This Month In Alzheimer Disease: July’s Pharmacology and Research Developments

Clinical Trial Updates

Positive Safety and Biomarker Phase 1b Results for PMN310 Mild Cognitive Impairment and Alzheimer Disease

ProMIS Neurosciences reported positive 6-month interim safety and biomarker data from a phase 1b trial of PMN310, a monoclonal antibody selectively targeting toxic amyloid-beta oligomers in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease. The randomized, double-blind, placebo-controlled study enrolled 144 patients across 3 intravenous dose cohorts (5, 10, and 20 mg/kg) for 12 months; interim analysis included 136 patients. No amyloid-related imaging abnormalities-edema (ARIA-E) occurred, even among APOE4 carriers, 11% of whom were homozygotes. Total ARIA prevalence was 4.4%, limited to mild, asymptomatic microhemorrhage. Most patients showed declines in plasma pTau217 (68.5%) and CSF MTBR-tau243 (62.5%) relative to expected natural-history trajectories, though investigators cautioned this does not yet confirm efficacy.

Oral Cannabinoid From MediPharm Shows Significant Reduction in Agitation in Alzheimer Disease and Dementia

The phase 2 LiBBY (Life's End Benefits of Cannabidiol and Tetrahydrocannabinol) trial met its primary endpoint, demonstrating reduced agitation in hospice-eligible patients with Alzheimer disease or other dementia treated with MediPharm Labs' oral cannabinoid formulation. The randomized, double-blind, placebo-controlled study enrolled 120 participants who received either placebo or 2 mg tetrahydrocannabinol (THC)/100 mg cannabidiol (CBD) twice daily for 12 weeks, with an optional open-label extension. At week 2, the treatment group showed a 6.27-point greater reduction in Cohen-Mansfield Agitation Inventory scores versus placebo; by week 12, the difference grew to 8.23 points, with clinician-rated global improvement reported in 87.2% of treated patients versus 23.6% of those on placebo. Overall adverse event rates were similar between groups, though serious adverse events were more frequent with treatment (23.3% vs 11.9%). No serious adverse events were considered treatment-related. The company developing the drug is reviewing next steps, including potential regulatory pathways and further clinical development.

VY1706 for Treatment of Alzheimer Disease Shows Tau Reductions and Favorable Tolerability

Voyager Therapeutics presented 6-month good laboratory practice toxicology data for VY1706, an investigational intravenous gene therapy targeting extracellular tau, at the Alzheimer's Association International Conference. In nonhuman primates, a single dose produced durable, dose-dependent reductions in microtubule-associated protein tau (MAPT) mRNA and tau protein of up to 75% across Alzheimer disease-relevant brain regions through 6 months, with no adverse clinical pathology or histopathological findings in the central nervous system, dorsal root ganglia, or peripheral organs at doses up to 5×10¹³ vg/kg. The therapy showed none of the liver transaminase elevations typical of adeno-associated virus (AAV) vectors, with roughly 30-fold lower liver biodistribution than a comparable wild-type AAV9 construct; plasma neurofilament levels remained stable, with no cellular immune activation. Alkaline phosphatase appeared to mediate blood-brain barrier transport, supporting potential cross-species translation. VY1706 is the first tau-targeted gene therapy to receive investigational new drug clearance from the FDA. Dosing in adults with early Alzheimer disease is expected to begin in the second half of 2026.

Remlifanserin for the Treatment of Alzheimer Disease Psychosis Receives FDA Fast Track Designation

The FDA granted Fast Track designation to remlifanserin, Acadia Pharmaceuticals' investigational, highly selective 5-HT2A receptor inverse agonist for hallucinations and delusions associated with Alzheimer disease psychosis. The mechanism is intended to restore excitatory/inhibitory balance without direct dopamine blockade, potentially avoiding the tolerability issues associated with atypical antipsychotics. Enrollment in the phase 2 RADIANT trial has been completed, with topline results anticipated in September or October 2026. Acadia has also begun screening and enrollment for planned phase 3 studies following the RADIANT design.

Expert Insights: Neuroinflammation, TBI, and Alzheimer Pathology

A Preventive Window In Post-TBI Care and Subsequent Alzheimer Pathology

Kirsty J. Dixon, PhD, discussed preclinical findings linking traumatic brain injury (TBI) to Alzheimer pathology through soluble tumor necrosis factor (TNF) signaling. Using a 3xTg-AD mouse model, Dixon and collaborators showed that moderate TBI produced a transient rise in BACE1, amyloid beta 42, and the apoptotic marker caspase-3, alongside deficits in learning, memory, and pain sensitivity. Selective neutralization of soluble TNF with the investigational agent XPro1595, given shortly after injury, blocked this cascade and prevented the associated cognitive and pain deficits. Dixon emphasized that post-injury inflammation appeared to drive pathology rather than merely marking it, and that cognitive and pain outcomes moved together, suggesting a shared inflammatory mechanism underlying symptoms often managed separately in clinical practice. She noted that XPro1595 already has an established human safety profile, distinguishing it from earlier-stage compounds, and that findings support moving toward human trials in patients with TBI. Outstanding questions include whether delayed post-injury treatment could match the efficacy of acute intervention, given real-world constraints on immediate access to care.

Preventing Alzheimer Disease After Brain Injury: Targeting TNF With XPro1595

Christopher J. Barnum, PhD, vice president of neuroscience at INmune Bio, discussed the same preclinical dataset from a drug-development perspective. He explained that XPro1595 selectively neutralizes soluble TNF, the pro-inflammatory driver of neurodegeneration, while sparing membrane-bound TNF, which supports glial homeostasis—a distinction he contrasted with nonselective TNF inhibitors used in rheumatologic disease, which have worsened outcomes in multiple sclerosis. In the 3xTg-AD mouse model, neutralizing soluble TNF after TBI prevented the amyloid response, neuronal death, and behavioral deficits that otherwise followed injury. Barnum characterized the translational risk as unusually low, since XPro1595 already has established human safety, pharmacokinetic, and blood-brain barrier penetration data from ongoing Alzheimer disease clinical development. He noted that no approved therapy currently addresses long-term dementia risk after TBI in populations such as athletes, veterans, and accident survivors, and positioned XPro1595 as an upstream intervention distinct from later-stage anti-amyloid antibodies, with near-term relevance for post-TBI cognitive and pain outcomes independent of long-term dementia risk.

Targeting APOE4: A Promising Therapeutic Strategy for Alzheimer Disease

Following his presentation at the SLEEP 2026 Annual Meeting, Tri Doan, MD, PhD, discussed research on APOE4-driven sleep circuit impairment in Alzheimer disease models. In APP/PS1 mice, co-expression of APOE4 accelerated and intensified deficits in non-REM slow-wave sleep compared with APP/PS1 mice lacking the gene, potentially explaining why APOE4 carriers develop dementia earlier. Doan hypothesized that APOE4 may accelerate neuroinflammation and soluble amyloid-beta production, which in turn provokes sleep disturbance in a bidirectional cycle with disease progression. Treatment with CN-105, an apolipoprotein E-mimetic peptide, rescued sleep impairments in APOE4-expressing mice; separately, Doan's group previously showed that zolpidem improved sleep duration and slowed amyloid plaque accumulation in APP/PS1 mice. He noted that slow-wave deficits preceded measurable plaque accumulation, underscoring sleep as an early and potentially modifiable target. Doan added that sleep disruption in Alzheimer disease may also contribute to comorbid anxiety and mood symptoms, and that CN-105 is currently under clinical investigation, with hope for eventual use alongside anti-amyloid therapies in APOE4 carriers.

Emerging Therapeutic Strategies

Classic Drug, New Target: Lithium as Disease-Modifying in Alzheimer Dementia

Laura Nisenbaum, PhD, executive director of drug development at the Alzheimer's Drug Discovery Foundation, discussed a narrative review synthesizing more than 20 years of preclinical, neuroimaging, epidemiologic, and early clinical trial data supporting further study of lithium as a disease-modifying therapy in Alzheimer disease. Unlike many investigational candidates, lithium carries decades of clinical familiarity, with well-established dosing, safety, and monitoring parameters, though Nisenbaum stressed the review does not support routine dementia prescribing. Lithium's proposed multi-target biological profile—spanning protein clearance, mitochondrial function, and tau pathology—was highlighted as a potentially meaningful departure from single-pathway drug candidates, given Alzheimer disease's multifactorial nature. Nisenbaum called for a biomarker-guided randomized trial in patients with mild cognitive impairment to determine whether lithium modifies underlying disease biology rather than transiently stabilizing cognitive scores. She noted most prior studies used lithium carbonate, while a 2025 study in Nature suggested lithium orotate may have distinct, potentially more favorable preclinical properties, though it remains far less studied in patients. That same research raised the possibility that endogenous lithium deficiency could be an early event in Alzheimer pathogenesis, raising longer-term questions about prevention prior to symptom onset.