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Wisdom Wednesdays: Is this the Alzheimer's disease and cognitive decline breakthrough we've been waiting for? · Hardiness with Dr Paul Taylor

• 0:08
  Speaker 1: Hey folks.
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  Speaker 2: your place there And now only the podcast. Hey everybody,
• 2:13
  Speaker 2: welcome to another edition of Wisdom Wednesdays. Today I am
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  Speaker 2: going to talk about some new research that offers a
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  Speaker 2: little bit of tantalizing hope for Alzheimer's disease. And it
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  Speaker 2: is all about a compound called lithium.
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  Speaker 1: Now you may have heard of it before, you may not.
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  Speaker 2: It has actually been used for decades as a psychiatric medication,
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  Speaker 2: most famously for bipolar disorder. But what you probably don't
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  Speaker 2: know is that lithium is also a naturally occurring trace
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  Speaker 2: element that's found in our soil, our food, and even
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  Speaker 2: more relevant for this, in our brains. And a recent
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  Speaker 2: fascinating study out of Harvard Medical School has generated some
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  Speaker 2: real buzz suggesting that tiny amounts of lithium, particularly in
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  Speaker 2: a form called lithium or rotate, might have powerful effects
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  Speaker 2: on brain aging and even help protect against Alzheimer's disease. Now,
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  Speaker 2: before we start thinking we finally found the long awaited
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  Speaker 2: silver bullet, let's really unpack the research and tell us
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  Speaker 2: what is the state of play, what's exciting, what is
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  Speaker 2: still speculative, and why we should be cautiously optimistic. So
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  Speaker 2: let's first of all talk about the Alzheimer's challenge. You
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  Speaker 2: would have heard me talk many times on this podcast
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  Speaker 2: about Alzheimer's disease being one of medicine's greatest unsolved puzzles
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  Speaker 2: because billions of dollars have been spent on drugs and
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  Speaker 2: with no avaal to this point. Now, Alzheimer's is the
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  Speaker 2: leading cause of dementia worldwide, and we really have only
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  Speaker 2: made a very modest progress in its prevention and treatment,
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  Speaker 2: and for decades it has been framed as an amyloid
• 4:04
  Speaker 2: versus tao battle, with these amyloid beta plaques and toy
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  Speaker 2: tau tangles viewed as the central villains. But some researchers
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  Speaker 2: have actually called that into question and said that even
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  Speaker 2: though we see these things appear in the brain, they
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  Speaker 2: might not be the cause. And this new study introduces
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  Speaker 2: a third player. The trace element that we talked about
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  Speaker 2: lithium measured in micrograms, and this might be very very important.
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  Speaker 2: So in this harvardly had study, researchers examined post more
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  Speaker 2: than brain tissue for people who had either normal cognition,
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  Speaker 2: mild cognitive impairerment, which is often a precursor to Alzheimer's
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  Speaker 2: or other forms of dementia, or full blown Alzheimer's disease.
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  Speaker 2: And they measured twenty seven different metals and they find
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  Speaker 2: that only lithium was consistently lower in people with cognitive decline,
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  Speaker 2: and even more interestingly, lithium wasn't just missing, it was
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  Speaker 2: actually misplaced. The team found that amyloid plaques actually trapped
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  Speaker 2: lithium inside them, acting like molecular sponges, and that meant
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  Speaker 2: that the brain regions most affected by Alzheimer's, particularly the
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  Speaker 2: prefrontal cortex, were effectively lithium deficient, and the lower the
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  Speaker 2: lithium levels in these healthy brain regions, the worst the
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  Speaker 2: person's memory and cognitive test scores had been before death.
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  Speaker 2: And this suggested that disrupted lithium distribution might not just
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  Speaker 2: be a side effect, it could actually be part of
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  Speaker 2: the disease process itself. So let's talk about testing the
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  Speaker 2: theory what happens when the brain runs low on lithium.
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  Speaker 2: So to explore that idea, the researchers turned to mouse models,
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  Speaker 2: including what's called transgenic mice that develop Alzheimer's like pathology,
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  Speaker 2: and they compare them to normal aging mice, and they
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  Speaker 2: cut dietary lithium by about half, which in turn reduced
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  Speaker 2: brain lithium levels by roughly fifty percent.
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  Speaker 1: And what happened was remarkable.
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  Speaker 2: Those lithium deficient mice began to show all the early
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  Speaker 2: features of Alzheimer's disease, including more amyloid plaques and more
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  Speaker 2: phosphorylated taul, increased brain inflammation, loss of synapses, axons, and
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  Speaker 2: mile in sheath, which is the coating around the nerves
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  Speaker 2: in the brain, and importantly clear deficits in learning and memory.
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  Speaker 2: Even normal aging mice who don't usually develop amyloid pathology
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  Speaker 2: showed faster cognitive decline when lithium was low. So just
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  Speaker 2: lowering lithium alone was enough to trigger Alzheimer's like changes
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  Speaker 2: in the brain. So let's talk about the molecular break
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  Speaker 2: to understand how this happens. What the researchers did was
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  Speaker 2: was looked at one of lithium's best known targets. It's
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  Speaker 2: an enzyme and they all have silly, ridiculous earning names.
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  Speaker 2: It's glycogen synthius kinikinis three beta or GSK three beta.
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  Speaker 2: This enzyme is actually at the heart of Alzheimer's biology.
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  Speaker 1: Now this gets a little bit complicated, but what it.
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  Speaker 2: Does is it promotes tall phosphorylation, it drives amyloid production,
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  Speaker 2: and it ramps up inflammation and under normal conditions, lithium
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  Speaker 2: acts as a natural break on this enzyme, keeping X.
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  Speaker 1: Activity in check.
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  Speaker 2: But in the study, lithium deficiency unleashed this enzyme GSK
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  Speaker 2: three beta, pushing it into a hyperactive state, and the
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  Speaker 2: result was the perfect storm. When it comes to brain aging,
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  Speaker 2: which included the development of tau tangles. In inflammation demilation
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  Speaker 2: as in stripping off the mielin from the nerves and
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  Speaker 2: synaptic loss, and when the researchers chemically blocked GSK three beta,
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  Speaker 2: those changes largely reversed. So there's a real smoking gun here.
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  Speaker 2: We understand the process and aim by damaging or stopping
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  Speaker 2: the process, the damage actually reversed. And it's a really
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  Speaker 2: strong hint that lithium's protective role in the brain may
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  Speaker 2: stem from its ability to keep this enzyme under control.
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  Speaker 2: So the next logical question is can we just give
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  Speaker 2: lithium back If low lithium drives disease, can replacing it
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  Speaker 2: fix the problem? In theory, yes, but the practical challenge
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  Speaker 2: has always been formulation and safety. The lithium that has
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  Speaker 2: typically been used clinically, lithium carbonate, is effective for mood disorders,
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  Speaker 2: but comes with a very narrow therapeutic window. Doses high
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  Speaker 2: enough to impact the brain can cause kidney and thyroid toxicity,
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  Speaker 2: and in Alzheimer's most of that lithium ends up driven
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  Speaker 2: into these amyloid plaques, where it's essentially useless. So the
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  Speaker 2: Harvard team then screened sixteen different lithium salts to find
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  Speaker 2: one that could deliver lithium into healthy Brian tissue without
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  Speaker 2: binding to amyloid, and they found one that stood out,
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  Speaker 2: and it's this lithium oratate. Lithium ritate is basically a
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  Speaker 2: smarter delivery vehicle. It turned out to have a much
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  Speaker 2: lower affinity for the amyloid plax, meaning it didn't drive
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  Speaker 2: itself there and it stayed free in Brian tissue with
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  Speaker 2: the neurons actually need it. And then the Alzheimer's prone
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  Speaker 2: mice long term treatment with tiny doses of lithium oritate,
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  Speaker 2: achieving blood levels similar to those seen naturally in humans,
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  Speaker 2: actually produced dramatic effect. What they found was the amyloid
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  Speaker 2: and tau accumulation were almost completely blocked, brain inflammation was
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  Speaker 2: markeably reduced synaptic density and mielin integrity were preserved, and
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  Speaker 2: on learning and memory tasks that traded mice performed as
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  Speaker 2: well as cognitively normal controls. Even normal aging mice benefited.
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  Speaker 2: Lithium ooritated reduced markers of brain inflammation, preserved synaptic connections,
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  Speaker 2: and largely prevented age related cognitive decline, and crucially, it
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  Speaker 2: did so at very low, non toxic doses. The doses
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  Speaker 2: they used were several thousand times lower than those used
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  Speaker 2: to treat bipolar disorder. So let's talk about human evidence. Now,
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  Speaker 2: this obviously is still animal data and humans aren't big mice,
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  Speaker 2: but there's alrarely a small body of human work hinting
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  Speaker 2: that lithium could slow cognitive decline. Over the past two
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  Speaker 2: several randomized trials have tested low dose lithium carbonate in
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  Speaker 2: people with mild cognitive impairment or early Alzheimer's, and in
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  Speaker 2: one two year study, lithium treatments stabilized memory and attention
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  Speaker 2: while the placebo group declined, and their biomarker analysis that
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  Speaker 2: they did showed reduced phosphorylated tawel and the higher levels
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  Speaker 2: of alpha beta forty two in this cerebral spinal fluid,
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  Speaker 2: which suggested slower amyloid accumulation. I know that's all a
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  Speaker 2: bit geeky, but basically this is a good thing. And
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  Speaker 2: then a smaller trial found that even microdoses three hundred
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  Speaker 2: micrograms per day helps stabilize cognition in people already diagnosed
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  Speaker 2: with Alzheimer's disease. When all the data are pulled, meta
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  Speaker 2: analysis suggests that lithium therapy, usually in very low doses
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  Speaker 2: produces the modest but measurable slowing of cognitive decline. And meanwhile,
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  Speaker 2: observational data are are also interesting. People prescribe lithium for
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  Speaker 2: mood disorders appear to have a roughly forty percent lower
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  Speaker 2: risk of developing Alzheimer's disease.
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  Speaker 1: And though you know, we've got to say that correlation.
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  Speaker 2: Doesn't prove causation, but certainly evidence is starting to stack up.
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  Speaker 2: Now what makes lithium oority it so exciting is that
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  Speaker 2: it could overcome two major barriers that have limited lithium's
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  Speaker 2: therapeutic potential, and that being the poor brain bioavailability ie
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  Speaker 2: lithium's hard to be taken up by neurons and toxicity
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  Speaker 2: at higher doses.
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  Speaker 1: Because the lithium.
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  Speaker 2: Orty it crosses the blood brain barrier more readily and
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  Speaker 2: doesn't get trapped in amyloid, it could theoretically deliver the
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  Speaker 2: same neuroprotective benefits at much lower, safer concentrations. And if
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  Speaker 2: these findings translate to humans, we might finally have a
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  Speaker 2: low dose, low toxicity way to restore natural levels of
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  Speaker 2: lithium in the aging brain.
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  Speaker 1: Now is still early days, but all of this.
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  Speaker 2: Data provides a strong rationale for the first clinical trials
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  Speaker 2: of lithium oritate in mild cognitive impoerment and early Alzheimer's disease,
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  Speaker 2: and you can bet your bottom dollar they're already starting
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  Speaker 2: to design these studies. Now, before you start googling lithium
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  Speaker 2: oritate supplements, let's talk about safety and lithium in any
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  Speaker 2: form is not something to just pop like vitamin C right.
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  Speaker 2: Even tristosis can accumulate over time, and the margin between
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  Speaker 2: therapeutic and toxic levels is pretty narrow. Lithium toxicity can
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  Speaker 2: damage the kidneys, the thyroid, and in severe cases, the heart,
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  Speaker 2: and we simply don't have enough long term safety data
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  Speaker 2: on lithium ooritate in humans, particularly in older adults who
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  Speaker 2: may already have reduced kidney function. So for ANWYE, this
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  Speaker 2: is not a do it yourself experiment. Lithium should only
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  Speaker 2: be used under medical supervision, with regular monitoring of seri
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  Speaker 2: lithium levels, kidney function, and thyroid function. And it's also
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  Speaker 2: worth noting that lithium is not recommended during pregnancy, as
• 14:19
  Speaker 2: it can cross the placenta and slightly increase the risk
• 14:22
  Speaker 2: of birth defects or pre term breaths. Now, despite all
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  Speaker 2: of those caveats, and this study really does change how
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  Speaker 2: we think about lithium. It reframes it as a nutrient
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  Speaker 2: for brain resilience, something that the brain uses naturally to
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  Speaker 2: keep key enzymes in signaling pathways and balance. And much
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  Speaker 2: like ourn deficiency leads to anemia, a lithium deficiency might
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  Speaker 2: accelerate neurodegeneration.
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  Speaker 1: And restoring lithium to its physiological.
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  Speaker 2: Range safely and in the right form could be one
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  Speaker 2: piece of the Alzheimer's prevention puzzle, although we're not there yet,
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  Speaker 2: so I'm not recommending that you go out and take
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  Speaker 2: lithium or go out and buy it.
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  Speaker 1: Do I take it? Yes, I do.
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  Speaker 2: Because of this, I take lithium or TAD five milligrams
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  Speaker 2: a couple of times a week. But I am not
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  Speaker 2: suggesting that you do this, and I am certainly suggesting
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  Speaker 2: that you talk to your doctor if you're even thinking
• 15:24
  Speaker 2: about taking any form of lithium at all. But this
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  Speaker 2: certainly is a very, very exciting development, and I'm sure
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  Speaker 2: that there are clinical trials right now being designed and
• 15:38
  Speaker 2: registered both to determine the safe and affected dose of it,
• 15:43
  Speaker 2: just like any drug has to go through that process
• 15:46
  Speaker 2: and then as interventions for people with Alzheimer's disease and
• 15:50
  Speaker 2: mild cognitive impowerment. But it is certainly a space that
• 15:55
  Speaker 2: is worth watching and that I think we will get
• 15:59
  Speaker 2: to those answers pretty dumb quickly.
• 16:02
  Speaker 1: So that's it for this weeaks folks. Catch you next time.