Onset Alzheimer's Disease Cases Research Articles

Transmembrane and coiled-coil 2 associates with Alzheimer's disease pathology in the human brain.

Transmembrane and coiled-coil 2 (TMCC2) is a human orthologue of the Drosophila gene dementin, mutant alleles of which cause neurodegeneration with features of Alzheimer's disease (AD). TMCC2 and Dementin further have an evolutionarily conserved interaction with the amyloid protein precursor (APP), a protein central to AD pathogenesis. To investigate if human TMCC2 might also participate in mechanisms of neurodegeneration, we examined TMCC2 expression in late onset AD human brain and age-matched controls, familial AD cases bearing a mutation in APP Val717, and Down syndrome AD. Consistent with previous observations of complex formation between TMCC2 and APP in the rat brain, the dual immunocytochemistry of control human temporal cortex showed highly similar distributions of TMCC2 and APP. In late onset AD cases stratified by APOE genotype, TMCC2 immunoreactivity was associated with dense core senile plaques and adjacent neuronal dystrophies, but not with Aβ surrounding the core, diffuse Aβ plaques or tauopathy. In Down syndrome AD, we observed in addition TMCC2-immunoreactive and methoxy-X04-positive pathological features that were morphologically distinct from those seen in the late onset and familial AD cases, suggesting enhanced pathological alteration of TMCC2 in Down syndrome AD. At the protein level, western blots of human brain extracts revealed that human brain-derived TMCC2 exists as at least three isoforms, the relative abundance of which varied between the temporal gyrus and cerebellum and was influenced by APOE and/or dementia status. Our findings thus implicate human TMCC2 in AD via its interactions with APP, its association with dense core plaques, as well as its alteration in Down syndrome AD.

Mini-review: Role of the PI3K/Akt pathway and tyrosine phosphatases in Alzheimer's disease susceptibility.

A variety of findings from in vitro experiments and animal models support the hypothesis that one contribution to pathogenesis in Alzheimer's disease (AD) is enhanced phosphorylation of tau protein, which may be triggered by amyloid β (Aβ) and mediated by impaired activity of the PI3K/Akt signaling pathway. A number of tyrosine phosphatases act to reduce PI3K/Akt activity, and inhibition of tyrosine phosphatases is protective against Aβ toxicity in cell cultures and whole animals. Results from analysis of exome sequenced late onset AD cases and controls similarly show that rare coding variants predicted to damage PI3K functioning increase AD risk, whereas those which are predicted to damage genes for tyrosine phosphatase genes are protective. Taken together, these results support the proposition that tyrosine phosphatase antagonists might be trialed as therapeutic agents to protect against the development of AD.

Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

IntroductionThere is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C. MethodsTen single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger. ResultsBased on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7). DiscussionOur study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.

NOVEL CANDIDATE VARIANTS IN LOAD DETECTED BY THE FAMILIAL ALZHEIMER SEQUENCING (FASE) PROJECT

Recent studies suggest that the missing heritability in Alzheimer disease (AD) may lie under the cumulative effect of rare variants that cause functional changes. Families enriched in AD cases are a powerful source for detecting novel variants that may confer risk towards disease. In this work we analyze a highly selected cohort of 493 multigenerational families enriched in late onset AD cases for the identification of novel variants and genes implicated on AD. We have performed whole-exome or whole-genome sequencing on 1,077 clinically diagnosed LOAD and 440 non-demented relatives. All samples were recruited by the Knight ADRC or the NIA-LOAD family study group. Variant discovery was performed following GATK's best practice followed by stringent quality control. We focused our analysis on nonsynonymous variants with a minor allele frequency <1% in the general population (ExAC). We perform genome-wide scans to examine the presence of causative and low frequency coding variants in the most common neurodegenerative diseases, as well as in novel candidate genes. Known pathogenic mutations were found in 4.42% of the families as well as an enrichment of non-synonymous variants in AD and frontotemporal lobular dementia (FTLD) genes. We have detected potential risk variants that present perfect segregation in several families of 7 members in addition to few novel candidate genes with genome-wide significance associated to disease risk. Known pathogenic and low frequency coding variants in AD, FTD and PD genes can be found in clinical AD cases; indicating that more stringent selecting criteria and genetic testing must be performed before incorporating new samples into analysis. We have identified some preliminary candidate variants and genes that would confer risk to AD; network analysis and replication are underway.

COLLECTION OF MULTIPLEX FAMILIES WITH UNEXPLAINED EARLY-ONSET ALZHEIMER’S DISEASE FOR GENOMIC RESEARCH

The ongoing genomic studies of Alzheimer's disease (AD) primarily focus on non-Hispanic White participants affected by late-onset AD or the study of early onset AD cases from families showing Mendelian inheritance associated with mutations in APP, PSEN1 and PSEN2. However, mutations in these three genes explain only ∼10% of EOAD cases, and among mutation carriers age at onset (AAO) is often highly variable. There are no concerted large-scale efforts to collect and study the remaining 90% of EOAD cases “unexplained” by known mutations in APP, PSEN1, and PSEN2. Our current sample exists of 85 multiplex Caribbean Hispanic and 22 non-Hispanic White families without known EOAD mutations and at least 2 EOAD cases per family recruited through the EFIGA and CAP efforts. EOAD was defined as age of onset (age at first symptom or diagnosis) before the age of 65. Our overall goal is to build up a larger resource of ”unexplained” EOAD families for genomic analyses by extension of the existing and recruitment of additional multiplex EOAD families. In the 85 Caribbean Hispanic families, 979 individuals were sampled, out of these 62.3% are women, 505 individuals are free of dementia and 200 have EOAD (mean AAO: 56.8±7.5); 101 of these cases have an onset < 60 years. 60.5% of the affecteds and 43.3% of the unaffecteds are carriers of an APOEe4 allele. In the 22 non-Hispanic White families, over 120 EOAD cases and controls were sampled. Of these 57.5% are women, 68 are free of dementia, and 52 have EOAD (mean AAO: 53.2±6.2). Of those, 42 have onset under age 60. Additional late-onset AD cases are available for these families. The slight difference in mean age of onset in EOAD cases between the two cohorts is likely explained by differences in ascertainment (ie. age at first symptom or diagnosis). Building up a larger resource of ”unexplained” EOAD families for genomic analyses will fill a critical gap in AD research, can help identify novel variants not detectable by the ongoing efforts and allows to examine the role of variants discovered in LOAD datasets in samples with earlier onset.

Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease

Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimer's disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease.

Commentary on “Perspective on race and ethnicity in Alzheimer's disease research”

There are persistent disparities in Alzheimer's disease by race and ethnicity that are not well understood. The emphasis given to seeking a genetic basis for racial differences might be a distraction from the more relevant issue of identifying preventable causes of Alzheimer's disease. The majority of Alzheimer's disease cases are diagnosed as the late onset type and are unlikely to be inherited. Late onset Alzheimer's disease cases, therefore, more likely represent variations in gene expression than gene frequency. Although conceptual and methodologic problems have limited our understanding of this relationship, race-based studies provide important opportunities to understand the environmental factors associated with gene expression. Improving our understanding of the factors associated with race and ethnicity might help to clarify the epidemiology and course of Alzheimer's disease.

Novel ‘inflammatory plaque’ pathology in presenilin‐1 Alzheimer's disease

Inflammation, in the form of reactive astrocytes and microglia, is thought to play an important role in Alzheimer's disease (AD) pathogenesis where it correlates with brain atrophy and disease severity. The Abeta protein, which comprises senile plaques, is thought to be responsible for initiating this inflammatory response. Despite having a more aggressive disease process and greater Abeta deposition, few studies have investigated inflammation in early onset AD cases with mutations in the presenilin-1 (PS-1) gene. In fact, many researchers place importance on a variant plaque pathology in PS-1 cases, known as cotton wool plaques, which lack significant inflammatory infiltrate. We investigated the association between inflammation and plaque pathology in PS-1 AD. Classic cored, cotton wool and diffuse Abeta plaques were observed in all cases. PS-1 cases also exhibited a novel plaque pathology with a significantly greater inflammatory response in the form of reactive microglia and astrocytes. These 'inflammatory plaques' consisted of a dense cresyl violet-, silver-, and thioflavin S-positive, but Abeta-, tau-, apolipoprotein E (ApoE)-, non-Abeta component of Alzheimer's disease amyloid (NAC)- and PS-1-negative core. These findings indicate potent stimulator(s) of inflammation that are not typical of the Abeta that accumulates in the pathological hallmarks of sporadic AD. Identification of this substance may be important for the development of future therapeutic strategies.

Further evidence for role of a promoter variant in the TNFRSF6 gene in Alzheimer disease.

The tumor necrosis factor receptor superfamily, member 6 gene (TNFRSF6) is situated on chromosome 10q, near the region indicated in several AD linkage studies. In a previous study a significant association was found between a promoter variant within the TNFRSF6 gene and Alzheimer disease (AD). To further investigate the TNFRSF6 region, 34 SNPs within 180 kb were first genotyped in an exploratory set of 121 early-onset dementia cases and 152 controls in order to establish the extent of linkage disequilibrium (LD) and the major haplotypes in the region. This analysis showed that the LD was clustered in two large blocks within each of which a limited number of haplotypes represented most of the diversity. Haplotype tagging markers were chosen and genotyped in an additional 204 late onset AD cases and 177 controls. Tests of association were performed for single markers for case/control status and for a quantitative measure of cognitive ability [Mini-Mental State Examination (MMSE) scores] within cases only. The previously associated marker, located in the promoter of TNFRSF6, now gave significant association with cognitive status in the Scottish early-onset dementia samples (p = 0.005) with the strongest signals being evident in the APOE-e4 carrier subgroup, thus providing a second independent positive result for this marker. The same marker was also significantly associated with cognitive performance in the Swedish APOE-e4 carriers (p = 0.014), providing a third independent signal. Association analysis was also performed using the major haplotypes in the region, employing both case/control status and MMSE scores. The haplotype analysis did not give further significant findings. These results together with previous data suggest that a promoter marker in TNFRSF6 plays a moderate but demonstrable role in AD etiology.

Genetic association of anLBP-1c/CP2/LSFgene polymorphism with late onset Alzheimer's disease

OBJECTIVESThe only locus unequivocally associated with late onset Alzheimer's disease (AD) risk is APOE. However, this locus accounts for less than half the genetic variance. A recent study suggested that...

Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer's disease in Northern Ireland.

alpha1-antichymotrypsin (AACT) is a serine protease inhibitor that has been associated with amyloid plaques in the brains of patients with Alzheimer's disease (AD). It has been reported that AACT serum levels are higher in AD patients than in age and sex matched controls. In addition, polymorphisms in the signal peptide and 5' of the AACT gene have been reported to increase the risk of developing AD. Serum AACT has also been suggested to be associated with cognitive decline in elderly subjects. Our objective was to investigate whether a relationship existed between serum AACT levels, AACT genotypes and risk for AD in a case control association study using 108 clinically well defined late onset AD cases and 108 age and sex matched controls from Northern Ireland. We also wished to determine whether higher serum AACT affected levels of cognition as had been previously reported. Serum AACT levels were found to be significantly raised in cases compared to controls (t=3.8, df=209, p<0.001). However, we detected no relationship between serum AACT levels and cognitive decline. We report allelic association of the AACT signal polymorphism with AD (chi(2)=3.70, df=1, p=0.04) but we failed to show any correlation between AACT serum levels and genotype.

De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group.

The presenilin 1 (PS1) gene, located on chromosome 14, is the major gene involved in the autosomal dominant forms of early onset Alzheimer's disease (AD). In order to estimate the...

Alteration in Brain Presenilin 1 mRNA Expression in Early Onset Familial Alzheimer's Disease

The expression of the presenilin 1 (PS–1) gene has been investigated by in situhybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14–linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. The in situhybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS–1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5′end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.