Alzheimer's Disease and the Amyloid Cascade Hypothesis: A Critical Review

Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer's disease (AD). It proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. While there is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and (2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive. This paper provides a critical overview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions

Genetic and Vascular Risk Factors for Cognitive Decline and Cerebral Small-Vessel Disease

One of the earliest known written reports on dementia is attributed to Pythagoras in the 7th century BC, who described old age as a period of decline and decay of the human body and regression of mental capacities. In 1907, Alois Alzheimer, a german psychiatrist and scientist, observed at necropsy an overload of - at that time still unknown - amyloid plaques and neurofi brillary tangles in the brain of a 51 year old woman who had suff ered during her life course from progressive cognitive decline. Nowadays, amyloid plaques and neurofi brillary tangles are considered the main neuropathological hallmarks of Alzheimer’s disease, which is regarded the most frequent subtype of dementia. Over the past two decades evidence has been accumulating that dementia is a heterogeneous and multifactorial disorder, and that besides accumulation of beta amyloid and neurofi brillary tangles, other factors, in particular vascular risk factors and cerebrovascular disease, may be involved, especially in late-onset dementia. Observational studies reported associations between several vascular risk factors and cognitive decline and dementia. In autopsy studies, about 35% of the brains of elderly persons, who had been diagnosed with dementia during their lifetime, had not only a higher burden of amyloid plaques and neurofi brillar tangles but rather a mixed pathology also consisting of signifi cant cerebrovascular disease. Stroke has been reported to considerably increase the risk of dementia, with prevalence rates of poststroke dementia of about 30%, refl ecting a 3.6 to 5.8-fold increased risk of dementia compared to stroke-free subjects. Cerebral small-vessel disease, which is defi ned as cerebral white matter lesions and asymptomatic lacunar brain infarcts and is a common fi nding on brain scans of elderly persons, has been reported to more than double the risk of dementia

Genome-wide Association Studies in Alzheimer’s Disease: A Review

Over the past decade, research aiming to disentangle the genetic underpinnings of late-onset Alzheimer’s disease has mostly focused on the identification of common variants through genome-wide association studies. The identification of several new susceptibility genes through these efforts has reinforced the importance of amyloid precursor protein and tau metabolism in the cause of the disease and has implicated immune response, inflammation, lipid metabolism, endocytosis/intracellular trafficking, and cell migration in the cause of the disease. Ongoing and future large-scale genome-wide association studies, translational studies, and next-generation whole genome or whole exome sequencing efforts, hold the promise to map the specific causative variants in these genes, to identify several additional risk variants, including rare and structural variants, and to identify novel targets for genetic testing, prevention, and treatment

The cross of Christ in the tension between gospel and culture : interpretations of the cross within the context of Bosch's paradigm shift theory

In this research study, the correlation between culture and gospel is investigated by examining changes in the interpretation of the cross of Christ from Early Christianity up to present times, using the method of paradigmatic analysis designed by David J. Bosch. Following the concept of the Missio Dei within mission theology, this study aims to find a perspective on the event of the cross which is relevant for today's practice. With reference to the topics of cultural context, sin, sacrifice, vicariousness, cross and mission, this study shows that in every paradigm the diverse perspectives of the interpretation of Jesus' death were explicable and helpful within their relevant contexts. It can also be seen that in its objectives, message and practice, mission correlates with the respective motifs prevalent at the time. In conclusion, after determining the proper place of the results within the concept of Missio Dei in mission theology, the study examines the relevance of these results for the Missio Christi, in order to offer a contribution to the debate and a potential perspective for explaining the significance of Jesus' death in the current German-speaking cultural context.Christian Spirituality, Church History and MissiologyM. Th. (Missiology

Organic agricultural practice enhances arbuscular mycorrhizal symbiosis in correspondence to soil warming and altered precipitation patterns

Climate and agricultural practice interact to influence both crop production and soil microbes in agroecosystems. Here, we carried out a unique experiment in Central Germany to simultaneously investigate the effects of climates (ambient climate vs. future climate expected in 50–70 years), agricultural practices (conventional vs. organic farming), and their interaction on arbuscular mycorrhizal fungi (AMF) inside wheat (Triticum aestivum L.) roots. AMF communities were characterized using Illumina sequencing of 18S rRNA gene amplicons. We showed that climatic conditions and agricultural practices significantly altered total AMF community composition. Conventional farming significantly affected the AMF community and caused a decline in AMF richness. Factors shaping AMF community composition and richness at family level differed greatly among Glomeraceae, Gigasporaceae and Diversisporaceae. An interactive impact of climate and agricultural practices was detected in the community composition of Diversisporaceae. Organic farming mitigated the negative effect of future climate and promoted total AMF and Gigasporaceae richness. AMF richness was significantly linked with nutrient content of wheat grains under both agricultural practices

Impact of Genetic Variation in SORCS1 on Memory Retention

We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory.We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses.Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = -0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002<p<0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02,p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases.Variation in intron 1 in SORCS1 is associated with memory changes in AD

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease

INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations