Research Highlights from Padmaja Genesh
AZTherapies Completes Enrollment for ALZT-OP1 Trial for Early Alzheimer’s
- has completed enrollment for its Phase 3 COGNITE trial, testing the safety and efficacy of its investigational for the treatment of early (AD).
- In Alzheimer’s disease, the activation of brain immune cells such as and release excessive amounts of inflammation-causing molecules, known as , which can damage nerve cells. The accumulation of also are known to trigger this neuroinflammatory process.
- ALZT-OP1 is a two-part therapy that consists of a dry-powder inhaler containing (designated ALZT-OP1a), and an oral pill containing (designated ALZT-OP1b).
- Cromolyn is an FDA-approved therapy to treat asthma, but it was shown to halt the formation of toxic amyloid plaques. The therapy also has an anti-inflammatory effect, which is the main function of ibuprofen, the second agent in ALZT-OP1.
- The COGNITE trial (), underway in 90 clinical sites in the U.S., Canada, Australia, and certain countries in Europe, has now enrolled 620 patients, ages 55 to 79, with early Alzheimer’s disease.
AC Immune’s Anti-Tau Vaccine ACI-35.030 to Be Tested in Phase 1b/2a Trial
- is launching a Phase 1b/2a clinical trial to evaluate an investigational anti-tau vaccine called as a potential disease-modifying treatment for and other disorders characterized by the accumulation of tau protein.
- Tau proteins are necessary components of healthy brain nerve cells, but in Alzheimer’s, these proteins undergoes a chemical process called hyperphosphorylation that makes them stick together, forming the tau tangles.
- developed in collaboration with is a liposome-based vaccine consisting of a synthetic peptide antigen (a molecule capable of inducing an immune response) and a fat-made anchor. ACI-35.030 mimics the structure of the toxic tau protein to induce an anti-immune response against it.
- In preclinical studies, ACI-35.030 showed a good safety profile and high specificity for toxic forms of tau. Moreover, the vaccine triggered a potent and long-lived antibody immune response against phosphorylated tau.
- The upcoming multicenter, placebo-controlled Phase 1b/2a trial will randomize patients with to different doses of ACI-35.030.
- The main objective is to assess the vaccine’s safety and tolerability, and to test its potential to induce an immune response against the toxic form of tau protein. Additional objectives include early signs of efficacy, such as measuring the vaccine’s impact on key biomarkers linked to Alzheimer’s progression.
Chemical Compound Can Restore Neural Function in Familial Alzheimer’s, Study Finds
- Most familial Alzheimer’s cases are caused by mutations in the gene, which codes for a protein called presenilin.
- A team of researchers at Russia’s investigated a mutation in the gene called PSEN1ΔE9, found in a group of familial Alzheimer’s patients in Finland.
- The researchers investigated how the mutation affected the formation of dendritic spines, small protrusions that emerge from the dendrites (branched extensions) of neurons and where the majority of synapses occur. Synapses are the junctions between two nerve cells that allow them to communicate.
- Compared to controls (healthy) neurons, cells with the PSEN1ΔE9 mutation had significantly fewer dendritic spines and more thin spines, meaning that the area of contact between neurons was reduced.
- The mutated neurons showed increased activity of calcium “gates”, which regulate release of calcium. This in turn influences the release of chemical messengers that allow correct communication between nerve cells.
- Blocking the activity of these calcium gates with a chemical compound — called EVP4593 — partially rescued mushroom spine loss in mutated neurons and restored neural functions close to normal levels.
- However, Alzheimer’s being a multifactorial disease, other pathways also contribute to disease onset and progression, and as such selection of potential therapeutic agents may require careful analysis of underlying causes of the disease for each individual patient.
New Alzheimer's Blood Test 94% Accurate
- A new blood test to detect brain changes indicative of early Alzheimer's disease (AD) has moved one-step closer to reality and could be a "game changer" for the field.
- Researchers found that measuring the ratio of β-amyloid (Aβ) 42 and Aβ40 in blood using a high-precision assay is 94% accurate in diagnosing brain amyloidosis, using amyloid PET or CSF phosphorylated (p-tau) 181/Aβ42 as reference standards.
- The researchers found that plasma Aβ42/Aβ40 had a high correlation with amyloid PET status and CSF p-tau. The combination of plasma Aβ42/Aβ40, age, and APOE ε4 status had a very high correspondence with amyloid PET.
- Individuals with a negative amyloid PET scan at baseline and a positive plasma Aβ42/Aβ40 had a 15-fold greater risk of conversion to amyloid PET-positive compared to individuals with a negative plasma Aβ42/Aβ40.
- Conclusions Plasma Aβ42/Aβ40, especially when combined with age and APOE ε4 status, accurately diagnoses brain amyloidosis and can be used to screen cognitively normal individuals for brain amyloidosis. Individuals with a negative amyloid PET scan and positive plasma Aβ42/Aβ40 are at increased risk for converting to amyloid PET-positive. Plasma Aβ42/Aβ40 could be used in prevention trials to screen for individuals likely to be amyloid PET-positive and at risk for Alzheimer disease dementia.
- Classification of evidence This study provides Class II evidence that plasma Aβ42/Aβ40 levels accurately determine amyloid PET status in cognitively normal research participants.
Source: First published August 1, 2019 in the journal Neurology , DOI: https://doi.org/10.1212/WNL.0000000000008081
High BMI in Early-Old Age Tied to Brain Thinning in Later-Life
- Obesity in midlife has been associated with a higher risk for dementia. Yet, the underlying mechanisms behind how obesity may affect brain aging is unclear. Now, emerging evidence points to two predictors associated with brain thinning in early-old age: greater body mass index (BMI) and waist circumference, according to a study published in online edition of Neurology.
- For overweight people, every unit increase in BMI was associated with a 0.098 millimeter (mm) thinner cortex, and for obese people, a 0.207 mm thinner cortex, compared with people with normal weight. A bigger waist was also associated with a thinner cortex.
- The researchers noted the risks for obesity differed by minority groups and gender. For example, greater BMI and smaller total intracranial volume were notable among both Hispanics/Latinos and non-Hispanic blacks, but the results were not of statistical significance for the latter.
- For men, greater central obesity, which is defined by waist circumference, was related to a greater odds ratio of subclinical brain infarct, but not for women.
- They concluded further research is needed to elucidate the casual relationships between greater BMI, obesity, and greater waist circumference and reduced gray matter and to explore the associations with specific brain regions.
Blood Markers May ID People Most Likely to Gain Cognitively with Aerobic Exercise, Study Reports
- Several Phase 3 trials are testing the potential benefits of exercise in Alzheimer’s disease. However, patients’ response to exercise varies, and effective tools that can help spot those patients most likely to respond best to this therapeutic approach would be helpful.
- The Minnesota team evaluated changes in Alzheimer’s patients’ metabolites — small molecules that are produced by the cell’s metabolism and enter blood circulation — that were previously associated with cognitive performance in older adults.
- They used blood samples from the FIT-AD trial (), which is assessing the effects of a six-month, individualized and moderate-intensity cycling intervention (20-50 minutes of exercise, three times a week) on cognition and neurodegeneration in 96 people with mild-to-moderate Alzheimer’s. Patients, ages 66 and older, were assigned to either a cycling group or a low-intensity stretching/range of motion exercise group as controls. After the exercise program concluded, all were followed for another six months.
- Researchers analyzed blood samples from 26 study participants and measured the levels of 188 metabolites at the trial’s start and again after 12 months. Patients’ cognitive skills were also evaluate at the study’s beginning and end using the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog).
- From among the 188 metabolites, researchers identified two fat molecules (phospholipids called lysoPC a C18.2 and PC aa C40.6) and five amino acids (the building blocks of proteins; specifically here: isoleucine, leucine, methionine, tyrosine, and valine) whose levels were linked to changes in cognition after 12 months.
- Specifically, the team saw that higher levels of PC aa C40.6 and the five amino acids were predictors of better cognitive responses to exercise, as were lower levels of lysoPC aC 18.2.
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