Figure 3.

Age and haplotype correlation with TMEM106B CTF burden scores measured by immunoblotting and immunohistochemistry. (A) Age at death distribution of all study individuals, stratified by modified CTF burden score (no/mild, moderate or abundant/severe) measured by immunoblot (left) and immunohistochemistry (IHC) (right). Symbols represent different control and patient groups: diamonds are neuropathologically normal individuals, triangles are GRN mutation carriers and round dots indicate all other patient groups included in the study. The colour of the symbols indicates the TMEM106B haplotype. Horizontal dotted lines are used to indicate an age at death of 65 years, whereas full lines in each category represent the mean age at death in that group. Overall, more CTFs were detected by IHC than by immunoblot, with a larger proportion of cases presenting with abundant/severe IHC pathology as compared to immunoblot. Of note, the elderly individuals with two protective TMEM106B haplotypes (SS; highlighted by the black box) and neuropathologically normal individuals (diamond symbols), consistently showed a lower CTF burden on immunoblot as compared to IHC. In fact, of the 10 neurologically normal cases (diamonds) only the three oldest (grey arrows) had immunoblot scores greater than one. In addition, GRN mutation carriers (triangle symbols) had overall a higher burden of CTFs across both methods even in younger individuals, with all cases having abundant/severe pathology by IHC. (B and C) Immunoblot (B) and IHC (C) results of four representative Lewy-body disease cases above age at death of 65 years, carrying either two (Case 52), one (Case 53) or no (Cases 54 and 55) TMEM106B risk haplotypes (T). While immunoblot results show TMEM106B CTFs only in Cases 52 and 53, who carry at least one TMEM106B risk haplotype, IHC result shows TMEM106B pathology in all cases irrespective of TMEM106B haplotype.