Fight Aging!

The proof of concept demonstration outlined in today's research materials is chiefly interesting as a demonstration that energy metabolism may be more important than suspected in the onset and progression of Alzheimer's disease. The brain has high energy requirements, and it was certainly thought that age-related neurodegeneration is caused in part by the negative impact on energy metabolism of a reduced supply of oxygen and nutrients to the brain alongside impaired mitochondrial function. But how big is that part, relative to other contributions? This is always the question, and the fastest way to obtain answers remains to try various forms of therapy and observe the results.

The cautions here are twofold. Firstly that Alzheimer's mouse models are artificial and each model encapsulates assumptions about the driving pathology of the condition that may or may not be relevant in humans. Mouse model Alzheimer's pathology is not the human disease. Secondly, the researchers here focus on NAD+, a necessary component of mitochondrial energy metabolism that declines in availability with age. While they claim important differences in the specifics of the approach taken, increasing NAD+ levels via vitamin B3 derivatives and a few other methodologies has in the past performed poorly in clinical trials for a range of conditions. So on the one hand the data in mice presented here is quite good, and may indeed say something important about energy metabolism in the aging brain, but on the other both the approach taken and the models used come with caveats.

New Study Shows Alzheimer's Disease Can Be Reversed in Animal Models to Achieve Full Neurological Recovery, Not Just Prevented or Slowed

Researchers have shown that the brain's failure to maintain normal levels of a central cellular energy molecule, NAD+, is a major driver of Alzheimer's disease (AD), and that maintaining proper NAD+ balance can prevent and even reverse the disease. NAD+ levels decline naturally across the body, including the brain, as people age. Without proper NAD+ balance, cells eventually become unable to execute critical processes required for proper functioning and survival. In this study, the team showed that the decline in NAD+ is even more severe in the brains of people with AD, and that this also occurs in mouse models of the disease.

After finding that NAD+ levels in the brain declined precipitously in both human and mouse AD, the research team tested whether preventing the loss of brain NAD+ balance before disease onset, or restoring brain NAD+ balance after significant disease progression, could prevent or reverse AD, respectively, using a well-characterized pharmacologic agent known as P7C3-A20.

Not only did preserving NAD+ balance protect mice from developing AD, but delayed treatment in mice with advanced disease also enabled the brain to fix the major pathological events of AD. Moreover, both lines of mice fully recovered cognitive function. This was accompanied by normalized blood levels of phosphorylated tau 217, a recently approved clinical biomarker of AD in people, providing confirmation of disease reversal and highlighting a potential biomarker for future clinical trials.

Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain

Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD+) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217.

P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD+ homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD+ homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.