Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found.
We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles.
Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases.
Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently, there are no approved drugs for blast brain injury.
Exendin-4 (Ex-4), administered subcutaneously, was evaluated as a pretreatment (48 hours) and postinjury treatment (2 hours) on neurodegeneration, behaviors, and gene expressions in a murine open field model of blast injury.
B-TBI induced neurodegeneration, changes in cognition, and genes expressions linked to dementia disorders. Ex-4, administered preinjury or postinjury, ameliorated B-TBI–induced neurodegeneration at 72 hours, memory deficits from days 7–14, and attenuated genes regulated by blast at day 14 postinjury.
The present data suggest shared pathologic processes between concussive and B-TBI, with end points amenable to beneficial therapeutic manipulation by Ex-4. B-TBI–induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiologic studies of Barnes et al. who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.
The Global Alzheimer's Association Interactive Network (GAAIN) is consolidating the efforts of independent Alzheimer's disease data repositories around the world with the goals of revealing more insights into the causes of Alzheimer's disease, improving treatments, and designing preventative measures that delay the onset of physical symptoms.
We developed a system for federating these repositories that is reliant on the tenets that (1) its participants require incentives to join, (2) joining the network is not disruptive to existing repository systems, and (3) the data ownership rights of its members are protected.
We are currently in various phases of recruitment with over 55 data repositories in North America, Europe, Asia, and Australia and can presently query >250,000 subjects using GAAIN's search interfaces.
GAAIN's data sharing philosophy, which guided our architectural choices, is conducive to motivating membership in a voluntary data sharing network.
Cerebrospinal fluid (CSF) amyloid-β 1–42 (Aβ42) is an important biomarker for Alzheimer's disease, both in diagnostics and to monitor disease-modifying therapies. However, there is a great need for standardization of methods used for quantification. To overcome problems associated with immunoassays, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a critical orthogonal alternative.
We compared results for CSF Aβ42 quantification in a round robin study performed in four laboratories using similar sample preparation methods and LC-MS instrumentation.
The LC-MS results showed excellent correlation between laboratories (r2 >0.98), high analytical precision, and good correlation with enzyme-linked immunosorbent assay (r2 >0.85). The use of a common reference sample further decreased interlaboratory variation.
Our results indicate that LC-MS is suitable for absolute quantification of Aβ42 in CSF and highlight the importance of developing a certified reference material.
The success rate of the pharmaceutical research and development (R&D) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK-based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal-to-noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end-point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.