Beyond Beta-Amyloid: Alzheimer’s and Gene Therapy

You have an idea that could benefit hundreds of millions of people, but pursuing it might kill your career.

So, you stick with the accepted way of doing things, even though, after many decades, it’s not yielding any promising leads. It’s a flawed idea rooted in a shallow understanding of a complicated problem.

This fixedness is costing people their savings and their lives.

This was, and is, the state of affairs in Alzheimer’s research thanks to the beta-amyloid hypothesis. Dr. Rachel Neve, a neurobiologist at Mass General, calls the amyloid hypothesis “one of the most tragic stories [in] disease research.”

Critics contend this narrow focus has significantly delayed the discovery of viable treatments. Despite billions spent, very little has materialized.

There are just four approved Alzheimer’s drugs. All of them provide only fleeting improvements. They do not slow, and certainly do not reverse, disease progression.

AD takes a tremendous toll on families and healthcare systems; it is the costliest health condition in the world, and one of the most heart-wrenching to see up close. The need for effective interventions has never been more urgent (Cire, 2015).

The Silver Tsunami is here, but the alarm bells are just beginning to sound. Alzheimer’s is an especially tragic example of what misplaced attention does, but it’s not the only one.

While admirable strides have been made in cancer and cardiovascular issues, headway in these areas has also been stifled by outmoded models of sickness and health.

Now scientists are turning their sights to other contributors to AD: from neuroinflammation to oxidative stress to telomere shortening and infectious agents. Yet there is one unifying factor, one that indisputably elevates our risk of developing Alzheimer’s more than any other.

And that is aging.

Like so many other infirmities, Alzheimer’s is primarily caused by biological aging. The hallmarks of aging, like telomere shortening and mitochondrial dysfunction, are the same processes that gray our hair and crease our faces. They are responsible for the invisible, and painfully noticeable, changes associated with getting older.

Amyloid plaques appear in the brains of many Alzheimer’s patients, but not all.

As it accounts for 70% of all dementias, AD is the most widely known and extensively studied, but it shares common causes with the vascular, mixed, and Lewy Body varieties. For AD and other dementias, Michael Fossel, an expert in telomere biology, has proposed a systems approach, one where cellular senescence is front and center (Fossel, 2020).

One of the most familiar culprits behind cellular senescence is telomere shortening.

But how can telomere length affect cells that don’t replicate?

It’s true: brain cells normally don’t divide, although in some regions of the brain it is critical that they do. The nearly settled controversy over adult neurogenesis, the production of new brain cells, is relevant (Tobin, 2019). One area where neurogenesis probably takes place is the hippocampus.

Changes in neurogenesis in the hippocampus here could have wide-ranging implications.

Microglia and astrocytes perform maintenance tasks. They can be thought of as the brain’s dutiful custodians and watchmen. One of them is immune function and the protection of our neurons. Dysfunction contributes to inflammation and oxidative damage, two known drivers of AD.

This isn’t a fresh revelation. These connections were made decades ago (Akiyama, 2000). Strong correlations between microglial activation and cognitive decline are also documented (Cagnin et al. 2001; Versipt et. al. 2003).

This fits with the well-known fact that cellular senescence disrupts immune function and creates a pro-inflammatory environment (Zhang, 2022).

Telomere shortening in T Cells aligns with AD’s advancement, as noted by Panossian et al. in 2003. More recent studies, like those by Solana in 2018, have proposed that the aging of Natural Killer Cells can serve as biomarkers for disease progression.

Astrocytes are the most abundant cells in our nervous systems. They are also among the most versatile. In the context of neurodegenerative disease their most notable job is shielding neurons from oxidative damage.

It’s no surprise that astrocyte dysfunction is involved in AD and Huntington’s chorea. It’s been hypothesized that the neuronal toxicity from astrocyte dysfunction contributes to Parkinson’s as well (Booth, 2017).

Yet telomeres are not the only targets worth considering. The hallmarks of aging are intertwined. It will require a large gene therapy delivery system, like BioViva’s CMV platform, to address them simultaneously.

Klotho has a profound impact on cognitive function. More closely associated with IQ than any single gene, Klotho not only improved brain function, but did so within four hours. This was observed in both young and old mice, as well as a mouse model of Alzheimer’s (Dubal, 2014; Dubal, 2015).

A recent Nature article showed that in aged Macaques Klotho had a profound effect; the veritas group scored 10% higher on difficult memory tasks, and 5% higher on less demanding ones (Castner, 2023).

There should be no such thing as “normal” cognitive decline. Gene therapies can be designed to treat, prevent, and even reverse Alzheimer’s and other forms of dementia by getting to its root causes. That’s why

BioViva has designed its own gene therapy for dementia, BV-702.

BioViva is where the right paradigm has found the right treatment modality.

Authored by Adam Alonzi

Adam is a writer, independent researcher, and video maker. He is the Marketing Director for BioViva Science. Visit adamalonzi.com for more.

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