Genetics of neurodegeneration : phenotypic effects of C9orf72 intermediate-length alleles and the association of genetic and neuropathological features of dementia

In neurodegenerative diseases neurons gradually die leading to various symptoms based on the affected nervous region. Often memory, movements or both are affected, and the symptoms worsen over time greatly affecting the quality of life. Neurodegenerative diseases are often caused by many factors, both intrinsic and environmental. Genetics often play an important role in neurodegenerative diseases and genetic research can help to elucidate disease mechanisms. Since many neurodegenerative diseases share overlapping mechanisms, insights in one disease can elucidate the mechanisms of other diseases as well. The aim of this thesis was to study the genetics of three neurodegenerative diseases: amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and the closely related dementia with Lewy bodies (DLB). ALS is characterized by a progressive loss of voluntary movements that leads to respiratory failure. AD and DLB lead to dementia but DLB patients often also have parkinsonism and visual hallucinations. In Publication I, we determined the C9orf72 GGGGCC hexanucleotide repeat length of 3142 Finns. The C9orf72 hexanucleotide expansion is the most common cause of ALS and frontotemporal lobar degeneration (FTLD) in populations of European ancestry, but the exact pathogenic repeat length and the role of intermediate length alleles in disease is unclear. Often 30 repeats is used as the expansion threshold. We presented the distribution of C9orf72 repeat length in older individuals and found that 0.38% have 30-45 repeats. However, these individuals had no apparent accumulation of neurodegenerative or psychiatric symptoms. We found no association with intermediate repeat length alleles (7-45 or 20-45) and AD or cognitive impairment. Intermediate-length alleles with ≥20 repeats were found to be more common in Finland than elsewhere. In Publication II, we utilized the same cohorts from the first study as controls and additionally determined the repeat lengths of 750 Finnish ALS patients and additional 800 younger controls aged 18-65 years. There have been mixed results on the association of intermediate repeat length alleles with ALS so we tested the association using several thresholds: 7-45, 17-45, 21-45, 24-45 and 24-30. None of these intermediate repeats associated with ALS when only the effect of the longer allele was considered. However, carrying two copies of intermediate-length alleles was associated with ALS especially when the longer allele was over 17 repeats (p=0.002, OR 5.32, 95% CI 2.02-14.05). In Publication III, we studied the distribution of Lewy-related pathology (LRP) in the Vantaa 85+ population cohort. Our results confirmed that LRP progresses caudo-rostrally in 64% individuals with LRP, whereas a third have amygdala-based progression pattern. Moreover, the amygdala-based progression pattern was associated with AD pathology and APOE ε4. Our findings suggest that DLB should not be viewed as a single entity, but two. In Publication IV, we studied the association of previously identified genetic risk loci for AD with the different neuropathological features of AD. These features were amyloid β deposition (CERAD score), tau pathology (Braak staging), cerebral amyloid angiopathy and capillary amyloid β. We identified risk loci for every neuropathological feature including capillary amyloid β for which there were no previously identified risk loci. Our findings help to match known AD loci to neuropathological changes elucidating the role of each gene in AD pathogenesis.