Abstract: The FTD-ALS disease spectrum is characterized by pathological aggregation of RNA-binding proteins, most prominently TDP-43 and FET family proteins (FUS and TAF15). Within frontotemporal lobar degeneration (FTLD), neuropathological subtypes are defined by the aggregated protein, and the major causal genes (MAPT, GRN, and C9orf72) align closely with these pathological entities, suggesting distinct genetic mechanisms.
To leverage this relationship, we established the international FTLD-TDP and FTLD-FET consortia and assembled large collections of neuropathologically confirmed cases for genetic and molecular studies. Genome-wide association studies in FTLD-TDP identified shared risk loci, including TNIP1 and UNC13A, together with subtype-specific loci for FTLD-TDP subtypes A, B, and C.
Human genetics further demonstrates that disease expression in FTLD is frequently modifiable. Variants in TMEM106B modify disease in GRN mutation carriers, while incomplete penetrance is increasingly recognized in C9orf72-associated disease. These observations indicate that even highly penetrant genetic drivers operate within a broader landscape of genetic risk and modifier effects that shape disease susceptibility.
We recently identified an extreme example of this genetic architecture in atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), the most common subtype of FTLD-FET, which always presents as a sporadic disease. Through GWAS and long-read genome sequencing, we discovered a tandem repeat expansion within an intron of GOLGA8A as a major aFTLD-U risk factor. Long CT-dimers were most strongly associated with disease and present in nearly 60% of aFTLD-U patients.
These findings demonstrate how large-effect genetic variants can underlie apparently sporadic disease and underscore the value of neuropathological classification for defining the genetic architecture of the FTD-ALS spectrum.