Based on our recent findings, we propose that reducing the levels of the 4R tau isoform in the endolysosomal pathway through siRNA or antisense oligonucleotides, or employing a 4R to 3R splice switching antisense oligonucleotide strategy in the early disease stages, may represent an effective therapeutic approach to mitigate autophagic defects in FTD-ALS. This evidence concerns the gene MAPT and amyotrophic lateral sclerosis.