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We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 5.65 × 10−8, OR = 3.21, 95% CI = 2.11–4.88), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05–3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer’s disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer’s disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer’s disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer’s disease (P = 1.29 × 10−32, OR = 4.25, 95% CI = 3.35–5.39) and dementia with Lewy bodies + intermediate Alzheimer’s disease (P = 0.0011, OR = 2.31, 95% CI = 1.40–3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43–1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Few studies have investigated primary age-related tauopathy (PART) in a population-based setting. Here, we assessed its prevalence, genetic background, comorbidities and features of cognitive decline in an unselected elderly population.The population-based Vantaa 85+ study includes all 601 inhabitants of Vantaa aged ≥ 85 years in 1991. Neuropathological assessment was possible in 301. Dementia (DSM IIIR criteria) and Mini-Mental State Examination (MMSE) scores were assessed at the baseline of the study and follow-ups. PART subjects were identified according to the criteria by Crary et al and were compared with subjects with mild and severe Alzheimer's disease (AD) neuropathological changes. The effects of other neuropathologies were taken into account using multivariate and sensitivity assays. Genetic analyses included APOE genotypes and 29 polymorphisms of the MAPT 3' untranslated region (3'UTR region).The frequency of PART was 20% (n = 61/301, definite PART 5%). When PART subjects were compared with those with severe AD pathology, dementia was less common, its age at onset was higher and duration shorter. No such differences were seen when compared with those with milder AD pathology. However, both AD groups showed a steeper decline in MMSE scores in follow-ups compared with PART. APOE ε4 frequency was lower, and APOE ε2 frequency higher in the PART group compared with each AD group. The detected nominally significant associations between PART and two MAPT 3'UTR polymorphisms and haplotypes did not survive Bonferroni correction.PART is common among very elderly. PART subjects differ from individuals with AD-type changes in the pattern of cognitive decline, associated genetic and neuropathological features.

To analyze the frequencies of major genetic variants and the clinical features in Finnish patients with amyotrophic lateral sclerosis (ALS) with or without theA cohort of patients with motor neuron disease was recruited between 1993 and 2020 at the Helsinki University Hospital and 2 second-degree outpatient clinics in Helsinki. Finnish ancestry patients with ALS fulfilled the diagnosis according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined FALS-A if at least 1 first- or second-degree family member had ALS, and FALS-NP, if family members had additional neurologic or psychiatric endophenotypes.Of the 815 patients, 25% had FALS-A and 45% FALS-NP.These results provide further evidence for the short survival of

Background: C9orf72 repeat expansion (C9exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exprequires elaborative methods. Objective: Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp. Methods: We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9exp carriers among 218,792 Finns using the FinnGen database. The haplotype approach was first tested in an idiopathic normal pressure hydrocephalus (iNPH) patient cohort (European Alzheimer’s Disease DNA BioBank) containing C9exp carriers by comparing intermediate (15–30) and full-length (> 60 repeats) C9exp carriers (n = 41) to C9exp negative patients (< 15 repeats, n = 801). Results: In this analysis, rs3849942 was associated with carriership of C9exp (OR 8.44, p < 2 × 10–15), while the strongest association was found with rs139185008 (OR 39.4, p < 5 × 10–18). Unbiased analysis of rs139185008 in FinnGen showed the strongest association with FTLD (OR 4.38, 3 × 10–15) and motor neuron disease ALS (OR 5.19, 3 × 10–21). rs139185008 was the top SNP in all diseases (iNPH, FTLD, ALS), and further showed a strong association with ALS in the UK Biobank (p = 9.0 × 10–8). Conclusions: Our findings suggest that rs139185008 is a useful marker to identify potential C9exp carriers in the genotyped cohorts and biobanks originating from Finland.

The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

Objective To characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 (SOD1) p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance. Methods An index patient with autopsy-proven ALS was discovered to have the SOD1 p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data. Results Seven screened patients (1.5%) were found to carry the SOD1 heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare ANG and SPG11 mutations. One patient was compound heterozygous for SOD1 p.Ala90Val and p.Asp91Ala. Conclusions Our data suggest that the penetrance of SOD1 p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the SOD1 founder mutation.

The hexanucleotide repeat expansion in C9orf72 is a common cause of amyotrophic lateral sclerosis/frontotemporal dementia and also rarely found in other psychiatric and neurodegenerative conditions. Alleles with >30 repeats are often considered an expansion, but the pathogenic repeat length threshold is still unclear. It is also unclear whether intermediate repeat length alleles (often defined either as 7-30 or 20-30 repeats) have clinically significant effects. We determined the C9orf72 repeat length distribution in 3142 older Finns (aged 60-104 years). The longest nonexpanded allele was 45 repeats. We found 7-45 repeats in 1036/3142 (33%) individuals, 20-45 repeats in 56/3142 (1.8%), 30-45 repeats in 12/3142 (0.38%), and expansion (>45 repeats) in 6/3142 (0.19%). There was no apparent clustering of neurodegenerative or psychiatric diseases in individuals with 30-45 repeats indicating that 30-45 repeats are not pathogenic. None of the 6 expansion carriers had a diagnosis of amyotrophic lateral sclerosis/frontotemporal dementia but 4 had a diagnosis of a neurodegenerative or psychiatric disease. Intermediate length alleles (categorized as 7-45 and 20-45 repeats) did not associate with Alzheimer's disease or cognitive impairment. (C) 2019 The Author(s). Published by Elsevier Inc.

Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer’s disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer’s disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer’s disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer’s disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer’s disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer’s disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism.

ObjectiveTo test the association of distinct neuropathologic features of Alzheimer disease (AD) with risk loci identified in genome-wide association studies.MethodsVantaa 85+ is a population-based study that includes 601 participants aged ≥85 years, of which 256 were neuropathologically examined. We analyzed 29 AD risk loci in addition to APOE ε4, which was studied separately and used as a covariate. Genotyping was performed using a single nucleotide polymorphism (SNP) array (341 variants) and imputation (6,038 variants). Participants with Consortium to Establish a Registry for Alzheimer Disease (CERAD) (neuritic Aβ plaques) scores 0 (n = 65) vs score M + F (n = 171) and Braak (neurofibrillary tangle pathology) stages 0–II (n = 74) vs stages IV–VI (n = 119), and with capillary Aβ (CapAβ, n = 77) vs without (n = 179) were compared. Cerebral amyloid angiopathy (CAA) percentage was analyzed as a continuous variable.ResultsAltogether, 24 of the 29 loci were associated (at p < 0.05) with one or more AD-related neuropathologic features in either SNP array or imputation data. Fifteen loci associated with CERAD score, smallest p = 0.0002122, odds ratio (OR) 2.67 (1.58–4.49) at MEF2C locus. Fifteen loci associated with Braak stage, smallest p = 0.004372, OR 0.31 (0.14–0.69) at GAB2 locus. Twenty loci associated with CAA, smallest p = 7.17E-07, β 14.4 (8.88–20) at CR1 locus. Fifteen loci associated with CapAβ smallest p = 0.002594, OR 0.54 (0.37–0.81) at HLA-DRB1 locus. Certain loci associated with specific neuropathologic features. CASS4, CLU, and ZCWPW1 associated only with CAA, while TREM2 and HLA-DRB5 associated only with CapAβ.ConclusionsAD risk loci differ in their association with neuropathologic features, and we show for the first time distinct risk loci for CAA and CapAβ.

ObjectiveTo characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 (SOD1) p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance.MethodsAn index patient with autopsy-proven ALS was discovered to have the SOD1 p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data.ResultsSeven screened patients (1.5%) were found to carry the SOD1 heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare ANG and SPG11 mutations. One patient was compound heterozygous for SOD1 p.Ala90Val and p.Asp91Ala.ConclusionsOur data suggest that the penetrance of SOD1 p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the SOD1 founder mutation.

Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Some PLOSL-causing variants in TREM2 have also been associated with Alzheimer's disease when heterozygous. Here, we studied the PLOSLFIN TYROBP deletion that covers 4 of the gene's 5 exons. We genotyped 3220 older Finns (mean age 79, range 58-104) and found 11 deletion carriers (mean age 78, range 60-94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing Mini-Mental State Examination (MMSE) scores and diagnoses of dementia, we did not find any significant differences between TYROBP deletion carriers and noncarriers (all p-values >0.5). Neuropathological analysis of 2 deletion carriers (aged 89 and 94 years) demonstrated only minimal beta amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of cognitive impairment. (C) 2017 Elsevier Inc. All rights reserved.

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. Hermorappeumasairauksissa hermosolut vaurioituvat ja vähitellen kuolevat. Oirekuva riippuu hermoston vauriokohdista ja rappeutumisprosessin etenemisasteesta. Hermorappeumasairauksien syntyyn vaikuttavat perimä ja ympäristötekijät, mutta sairauksien tarkat syntymekanismit ovat puutteellisesti tunnettuja, ja hoitokeinoja on vielä vähän. On kuitenkin havaittu, että eri hermorappeumasairauksissa on samoja syntymekanismeja ja toisinaan myös samoja perimän muutoksia. Näin ollen eri hermorappeumasairauksien tutkimuksissa tehdyt havainnot voivat avata uusia tutkimussuuntia ja hoitomahdollisuuksia laajemminkin. Tässä väitöskirjassa tutkittiin kolmea hermorappeumasairautta ja niihin yhteydessä olevia perimän muutoksia. Amyotrofinen lateraaliskleroosi (ALS) on liikehermojen rappeumasairaus, joka johtaa etenevään halvaantumiseen ja kuolemaan. Alzheimerin tauti ja sitä muistuttava Lewyn kappale –tauti ovat väestötasolla kaksi yleisintä dementoivaa hermorappeumasairautta. Dementian lisäksi Lewyn kappale –tauti aiheuttaa usein myös Parkinsonin taudin kaltaisia liikehäiriöitä ja näköharhoja. ALS:in yleisin aiheuttaja eurooppalaisessa ja erityisesti suomalaisessa väestössä on C9orf72-geenissä oleva GGGGCC-toistojakson monistuma (ekspansio). Ensimmäisessä ja toisessa osatyössä selvitimme GGGGCC-toistojakson toistojaksomäärät yli 200 Alzheimer-potilaan, yli 700 ALS-potilaan ja yli 2000 verrokin suomalaisessa aineistossa. Osoitimme, että yleisesti monistuman toistomäärärajana pidetty 30 toistoa ei päde suomalaisessa väestössä, vaan parempi raja olisi ainakin 45 toistojaksoa. Lisäksi osoitimme, että keskipitkät alleelit eivät altista Alzheimerin taudille tai ALS:ille, jos toinen alleeli on normaalipituinen. Jos molemmat alleelit ovat keskipitkiä, niin riski sairastua ALS:iin nousee. Jos kahden keskipitkän alleelin kantajalla on toisessa alleelissa yli 21 toistojaksoa, riski sairastus ALS:iin on noin 15-kertainen. Kolmannessa osatyössä selvitimme Lewyn kappale –taudissa esiintyvien hermoston neuropatologisten muutosten (LRP, Lewy-related pathology) yleisyyttä ja etenemistapaa yli 85-vuotiaiden suomalaisten väestöpohjaisessa Vantaa85+ aineistossa. Tulosten perusteella pystyimme jakamaan LRP-muutosten etenemistavan kahdeksi eri tyypiksi. Toinen on aivojen pohjaosista ylöspäin etenevä muoto (caudo-rostral, 67% tapauksista) ja toinen on lähtöisin mantelitumakkeesta aivojen keskiosilta (amygdala-based, 32% tapauksista). Mantelitumakkeesta alkavat LRP-muutokset esiintyivät Alzheimerin taudin neuropatologisten muutosten kanssa ja liittyivät tunnettuun Alzheimerin taudin geneettiseen riskitekijään APOE ε4:ään. Sen sijaan aivojen pohjaosista alkavat LRP-muutokset (caudo-rostral) esiintyivät Alzheimer-patologiasta ja APOE ε4:stä riippumattomasti. Tulostemme perusteella Lewyn kappale -taudilla on siis todennäköisesti kaksi neuropatologisesti ja geneettisesti erilaista alatyyppiä. Neljännessä osatyössä selvitimme, miten Alzheimerin tautiin yhdistetyt 29 perimän riskilokusta liittyvät erityyppisiin Alzheimerin taudin neuropatologisiin muutoksiin. Tutkitut neuropatologiset muutokset olivat: 1. amyloidi β-peptidin kerääntyminen hermosolujen ulkopuolelle (CERAD score), 2, amyloidi β-peptidin kertyminen verisuonien seinämiin, 3. amyloidi β-peptidin kertyminen hiussuoniin ja 4. tau-proteiinin kerääntyminen hermosolujen sisään (Braak stage). Havaitsimme, että osalla Alzheimerin taudin perimän riskikohdista oli yhteys kaikkiin eri neuropatologisiin muutoksiin (esimerkiksi APOE), kun taas osalla oli yhteys vain tiettyyn neuropatologiseen muutokseen.