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 Aß 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 Aß staining. CONCLUSIONS: CRP gene variation affects early SP development in prodromal Alzheimer's disease, independent of APOE genotype.

Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age.

OBJECTIVE: To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community-dwelling normal population. METHODS: This neuropathological study used both silver staining and A beta immunohistochemistry in brain tissue microarrays, including SP coverage and NFT counts from frontal cortex and hippocampus, and APOE genotyping, and was performed on a consecutive prospective series of 603 subjects (aged between 0 and 97 years) of an unselected population living outside of institutions. Cases were subjected to autopsy following sudden or unexpected out-of-hospital death, covering 22.1% of the mortality of Tampere, Finland and its surroundings. None died of AD, although 22 (3.7%) were demented and 10 (1.7%) had memory problems. RESULTS: Of the series, 30.8% had SP, and 42.1% had NFT; these occurred more commonly among females and showed a strong relationship with age. Both changes had already appeared at around 30 years of age, reaching an occurrence of almost 100% in the oldest. SP were more frequent in APOE epsilon 4-carriers compared with noncarriers in every age group except the oldest (>90 years). The difference was most evident during the ages 50 to 59 years, where 40.7% of epsilon 4-carriers had SP, compared with 8.2% in noncarriers (odds ratio, 8.39; 95% confidence interval, 2.55-27.62). The difference in NFT prevalence between APOE genotypes was not statistically significant in any age group. INTERPRETATION: The brain changes associated with AD may already begin developing early in middle age, especially among APOE epsilon 4 carriers.

Large vessel cerebral atherosclerosis is not in direct association with neuropathological lesions of Alzheimer's disease.

INTRODUCTION: Cerebral hypoperfusion caused by large vessel atherosclerosis has been suggested to be associated with the pathogenesis of sporadic Alzheimer's disease (AD). Atherosclerosis and AD share risk factors such as age, diabetes, hypercholesterolemia, hypertension and apolipoprotein E epsilon4 (APOE epsilon4) allele. We studied the association between atherosclerosis of the circle of Willis (CW) and AD neuropathology in a large autopsy sample. METHODS: The present study comprised a consecutive autopsy series (n = 466) representing noninstitutionalized general population aged 50 years and over (mean 70.8, SD 11.5 years). The atherosclerosis of CW was scored semiquantitatively and the amyloid plaque (AP) load in the frontal cortex and the number of neurofibrillary tangles (NFT) in the hippocampus were measured. RESULTS: In a linear regression model, AP percentage area was associated with age (p < 0.0001) and APOE epsilon4 allele (p < 0.0001), but not with CW score (p = 0.70) or gender (p = 0.11). Similarly, the NFT count was predicted only by age (p > 0.0001), and not by CW score (p = 0.36), gender (p = 0.41) or APOE epsilon4 allele (p = 0.072). CONCLUSION: Our results suggest that cerebral large vessel atherosclerosis is not in direct association with APs or NFTs - hallmarks of AD neuropathology.

Upstream transcription factor 1 (USF1) polymorphisms associate with Alzheimer's disease-related neuropathological lesions: Tampere Autopsy Study.

The apolipoprotein E (APOE) gene associates with Alzheimer's disease (AD) and cholesterol levels. Upstream transcription factor 1 (USF1) regulates lipid metabolism genes, including APOE, and the AD Aß-precursor protein. We investigated associations between 6 haplotype-tagging USF1 single-nucleotide polymorphisms (and haplotypes) and AD-related neuropathological lesions [senile plaques (SP), neurofibrillary tangles (NFT) ] in an autopsy series comprising 603 cases (ages 0-97, mean 62 years, 215 women) that died out-of-hospital. In age- and APOE-adjusted analyses, the minor G-allele of rs2774276, previously linked to elevated cholesterol, associated with late-stage burnt out SP among women and early non-neuritic SP among men. The G-allele of the previously unreported rs10908821 showed significant risk of having SP, especially neuritic and burnt out SP, among women but not men. USF1 haplotype GCGCAC carriers (risk alleles of rs2774276 and rs10908821) associated with SP risk, especially neuritic and late-stage burnt out SP, among women but not men. Younger CCGCAC carriers (risk allele of rs2774276 and protective of rs10908821) were more likely to have non-neuritic and diffuse SP. Conversely, USF1 CCGCAC haplotype carriers had lower NFT prevalence among 65+ year-olds. These results suggest USF1 has an independent but gender- and age-associated effect on AD-related brain lesion development.

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 Aß 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.