Presentation made by Rosa Rademakers on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin

1. First identification of role TMEM106B in FTD
Van Deerlin et al., Nat Genet. 2010
• GWAS in FTLD-TDP
patients with and without
mutations in GRN showed
genome-wide significant
association with 3 SNPs in
TMEM106B (Top SNP =
rs1990622)
• Unexpectedly, effect was
most pronounced in GRN
mutation carriers.
GRN +
GRN -

2. Confirmation of TMEM106B association in GRN
mutation carriers
2
Finch et al., 2011
• All studies have consistently shown that frequency of homozygous minor allele carriers of
TMEM106B SNPs is 15-20% in controls and 1-2% in GRN mutation carriers.
• This suggests that individuals with a GRN mutation need at least one TMEM106B risk
allele to develop symptoms; OR GRN mutation carriers without any TMEM106B risk alleles
are highly protected from developing FTD and may not be seen in a dementia clinic.
• TMEM106B risk allele was associated with a decrease in age at disease onset in 4 large
GRN families.
TMEM106B
Unpublished

3. • Only one coding variant (p.T185S) on the associated
haplotype; also many non-coding variants
TMEM106B variants might regulate
TMEM106B expression
TMEM106B mRNA? TMEM106B protein?
Protective TMEM106B variant associated with lower TMEM106B expression?

4. Does TMEM106B variant affect GRN levels?
• Early studies reported that TMEM106B risk allele
was associated with lower GRN levels in plasma
(Finch et al. 2011, Cruchaga et al. 2011) but effects
are small!
• In CSF samples of
healthy controls, we do
not detect effect of
TMEM106B genotypes
on GRN levels by ELISA
(n=140) (unpublished)

5. TMEM106B in non-GRN TDP-43 proteinopathies
5
19.1 7.2 8.5 16.7
Van Blitterswijk et al., 2014
Gallagher et al., 2014
• TMEM106B minor alleles protect against FTD in C9ORF72 carriers (though
not as pronounced as observed in GRN carriers)
• TMEM106B minor alleles protect against TDP-43 pathology in range of
other diseases including Alzheimer’s disease
• TMEM106B is associated with hippocampal sclerosis of aging pathology
J Neuropathol Exp Neurol,
2015