS), or an analysis that includes both scores, should be performed.
Nevertheless, this is an important study examining the association of non-SNP genetic variation with AD risk. In the future, such studies may combine several types of genetic variation (SNPs, copy number variations, STRs) across the full frequency spectrum.
The paper presents evidence that genetic variation in the form of short tandem repeats may explain a proportion of Alzheimer’s disease heritability so far not accounted for by single nucleotide associations. This is an important observation and one which needs further investigation in the field.
There are major advantages in identifying STRs as they are more likely to have direct functional effects. Identifying their disease-relevant effects is more tractable. Furthermore, the STR’s themselves offer the possibility for gene editing therapies which are already being developed for other diseases with similar causal pathways.
Further, larger scale studies must now be considered to capture specific disease-associated STRs to aid our understanding and support future therapeutic advances.
We commend the recent advancements in understanding the role of expanded repeat sequences in Alzheimer's disease (AD) risk, as highlighted by the studies from the University of Pennsylvania and the University of Florida. These findings align with our ongoing research into the impact of intermediate-length CAG repeat expansions, particularly within the huntingtin (HTT) gene, on neurodegenerative diseases.
In our 2019 study, we observed a significantly higher frequency of HTT intermediate alleles (IAs) in AD patients (6.03 percent) compared to healthy controls (2.9 percent), suggesting a potential role for these alleles in AD pathogenesis (Menéndez-González et al., 2019). Further, our 2020 research expanded this investigation to include intermediate repeats in the ATXN1 and ATXN2 genes. We found an increased frequency of ATXN2 IAs in AD cases (4.1 percent vs. 1.8 percent in controls) and a notable association of HTT and ATXN1 IAs with progressive nonfluent aphasia, a subtype of frontotemporal dementia (Rosas et al., 2020).
Building upon these findings, our most recent study focused on the caudate nucleus, a region susceptible to HTT CAG expansions. We discovered that HTT IAs in late-onset AD patients are associated with altered microRNA profiles, leading to dysregulation of gene expression. This dysregulation affects key components of the spliceosome, resulting in an increased presence of the tau 3R isoform and a higher number of ghost tangles, potentially accelerating disease progression. These insights underscore the importance of genetic screening for HTT alleles in clinical practice to enable more accurate classification and personalized therapeutic interventions for AD patients (CastillaSilgado et al., 2025).
Collectively, these studies emphasize the significance of intermediate repeat expansions in neurodegenerative diseases. We encourage continued research in this area to deepen our understanding of these associations, which hold promise for advancing both research and clinical practices in neurodegenerative disorders.
References:
Menéndez-González M, Clarimón J, Rosas-Allende I, Blázquez M, San Martín ES, García-Fernández C, Lleó A, Dols-Icardo O, Illán-Gala I, Morís G, Ribacoba R, Álvarez V, Martínez C.
HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease.
Neurobiol Aging. 2019 Apr;76:215.e9-215.e14. Epub 2018 Nov 28
PubMed.
Rosas I, Martínez C, Clarimón J, Lleó A, Illán-Gala I, Dols-Icardo O, Borroni B, Almeida MR, van der Zee J, Van Broeckhoven C, Bruni AC, Anfossi M, Bernardi L, Maletta R, Serpente M, Galimberti D, Scarpini E, Rossi G, Caroppo P, Benussi L, Ghidoni R, Binetti G, Nacmias B, Sorbi S, Piaceri I, Bagnoli S, Antonell A, Sánchez-Valle R, De la Casa-Fages B, Grandas F, Diez-Fairen M, Pastor P, Ferrari R, Álvarez V, Menéndez-González M.
Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease.
Neurobiol Aging. 2020 Mar;87:139.e1-139.e7. Epub 2019 Nov 1
PubMed.
CastillaSilgado J, Perez-Oliveira S, Pinto-Hernandez P, Fernandez-Sanjurjo M, Corte-Torres MD, Iglesias-Gutierrez E, Menendez-Gonzalez M, Alvarez V, Tomas-Zapico C.
Synergistic impact of CAG intermediate alleles in the HTT gene and microRNA dysregulation exacerbates spliceosome impairment and accelerates Tau pathology in the caudate nucleus of late-onset Alzheimer's disease.
2025 Jan 19 10.1101/2025.01.19.25320764
(version 1)
medRxiv.
Comments
Institute of Neurology, UCL
To some extent, repeat expansions have been the dark matter of human disease. They are generally missed by SNP arrays and by short-read sequencing technologies and it is only with long-read sequencing we can see them and also appreciate their high mutation rates and perhaps appreciate also their roles as risk loci. What is not yet clear is what pathologies they are associated with: Is it plaque and tangle disease or (like C9orf72 and PGRN genes) is it more with TDP-43 pathology?
View all comments by John HardyVrije Universiteit Amsterdam
This study examined the relationship between short tandem repeat (STR) expansions, a frequently overlooked type of genetic variation, and the risk of AD. While one STR was significantly associated with AD risk, its association could be almost fully accounted for by the APOE-e4 genotype. This lack of single STR association is likely explained by a lack of power due to small sample size (~ 1,500 cases and 1,500 controls).
However, aggregating all STRs into a burden test yielded exciting results. Individuals with more than 30 STR expansions had more than a three-fold risk of AD. An odds ratio of this magnitude is similar to that of the largest genetic effect for late-onset AD, namely APOE4. Current odds-ratio GWAS estimates of this locus range between 2-5. Reassuringly, and in contrast to the single STR association, the authors show this STR burden effect is independent of APOE4.
It remains unclear how well common-variant, SNP-based GWASs tag STR expansions. If SNPs tag STR expansions well, then they would be unable to explain much of the missing heritability, which is part of the study's motivation. To address this, an analysis that adjusts the STR burden effect for a polygenic risk score (PRS), or an analysis that includes both scores, should be performed.
Nevertheless, this is an important study examining the association of non-SNP genetic variation with AD risk. In the future, such studies may combine several types of genetic variation (SNPs, copy number variations, STRs) across the full frequency spectrum.
View all comments by Emil UffelmannCardiff University
Cardiff University
Cardiff University
The paper presents evidence that genetic variation in the form of short tandem repeats may explain a proportion of Alzheimer’s disease heritability so far not accounted for by single nucleotide associations. This is an important observation and one which needs further investigation in the field.
There are major advantages in identifying STRs as they are more likely to have direct functional effects. Identifying their disease-relevant effects is more tractable. Furthermore, the STR’s themselves offer the possibility for gene editing therapies which are already being developed for other diseases with similar causal pathways.
Further, larger scale studies must now be considered to capture specific disease-associated STRs to aid our understanding and support future therapeutic advances.
View all comments by Rebecca SimsHospital Universitario Central de Asturias
We commend the recent advancements in understanding the role of expanded repeat sequences in Alzheimer's disease (AD) risk, as highlighted by the studies from the University of Pennsylvania and the University of Florida. These findings align with our ongoing research into the impact of intermediate-length CAG repeat expansions, particularly within the huntingtin (HTT) gene, on neurodegenerative diseases.
In our 2019 study, we observed a significantly higher frequency of HTT intermediate alleles (IAs) in AD patients (6.03 percent) compared to healthy controls (2.9 percent), suggesting a potential role for these alleles in AD pathogenesis (Menéndez-González et al., 2019). Further, our 2020 research expanded this investigation to include intermediate repeats in the ATXN1 and ATXN2 genes. We found an increased frequency of ATXN2 IAs in AD cases (4.1 percent vs. 1.8 percent in controls) and a notable association of HTT and ATXN1 IAs with progressive nonfluent aphasia, a subtype of frontotemporal dementia (Rosas et al., 2020).
Building upon these findings, our most recent study focused on the caudate nucleus, a region susceptible to HTT CAG expansions. We discovered that HTT IAs in late-onset AD patients are associated with altered microRNA profiles, leading to dysregulation of gene expression. This dysregulation affects key components of the spliceosome, resulting in an increased presence of the tau 3R isoform and a higher number of ghost tangles, potentially accelerating disease progression. These insights underscore the importance of genetic screening for HTT alleles in clinical practice to enable more accurate classification and personalized therapeutic interventions for AD patients (CastillaSilgado et al., 2025).
Collectively, these studies emphasize the significance of intermediate repeat expansions in neurodegenerative diseases. We encourage continued research in this area to deepen our understanding of these associations, which hold promise for advancing both research and clinical practices in neurodegenerative disorders.
References:
Menéndez-González M, Clarimón J, Rosas-Allende I, Blázquez M, San Martín ES, García-Fernández C, Lleó A, Dols-Icardo O, Illán-Gala I, Morís G, Ribacoba R, Álvarez V, Martínez C. HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease. Neurobiol Aging. 2019 Apr;76:215.e9-215.e14. Epub 2018 Nov 28 PubMed.
Rosas I, Martínez C, Clarimón J, Lleó A, Illán-Gala I, Dols-Icardo O, Borroni B, Almeida MR, van der Zee J, Van Broeckhoven C, Bruni AC, Anfossi M, Bernardi L, Maletta R, Serpente M, Galimberti D, Scarpini E, Rossi G, Caroppo P, Benussi L, Ghidoni R, Binetti G, Nacmias B, Sorbi S, Piaceri I, Bagnoli S, Antonell A, Sánchez-Valle R, De la Casa-Fages B, Grandas F, Diez-Fairen M, Pastor P, Ferrari R, Álvarez V, Menéndez-González M. Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease. Neurobiol Aging. 2020 Mar;87:139.e1-139.e7. Epub 2019 Nov 1 PubMed.
CastillaSilgado J, Perez-Oliveira S, Pinto-Hernandez P, Fernandez-Sanjurjo M, Corte-Torres MD, Iglesias-Gutierrez E, Menendez-Gonzalez M, Alvarez V, Tomas-Zapico C. Synergistic impact of CAG intermediate alleles in the HTT gene and microRNA dysregulation exacerbates spliceosome impairment and accelerates Tau pathology in the caudate nucleus of late-onset Alzheimer's disease. 2025 Jan 19 10.1101/2025.01.19.25320764 (version 1) medRxiv.
View all comments by Manuel Menendez-GonzalezMake a Comment
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