The Alzheimer's Solution

3 months ago

#kynurenine #glucosehypometabolism #alzheimersdisease

One of the causative factors in the multiple neurodegenerative cascades associated with Alzheimer's disease (AD) that captured my attention many years ago was the role of mitochondrial dysfunction and impaired energy metabolism that is a central aspect to many chronic health disorders.

In the Medical News Today report linked to here, researchers have identified an immunotherapy cancer drug an enzyme that that restores glucose metabolism in the brain via a well known pathway—the kynuerinine pathway.

"Using an Alzheimer’s mouse model, they found that blocking the enzyme, called indoleamine-2,3-dioxygenase 1, or IDO1, helped preserve memory and cognition in the early stages of the disease."

The cancer drug essentially blocked IDO1 which is a component in the kynuerinine pathway, is also a the major route (95%) of tryptophan degradation.

Why would blocking IDO1 be potentially important?

Increased IDO1 activity is a feature associated with aging, chronic inflammation (inflammaging), and the risk for age-related diseases.

Inflammaging and unregulation of the IDO1/kynurenine pathway further exacerbates a proinflammatory terrain of the body and brain which is a significant risk factor for age-related diseases such as cancer, cardiometabolic disease and Alzheimer's disease.

Another biomarker in the unregulated IDO1/kynurenine pathway is the Kynurenine/Tryptophan ratio.

A skewed Kynurenine/Tryptophan ratio—lower tryptophan and higher kynurenine levels—is an inflammaging biomarker.

Excess IDO1 stimulated kynurenine synthesis is associated with:

- chronic chronic immune activation and inflammation (inflammaging),

- = infections,

- stress, sleep disturbances, and

- dysregulation of gut microbiota (dysbiosis).

Elevated kynurenine also leads to the accumulation of quinolinic acid which is a neurotoxin linked to neuronflammatory responses and neurodegenerative diseases. (Not mentioned in the report)

And the increased metabolic shift toward the production of quinolinic acid also results in increased nicotinamide adenine dinucleotide (NAD), which normally is a critical cofactor in energy metabolism and other metabolic/biochemical reactions and pathways.

However, the induction of oxidative stress pathways due to elevated quinolinic acid depletes both NAD and ATP levels.

All in all, the research report emphasized that kynurenine dysmetabolism in critical housekeeping cells of the brain—astrocytes—and the subsequent shift of the kynurenine pathway is also a factor in the aberrant lactate and glucose metabolism (hypometabolism) seen in people with Alzheimer’s.

And not surprisingly, an unregulated IDO1/kynurenine pathway is also associated with brain beta-amyloid and tau protein burdens.

However, do we need a cancer drug to blunt IDO1 and restore a normal Kynurenine/Tryptophan ratio and a healthy energy and glucose metabolism in the brain?

In my book I detail how glucose hypometabolism in type 3 diabetes is linked to type 2 diabetes and "brain insulin resistance", and the important role astrocytes play in lactate and energy metabolism.

The earliest stage (preclinical) in the disease progression of late-onset Alzheimer's Disease (LOAD), is marked by several structural and functional features including inflammaging, and the decline in mitochondrial function and energy metabolism (glucose hypometabolism).

Early risk factor assessments by midlife is critical for designing intervention strategies that will prevent the gradual neurodegenerative pathology associated with type 3 diabetes and late-onset Alzheimer's disease.

Think Ahead!

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Alzheimer’s: Novel cancer drug restores cognition, memory loss in mice

www.medicalnewstoday.com

Researchers identified an enzyme that regulates glucose metabolism in the brain and discovered that a cancer drug may help treat early-stage Alzheimer's disease.

The Alzheimer's Solution

4 months ago

#reelincolbosvariant #earlyonsetAlzheimer'sdisease #dementiadelay

The NPR report linked to here highlights recent research reports on two genetic variants that are linked to the resilience and resistance to Alzheimer's disease in carriers of the PSEN1 gene.

The PSEN1 gene is deemed a determinant gene (highly penetrant), and the most common causative factor for early-onset Alzheimer's disease (EOAD).

The two protective genetic variants—the ApoE3 Christchurch variant, and the Reelin-COLBOS variants have previously been identified in earlier research findings.

Each of those variants are associated with extraordinary delay in cognitive decline and EOAD-related dementia, which normally manifests in carriers of the PSEN1 mutation by their mid-to-late 40s.

The ApoE3 Christchurch variant and the Reelin-COLBOS variant carriers, and their respective cases, are participants from the ongoing Columbian kindred study of EOAD, which consists of approximately 6,000 blood relatives, and about 1,200 are carriers of variant—the PSEN1 “Paisa” mutation (Presenilin-1 E280A)—a strong causative factor for EOAD.

In the case of the female ApoE3 Christchurch variant carrier, her cognition was intact into her 70s, despite a significant brain burden of tau and beta-amyloid deposition. She eventually exhibited signs of cognitive impairment and Alzheimer's-related dementia at age

Please read more about that remarkable story below in my previous post below this one, and note the description of HSPGs (heparan sulfate proteoglycans)—a key component as to why the ApoE3 Christchurch variant carrier resisted the onset of dementia for so many years.

Similarly, the Reelin-COLBOS resilience to dementia tale is about a male carrier of the variant, who also remained dementia-free with a brain riddled with beta-amyloid and tau protein aggregations until the age of 70 when he was diagnosed with cognitive impairment, a dementia two years later.

A key region of the Reelin-COLBOS carrier's brain associated with learning and memory—the entorhinal cortex—escaped the heavy tau brain burden associated with EOAD.

Reelin protein is a vital and integral component of the extracellular matrix (ECM)—a critical and functional structure which surrounds almost every cell of the body and brain.

In the adult brain, reelin exerts several key neuroprotective and neuromodulatory roles that are integral to synaptic plasticity, and learning and memory signaling cascades.

For example, reelin has been shown to inhibit the toxic effect of beta-amyloid aggregates on the integrity of synaptic receptor signaling pathways.

Note, I describe at length the synaptic disruption of toxic beta-amyloid aggregates on synaptic receptors in my book: "The Diabetic Brain in Alzheimer's Disease".

Reelin protein and related ECM mechanisms normally blunts the potential toxicity of beta-amyloid and tau protein processing.

With regard to tau protein, Reelin inhibits the spread of tau"seeds" and aberrant formation (hyperphosphorylation) of tau protein tangles (NFTs).

Similarly, ECM-related reelin mechanisms are important in blunting beta-amyloid accumulation and toxicity.

Reelin also plays a role in the autophagic clearance of beta-amyloid aggregates.

All in all, reelin signaling disruption and reelin depletion is linked to the very earliest stages of Alzheimer's disease, is a significant factor in the upregulation of toxic tau and beta-amyloid protein metabolism and deposition, and in the induction of synaptic dysfunction.

Finally, the takeaway from those two extraordinary EOAD case studies is that it points to three critical and MODIFIABLE risk factors associated with late-onset Alzheimer's disease.

The vital and brain-protective interactions between reelin, HSPGs, and the ECM can be nourished and protected via healthy diet, nutrition and lifestyle habits that blunts neuroinflammatory and oxidative stress cascades that underlies their depletion and dysfunction.

Look for my more expanded overview and book on brain resilience and resistance in cognitive super-agers, and how you can get there too.

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A protein called Reelin keeps popping up in brains that resist aging and Alzheimer’s

www.npr.org

Early in life, the protein Reelin helps assemble the brain. Later on, it appears to protect the organ from Alzheimer’s and other threats to memory and thinking.

The Alzheimer's Solution

4 months ago

#earlyonsetalzheimersdisease #apoe3christchurchvariant #dementiaprevention

Recently, an uptick on findings derived from the world's largest population study of Columbian Alzheimer's disease kindred that are carriers of a genetic determinant of early-onset Alzheimer's disease (EOAD) have surfaced in traditional and social media reports.

The deterministic (autosomal-dominant) EOAD gene, the PSEN1-E280 mutation, is one of several known autosomal-dominant genes (causative) associated with EOAD.

Despite the more recent reports, the Colombian autosomal dominant Alzheimer disease (ADAD) longitudinal study began in 1995, and the data analysis report of a retrospective cohort study between 1995 and 2012 which was first published in 2016.

Since then, a slew of insightful discoveries regarding the Colombia Alzheimer's disease kindred, have since been published.

Case in point, the 2019 case report of a Colombian woman that was found to be a carrier of a rare genetic variant, the rare ApoE3 Christchurch variant (ApoE3ch) that delayed the inevitable onset of dementia associated with EOAD (familial Alzheimer's disease) by approximately, 30 years.

She died of cancer at the age of 77 a few years after cognitive impairment and dementia was apparent.

In PSEN1 E280A mutation carriers the median age of onset of mild cognitive impairment (MCI) is 45, and onset of dementia is age 49.

However, a much more significant finding precedes that 5 year delay report from Mass General.

In an effort to unravel the seemingly miraculous and significant 30 year delay in the onset of MCI and dementia in the case of the Colombian female carrier of the PSEN1-E280A mutation and ApoE3ch variant (homozygous), a number of studies since her case report published in 2019 have emerged and shown that the protection imparted by the ApoE3ch variant is linked to a unique characteristic of the extracellular matrix (ECM) and glycosaminoglycans (GAGs) that occur on neurons.

So what is the ECM-GAG story all about?

The term, glycosaminoglycans (GAGs), are a reference to chains of carbohydrates (polysaccharides, sugar acids), and amino-sugars, and which often sulfated (sulfated GAGs).

Sulfated GAGs molecules such as heparan sulfate or chondroitin sulfate, are further linked as side chains to protein anchors (proteoglycans) which along with other molecules (e.g., laminin, fibronectin, hyaluronan) collectively form the extracellular terrain known as the extracellular matrix (ECM).

The ECM is a dynamic snd functional structure that is attached to almost every cell of the body and brain, and in the adult brain it serves as a critical structure that mediates signaling cascades which are central to maintaining and optimizing autophagy pathways, and synaptic plasticity.

Several studies have shown that the ApoEch variant's ECM-GAG profile (heparan-sulfate proteoglycans) protect against the more severe tau and beta-amyloid protein neuropathology associated with the PSEN1-E280 mutation and EOAD.

So what does the remarkable story of the ApoEch variant carrier's case study possibly represent for those of us that are fortunate to not carry RARE genetic mutations linked to familial Alzheimer's disease?

Well, a prime takeaway from the rare ApoEch carriers case for most individuals concerned about late-onset Alzheimer's (LOAD) disease and dementia linked to RISK genetic variants such as the ApoE4 variant, is that maintaining and optimizing a healthy ECM-GAG structure is an essential component to pathways connected to autophagy, mitochondrial function, and synaptic plasticity.

While the current EOAD research efforts seek to develop drug solutions, LOAD is preventable and the diet, nutrition and lifestyle habits nourish a healthy ECM-GAG structure and environment.

Please look for my next post with regard to another genetic variant revelation associated with the Colombian Alzheimer's kindred that sheds yet another insight about an ECM protein (reelin), and how the ECM-reelin synergism is associated with stem cell homeostasis, neurogenesis, and longevity pathways.

Note that reelin is also briefly described in the Mass General Brigham article linked to here—https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/one-copy-of-genetic-variant-protects-against-early-onset-alzheimers
— which describes the more recent finding linked to the Colombian kindred longitudinal study—a 5 year delay in onset of dementia in heterozygous (one copy) carriers of the ApoE3ch variant.

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www.medpagetoday.com/neurology/alzheimersdisease/110724 ... See MoreSee Less

Alzheimer's Onset Delayed by Rare Mutation

www.medpagetoday.com

Just one copy of the Christchurch variant conferred protection