Neuro News Roundup: World Alzheimer Day

In recent months, the NeurologyLive® team has been covering the news and conducting interviews with experts on the latest updates in the clinical care of individuals with dementia including Alzheimer disease (AD), frontotemporal dementia, dementia with Lewy bodies (DLB), and others.

For World Alzheimer Day — September 21, 2023 —the team has culminated some of the biggest pieces of news to offer updates on new developments in literature about AD to spread awareness on the prevention and treatment of the condition.

Click here for more coverage of the latest dementia and AD news from NeurologyLive®.

Latest Literature

Alzheimer Agent Blarcamesine Shows Significant Reduction of Amyloid-ß Biomarkers in Phase 2b/3 Trial

Newly announced findings from a follow-up analysis to the phase 2b/3 study (NCT03790709) assessing blarcamesine (Anavex Life Sciences), an investigational therapy, demonstrated a significant reduction in pathological amyloid-ß levels in plasma, as well as a significant slowing in the rate of pathological brain atrophy on MRI scans in treated patients with early AD.¹

In the study, blarcamesine-treated patients showed significant increases in validated biomarkers of amyloid-ß pathology, plasma Aβ42/40 ratio (P = .048), further demonstrating the agent’s strong antiamyloid effect. Additionally, MRI findings showed significant reduction in brain volume loss, including whole brain (P = .0005), when blarcamesine was comparedwith placebo.

The trial was a multicenter, randomized, double-blind, placebo-controlled, phase 2b/3 study that enrolled 508 participants with early symptomatic AD. The participants, recruited from 52 medical research centers and hospitals in 5 countries, were randomized to receive blarcamesine (n = 338) or placebo (n = 170) oral capsules once daily for 48 weeks. The Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) subscales were used as primary end points to assess the cognitive and functional efficacy of blarcamesine. Using a mixed model for repeated measures, all prespecified clinical end points were analyzed.

Alzheimer Agent ALZ-801 Improves Cognition, Reduces Relevant Biomarker Levels in 2-Year Analysis

Alzheon, the drug makers of ALZ-801, announced positive topline data from its phase 2 biomarker study (NCT04693520), with findings that showed significant reductions in plasma phosphorylated tau (p-tau) levels and improved cognitive scores after 2 years of treatment with the agent. Patients on ALZ-801 also demonstrated a statistically significant reduction in measures of hippocampal volume in comparison with an external control arm of matched ADNI patients, which were consistent with previously reported 12-month data.²

The open-label, single-arm phase 2 trial included 84 patients with early-stage AD who carried either 1 or 2 copies of the ε4 allele of apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively) and were treated over a 104-week period. Treatment with the agent resulted in a statistically significant 43% reduction in plasma p-tau181 (P <.009) after 52 weeks and a 31% reduction at week 104 (P <.045). Plasma amyloid-ß42 levels decreased throughout the treatment period, reaching a statistically significant 4% reduction from baseline (P <.042) at week 104, while the reduction in plasma Aß40 levels stabilized at 52 weeks at a new homeostatic level.

After 104 weeks of treatment, patients showed a statistically significant 28% reduction in hippocampal volume (P <.015) in comparison with external controls from the Alzheimer Disease Neuroimaging Initiative (ADNI). Controls from the ADNI which were matched based on APOE4 genotype, age, gender, and disease stage following FDA guidance from August 2023 on the use of real-world data and real-world evidence to support regulatory decision-making for drugs and biological products.

Performance of Simulated Real-Life Daily Functioning Test Associated With Risk of Alzheimer Disease

Recently published in the Journal of Alzheimer’s Disease, a new study showed that an older adult’s performance on a brief phone menu test was associated with AD pathologies, including amyloid and tau depositions in the brain. These preliminary findings suggest the test can detect the earliest changes in daily functioning in patients at risk of AD and could help inform prevention trials testing treatments for AD before the start of cognitive decline symptoms.³

Among 77 participants who were clinically normal, approximately under 26% of these patients showed evidence of elevated amyloid and tau in the brain regions while experiencing difficulties with challenging tasks of the daily functioning assessment. Authors noted these findings as significant since most people with AD begin with short-term memory difficulties, word-finding difficulties, and issues with sense of direction as well as have decreased motivation, depression, irritability, and anxiety.

The study examined the cross-sectional relationship between a performance-based activities of daily living test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in 77 cognitively normal older adult patients. The APT included 3 tasks an older patient may encounter on a phone menu such as a prescription refill (APT-Script), health insurance company call (APT-PCP) and a banking transaction (APT-Bank). The test asked participants to navigate an interactive voice response system for these specific tasks. In addition, the patients and their study partner completed other assessments on a variety of daily activities, which were then followed by standard cognitive testing and brain scans.

Treatment Effect of Neflamapimod Enriched When Excluding High P-Tau181 Level Patients

An additional prespecified analysis of the phase 2a AscenD-LB (NCT04001517) trial newly published in Neurology showed that patients with DLB without elevated plasma phosphorylated tau at position 181 (ptau181) levels were more responsive to neflamapimod (EIP Pharma) compared to those with such elevation. These findings suggest an association between ptau181 levels at baseline and patient response to treatment, highlighting the significance of this biomarker in clinical trials.⁴

During the 16-week treatment period, improvements in all end points were higher among neflamapimod-treated patients who were below the 2.2 pg/mL of ptau181 cutoff at baseline (below cutoff, n = 45; above cutoff, n = 40), compared with those above it. Participants below the cutoff showed significant improvement compared with placebo in an Attention Composite measure (+0.42; 95% CI, 0.07–0.78; P = .023, Cohen's d effect size = .78), the Clinical Dementia Rating Scale Sum of Boxes (-0.60; 95% CI, -1.04 to -0.06; P = .031, d = .74), the Timed Up and Go test (-3.1 sec; 95%CI, -4.7 to -1.6; P <.001, d = .74), and International Shopping List Test-Recognition (+1.4; 95% CI, 0.2–2.5, P = .024, d = 1.00).

AscenD-LB was a phase 2a double-blind, placebo-controlled, 16-week treatment study assessing neflamapimod among 91 patients with mild to moderate DLB. In the prespecified analysis and at the conclusion of the study, pretreatment plasma ptau181 levels were assessed in patients who had at least 1 on-study efficacy measure and grouped based on a cutoff of 2.2 pg/mL. Each subgroup treated with neflamapimod 40mg TID, the higher and more clinically active of 2 doses studied, had outcomes assessed using the Mixed Models for Repeated Measures.

Memory Consolidation in Epilepsy Enhanced During Sleep With Deep Brain Stimulation

In a recent study published in Nature Neuroscience, findings revealed that targeted deep-brain stimulation during a critical time in the sleep cycle was associated with improvements in memory consolidation among patients with epilepsy. These findings provide evidence to support how the brain consolidates memory during sleep and offer new clues for how deep-brain stimulation during sleep could help patients with memory disorders like AD.⁵

Among 18 patients with epilepsy assessed across 2 nights and mornings, each one performed better on the memory tests given following a night of sleep and the use of electrical stimulation in their brain compared with a night of undisturbed sleep. Notably, the key electrophysiological markers displayed the flow of information between the hippocampus and throughout the cortex, which provided evidence to support memory consolidation.

Memory consolidation during sleep was investigated via electrodes in patients with epilepsy recruited from UCLA Health. Electrodes were implanted in the patients to help with identifying the source of their seizures during their hospital stays, which typically lasted around the span of 10 days. Researchers developed a real-time closed-loop system to deliver electrical stimulation to the participants.

Prior to bedtime, participants were shown photo pairings of 25 animals and celebrities. Immediately after, they were tested on their ability to recall which celebrity was paired with which animal, and then asked again in the morning following a night of undisturbed sleep. On the second night, participants were shown 25 new animals and celebrity pairings before bedtime. They were then given targeted electrical stimulation overnight and were once again tested on their ability to recall the pairings in the morning.

REFERENCES
1. Anavex’s Phase 2b/3 Trial of Blarcamesine (ANAVEX®2-73) in Patients with Alzheimer’s Disease Shows Robust Clinical Efficacy and Slows NeurodegenerationSignificant Reduction of Amyloid Beta Biomarkers of Alzheimer’s Pathology. News Release. Anavex Life Sciences. Published September 14, 2023. Accessed September 20, 2023. https://www.anavex.com/post/anavex-sphase2b-3trialofblarcamesine-anavex-2-73-inpatientswithalzheimer-sdisease
2. Alzheon reports industry-leading biomarker, brain preservation and clinical benefits following 24 months of treatment in phase 2 trial of oral ALZ-801 (valiltramiprosate) in patients with early Alzheimer’s disease. News release. Alzheon. September 13, 2023. Accessed September 20, 2023. https://www.businesswire.com/news/home/20230913271705/en/Alzheon-Reports-Industry-Leading-Biomarker-Brain-Preservation-and-Clinical-Benefits-Following-24-Months-of-Treatment-in-Phase-2-Trial-of-Oral-ALZ-801-Valiltramiprosate-in-Patients-with-Early-Alzheimer%E2%80%99s-Disease
3. Phone Menu Test Detects Who May Be at Risk of Alzheimer’s Disease. News Release. Mass General Brigham. Published June 20, 2023. Accessed September 20, 2023. https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/phone-menu-test-detects-risk-of-alzheimers
4. CervoMed Announces Publication in Neurology® Results Showing a Blood Test at Study Entry Identified Patients Who Demonstrated Substantial Response to Neflamapimod in Dementia with Lewy Bodies. News Release. Published September 20, 2023. Accessed September 7, 2023. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-publication-neurologyr-results-showing-blood
5. Deep-brain stimulation during sleep strengthens memory. News Release. University of California, Los Angeles (UCLA), Health Sciences. Published June 1, 2023. Accessed September 20, 2023. https://www.uclahealth.org/news/deep-brain-stimulation-during-sleep-strengthens-memory