Chapter 104
Neurodegeneration — 10
Apill treatment that has raised new hopes of success modulates the p75 neurotrophin receptor, a potent molecular switch for neuron survival and synapse integrity. In a randomized trial of over 240 participants who received placebo or two different doses of a p75 modulator, twice daily, there were no safety concerns, and, in a prespecified subgroup, the twenty-six-week treatment led to about 50 percent slowing of cognitive decline, along with favorable impact on cerebrospinal fluid biomarkers and brain imaging. We await the results of large-scale testing, but as a pill, without risk of brain edema and hemorrhages, this intervention would be highly advantageous compared with the anti-amyloid antibodies.
OTHER POTENTIAL THERAPIES
Lexeo Therapeutics has moved forward with gene therapy for participants with two copies of APOE4. Participants received a copy of APOE2, the allele that carries a decreased risk of Alzheimer’s, which was attached to a virus vector and delivered directly into their cerebrospinal fluid via lumbar puncture. Subsequently, appearance of APOE2 was detected in their cerebrospinal fluid with lowering of Tau levels, and without serious side effects. Gene therapy (adding a gene) is quite different from genome editing (modifying a gene). The success in CRISPR genome editing for sickle cell disease, β-thalassemia, and other conditions has led to introducing the rare, protective APOE variant (APOE3-R136S, Christchurch) in the mouse model of Alzheimer’s providing protection, especially notable with two APOE4 copies. Other editing targets, such as the amyloid precursor protein (APP) and presenilin-1 (PSEN1), have been approached in experimental models and cells, respectively.
Quite intriguing is a nasally delivered Tau monoclonal antibody. A single dose had a marked impact in the aged mouse tauopathy model, clearing these pathologic Tau aggregates from inside cells and improving cognitive function. These antibodies have been shown to recognize Tau in human brain tissue. Hopefully this innovation, far simpler than the current monoclonal antibody administration requiring frequent intravenous infusion, will soon move into clinical testing.
Conceptually, rejuvenation of the aged immune system (immunosenescence) to prevent Alzheimer’s disease has appeal. Proof of concept was shown in an aged mouse study with bone marrow transplantation from young mice, which substantially reduced β-amyloid burden, degenerative changes of neurons, and brain inflammation, and improved behavioral deficits. Activation of microglia, resident immune cells in the brain, would also be expected to protect against age-related brain pathologies. We’ll come back to these prospects for immune system intervention later.
The use of MRI-guided focused ultrasound to open the blood-brain barrier in combination with β-amyloid monoclonal antibodies has been tried in a limited number of patients. With just three patients treated, this became the subject of extensive coverage by the 60 Minutes television news show. With such a small number of patients treated, without controls, and lack of clear-cut clinical benefit, these came across as a sensationalized report. Other strategies are being tested to open the blood-brain barrier to promote the drug treatments.
In a small randomized trial of fifty participants with mild to moderate Alzheimer’s, repetitive transcranial magnetic stimulation appeared to modestly slow cognitive decline while the sham control group had worsening of their results. A headset that uses gamma frequency light and sound stimulation has preliminary data for slowing decline of cognitive function and preventing brain atrophy, and is now completing a larger trial for potential FDA approval.