Basic Science and Pathogenesis

APOE and TMEM106B genotypes and MAPT haplotypes are established risk factors for neurodegenerative disease. There is conflicting evidence in the literature regarding the association of these risk factors with amyotrophic lateral sclerosis (ALS). We aimed to perform a systematic analysis of all three risk factors in an ALS cohort to understand their prevalence and to identify associations with disease outcomes in comparison to a broader neurodegenerative cohort.

Participants evaluated at the NIH Neurodegenerative Disorders Clinic were included in the analysis. Whole genome sequencing was performed to a mean coverage of 30x. Genome data were queried for high penetrance disease-associated variants, and the following SNPs were genotyped for MAPT haplotyping (rs8070723) and to determine APOE (rs429358 and rs7412) and TMEM106B risk allele status (rs1990622).

This preliminary analysis included 34 study participants of whom 53% were male; mean age was 64.1 years +/- 12.3. 21% of participants (n = 7) carried a diagnosis of ALS and the remaining 79% (n = 27) had non-ALS neurodegenerative disease (FTD, AD, DLB). The average CDR NACC FTLD-M sum of boxes was 5.8 +/- 6.5. One autosomal dominant pathogenic variant was identified in each group. Heterozygosity for APOE e4 was detected in 28.6% of ALS and 48.1% of non-ALS participants; 0 ALS and 11.1% of non-ALS participants were heterozygous for APOE e2. 71.4% of ALS and 81.5% of non-ALS participants harbored at least one TMEM106B risk allele. Similarly, 71.4% of ALS and 81.5% of non-ALS subjects were homozygous for the MAPT H1 haplotype.

While the differences between cohorts did not meet statistical significance (likely due to small sample sizes) the observed patterns are consistent with known associations of the risk loci. APOE e4 genetic risk was not enriched in the ALS cohort. TMEM106B-mediated risk and, unexpectedly given its association with tauopathies, MAPT H1 haplotype status were similar in both ALS and non-ALS cohorts. Future analyses will focus on increasing our sample size and defining the relationship of risk alleles to disease characteristics.