(300 WORDS MAX)Frontotemporal dementia (FTD) is the fourth most common form of dementia, yet substantial heterogeneity still characterizes its clinical diagnosis. Family history surveys suggest FTD to be significantly heritable. While various genetic mutations have been identified which explain some of the clinical differences between FTD sub-types, much of the clinical variability remains unexplained. Based on our genetic findings in late-onset Alzheimer's disease (AD), we propose two hypotheses on the role of complex genetic biomarkers (e.g. poly-T tracts, insertion/deletions, mutations, expansions) in risk and age-of-onset of FTD. The first hypothesis is that a complex genetic polymorphism, displayed as a variable length sequence of T nucleotides in the TOMM40 gene (rs10524523), influences the age-of-onset for FTD. Indeed, our previous work has shown the pivotal role of rs10524523 in modifying the age-of-onset of the related AD pathology. The second hypothesis is that the strong association signal in the TMEM106B gene region, reported using our Duke ADRC FTD cases, is due to a complex variant which can be uniquely tested using evolutionary (phylogenetic) analyses of highly accurate sequencing data of a gene region. Application of this type of analysis to the study of human neurodegenerative diseases is a unique strength of our group. Overall, findings by us and others, indicate a functional and clinical relevance of complex genetic biomarkers that may prove relevant for FTD as well. The proposed study is innovative because no similar work has yet comprehensively investigated genetic biomarkers related to complex variants in TOMM40 and TMEM106B in well-characterized FTD cases. Completion of this work will augment FTD subtyping, potentially providing a means of enriching delay-of-onset clinical trials with subjects most likely to progress to FTD in a given time-frame, and may provide biological basis for the development of effective therapeutic approaches to delay the onset and progression of FTD.