Genetic predisposition for developmental dyslexia in semantic variant primary progressive aphasia

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Abstract
Importance Mechanisms behind the asymmetric left-hemispheric atrophy observed in primary progressive aphasia (PPA), a neurodegenerative disorder related to either frontotemporal lobar degeneration or Alzheimer’s disease, remains a mystery. There is an increased prevalence of dyslexia in PPA patients and their relatives, especially in the logopenic variant PPA (lvPPA). This co-occurrence questions whether genetic variants associated with dyslexia are linked to selective neurodegeneration in language-associated brain regions. Objective To understand if genetic risk for dyslexia contributes to selective vulnerability in PPA, we determined whether polygenic risk scores (PRS) for dyslexia are elevated in PPA in comparison to other dementias and healthy controls. Given previous literature, we hypothesized that PRS for dyslexia is highest in individuals with lvPPA. Participants Genotyped participants from Amsterdam Dementia Cohort (ADC) diagnosed with semantic variant PPA (svPPA), non-fluent variant PPA (nfvPPA), lvPPA, right-temporal variant FTD (rtvFTD), PPA not otherwise specified (PPA NOS), behavioral variant FTD (bvFTD), Alzheimer’s dementia (AD) and dementia with Lewy bodies (DLB), in addition to controls, were included. Sex, age at blood sampling and education was collected. For each participant, PRS for dyslexia were created using genome-wide association study summary statistics on dyslexia (n = 51,800 cases and 1,087,070 controls, a study from 23andMe, Research Institute.). PRS were computed with LDpred2 and standardized. Main outcome(s) and Measure(s) Differences in PRS across diagnostic groups were assessed using linear regression models, with age, sex, education, diagnosis, and the diagnosis × sex interaction term as predictors. Since interaction term diagnosis*sex was significant, analysis was stratified for sex. Results A total of 3,407 ADC participants were included, of which n=969 controls, n=66 svPPA, n=30 nfvPPA, n=38 lvPPA, n=51 rtvFTD, n=17 PPA NOS, n=230 bvFTD, n=1750 AD and n=256 DLB cases. Within males, PRS for dyslexia were significantly higher in svPPA compared to all other diagnoses and controls (all p-values Conclusion and Relevance Our findings reveal a shared genetic basis between neurodevelopmental dyslexia and svPPA, indicating a link between developmental and neurodegenerative language disorders.

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