CLU, CR1 and PICALM genes associate with Alzheimer's-related senile plaques

Introduction APOE is the strongest risk gene for sporadic Alzheimer's disease (AD) so far. Recent genome wide association studies found links for sporadic AD with CLU and CR1 involved in Aβ clearance, and PICALM affecting intracellular trafficking. Methods We investigated the associations of senile plaques (SP) and neurofibrillary tangles (NFT) with the proposed risk genes and APOE, in the Tampere Autopsy Study (TASTY) series (603 cases), a sample of the general population (0 to 97 yrs), who died out-of-hospital. Results Age and the APOEε4 allele associated strongly with all phenotypes of SP, as expected. In age and APOEε4 adjusted analyses, compared to the most common homozygous genotype, burnt out SP were more common among carriers of the C-allele of CLU, whereas the T-allele of PICALM and C-allele of CR1 were linked with lower SP coverage. We found no significant associations between any of the genetic variants and NFT. Conclusions Marginal effects from CLU, CR1 and PICALM suggest that these genes have minimal effects on the development of AD lesions.BioMed Central Open acces

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson's disease

The dual-hit hypothesis of Parkinson's disease (PD) originally postulated that a neurotropic pathogen leads to formation of alpha-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with alpha-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.Peer reviewe

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+cohort exhibit two divergent patterns : a population-based study

Peer reviewe

CRP gene variation affects early development of Alzheimer's disease-related plaques

Introduction We used the Tampere Autopsy Study (TASTY) series (n = 603, age 0-97 yrs), representing an unselected population outside institutions, to investigate the pathogenic involvement of inflammation in Alzheimer's disease-related lesions. Methods We studied senile plaque (SP), neurofibrillary tangles (NFT) and SP phenotype associations with 6 reported haplotype tagging single nucleotide polymorphisms (SNPs) in the CRP gene. CRP and Aβ immunohistochemistry was assessed using brain tissue microarrays. Results In multivariate analyses (age- and APOE-adjusted), non-neuritic SP were associated with the high-CRP TA-genotype (3.0% prevalence) of rs3091244 and CA-genotype (10.8%) of rs3093075 compared to common genotypes. Conversely, the low-CRP C allele (39.3%) of rs2794521 reduced the risk of harbouring early non-neuritic SP, compared to the TT genotype. CRP haplotype TAGCC (high) associated with non-neuritic SP, whereas haplotype CCGCC offered protection. TT genotypes (high) of rs3091244 and rs1130864 were associated with CRP staining. There were no associations between SNPs or haplotypes and NFT. CRP staining of the hippocampal CA1/2 region correlated with Aβ staining. Conclusions CRP gene variation affects early SP development in prodromal Alzheimer's disease, independent of APOE genotype.BioMed Central Open acces

HSV presence in brains of individuals without dementia: the TASTY brain series

Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (Aβ) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had Aβ aggregations, most of those with Aβ aggregations did not have HSV present in the brain tissue

Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder

BackgroundAlcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken.MethodsAs markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates.ResultsThe majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain.ConclusionsThe present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain