Fight Aging!

Alzheimer's disease, and the other common age-related neurodegenerative conditions, are characterized by chronic inflammation in brain tissue. Aging in general is characterized by an increased level of constant inflammatory signaling. Numerous different mechanisms contribute to this constant inflammation, such as maladaptive reactions to mitochondrial DNA fragments released into the cytoplasm as a result of age-related mitochondrial dysfunction, and a growing burden of senescent cells that actively secrete pro-inflammatory signals. The gut microbiome changes in ways that provoke inflammation as well, and the intestinal barrier becomes leaky with age, allowing more unwanted bacteria and bacterial metabolites into the body. In the brain, clearance of metabolic waste is achieved in large part by circulation of cerebrospinal fluid and its drainage into the body via channels that atrophy or become dysfunctional with age. Reduced flow allows metabolic waste to build up in brain tissue, including the protein aggregates associated with neurodegenerative conditions - and all of this increases maladaptive inflammatory responses on the part of immune cells in the brain.

Any reasonably complete list of contributions to age-related inflammation is much longer than the few high points noted above. Comprehensively dealing with the inflammation of old age is a task that will require more than one therapy, if the objective is to remove the causes. This is perhaps why much of medical research tends to favor sabotaging inflammatory signaling or aspects of immune cell function rather than addressing causes. It is a bad long term strategy from the point of view of achieving radically better human health, but it works in the short term to get drugs approved and investors their profits. The therapy that is the subject of today's open access report on its initial clinical trial results is an example of the dominant class of approach to chronic inflammation - find a central mechanism involved in coordinating the inflammatory response, and sabotage it. Unfortunately the initial data suggests that this particular anti-inflammatory therapy may not work as well in humans as it does in mouse models of inflammatory neurodegeneration.

Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial

While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with fragment crystallizable (Fc) region-effector silencing and reduced neonatal fragment crystallizable receptor (FcRn) binding (IBC-Ab002) was engineered.

Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1 mg/kg to 30 mg/kg), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg/kg dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD.