Immune Defect As A Cause Of Alzheimer's Disease

An interesting hypothesis, abstract:

Inflammation is an immune activity designed to protect the host from pathogens and noxious agents. In its low-intensity form, presence of an inflammatory process must be inferred from appropriate biomarkers. Occult neuroinflammation is not just secondary to Alzheimer's disease (AD) but may contribute to its pathogenesis and promote its progression. A leaky blood-brain barrier (BBB) has been observed in early AD and may play a role in its initiation and development. Studies of the temporal evolution of AD's biomarkers have shown that, in AD, the brain's amyloid burden correlates poorly with cognitive decline. In contrast, cognitive deficits in AD correlate well with synapse loss. Oligomeric forms of amyloid-beta (oAβs) can be synaptotoxic and evidence of their deposition inside synaptic terminals of cognition-associated neurons explains early memory loss in AD better than formation of extracellular Aβ plaques. Among innate immune cells that reside in the brain, microglia sense danger signals represented by proteins like oAβ and become activated by neuronal damage such as that caused by bacterial endotoxins. The resulting reactive microgliosis has been implicated in generating the chronic form of microglial activation believed to promote AD's development. Genome-wide association studies (GWASs) have yielded data from patients with sporadic AD indicating that its causes include genetic variation in the innate immune system. Recent preclinical studies have reported that β-hydroxybutyrate (βOHB) may protect the brain from the adverse effects of both the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and the deacetylation of histone. Consequently, there is an urgent need for clinical investigations designed to test whether an orally administered βOHB preparation, such as a ketone ester, can have a similar beneficial effect in human subjects.

Immune problems and inflammation may be at the heart of many chronic disorders.  Hopefully, β-hydroxybutyrate  will be helpful.  Doing everything possible to improve immune function and reduce (unnecessary) inflammation may be helpful as well.

Nervous System Immune Cells

There are distinct populations of central nervous system immune cells comparing states of health, aging, and disease Alzheimer's disease and multiple sclerosis). This may assist in devising new therapeutic strategies against those diseases as well as giving insights into the human aging process. Abstract:

Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease. 

Blood-Brain Barrier And Neurodegeneration

The blood-brain barrier is important for maintaining the health and proper function of the central nervous system, and this barrier breaks down in neurodegenerative disease.  Abstract:

The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.

Immune Memory And Neurological Disease

Innate immune memory in the brain shapes neurological disease hallmarks; abstract:

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

Wnt Signaling, DKK3, and Alzheimer's Disease Models

More evidence of  dysfunctional Wnt signaling being involvedin the pathogenesis of Alzheimer’s disease (AD) is here, with the finding that the factor Dickkopf 3 (Dkk3) can alleviate AD in mouse models of the disease, through stimulating Wnt activity, and therefore Dkk3 can be a therapeutic target for AD. Abstract:

Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD.

Down Syndrome and Alzheimer's

Down syndrome patients accumulate brain features characteristic of Alzheimer's disease by age 40, and most go on to develop dementia.  Down syndrome is trisomy 21 and the APP gene is on that chromosome, but a mouse model shows that triplication of other non-APP genes on that chromosome can also cause similar amyloid problems. This can shed new light on Alzheimer's disease, possibly with therapeutic implications.  Abstract:

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.

Extracellular Vesicles And Neurodegeneration

Extracellular vesicles have effects on Alzheimer’s disease and other neurodegenerative diseases, mostly negative but possibly also some positive.  Thus can be a target for therapeutic intervention.  Abstract:

Extracellular vesicles (EVs), based on their origin or size, can be classified as apoptotic bodies, microvesicles (MVs)/microparticles (MPs), and exosomes. EVs are one of the new emerging modes of communication between cells that are providing new insights into the pathophysiology of several diseases. EVs released from activated or apoptotic cells contain specific proteins (signaling molecules, receptors, integrins, cytokines), bioactive lipids, nucleic acids (mRNA, miRNA, small non coding RNAs, DNA) from their progenitor cells. In the brain, EVs contribute to intercellular communication through their basal release and uptake by surrounding cells, or release into the cerebrospinal fluid (CSF) and blood. In the central nervous system (CNS), EVs have been suggested as potential carriers in the intercellular delivery of misfolded proteins associated to neurodegenerative disorders, such as tau and amyloid β in Alzheimer's Diseases (AD), α-synuclein in Parkinson's disease (PD), superoxide dismutase (SOD)1 in amyotrophic lateral sclerosis and huntingtin in Huntington's disease. Multiple studies indicate that EVs are involved in the pathogenesis of AD, although their role has not been completely elucidated. The focus of this review is to analyze the new emerging role of EVs in AD progression, paying particular attention to microglia EVs. Recent data shows that microglia are the first myeloid cells to be activated during neuroinflammation. Microglial EVs in fact, could have both a beneficial and a detrimental action in AD. The study of EVs may provide specific, precise information regarding the AD transition stage that may offer possibilities to intervene in order to retain cognition. In chronic neurodegenerative diseases EVs could be a novel biomarker to monitor the progression of the pathology and also represent a new therapeutical approach to CNS diseases.

Strains Of Misfolded Proteins And Alzheimer's Disease

Neurodegenerative diseases tend to involve tangled misfolded proteins, and for some diseases “strains” are already known.  Here we see that the same applies for amyloid and tau proteins in Alzheimer’s disease, a finding that can be helpful for targeted, personalized medicine.  Abstract:

Most neurodegenerative diseases are proteinopathies, which are characterized by the aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid-β (Aβ) and the protein tau aggregate to form plaques and tangles, respectively, which comprise the histopathological hallmarks of this disease. This Review discusses the complexity of Aβ biogenesis, trafficking, post-translational modifications and aggregation states. Tau and its various isoforms, which are subject to a vast array of post-translational modifications, are also explored. The methodological advances that revealed this complexity are described. Finally, the toxic effects of distinct species of tau and Aβ are discussed, as well as the concept of protein 'strains', and how this knowledge can facilitate the development of early disease biomarkers for stratifying patients and validating new therapies. By targeting distinct species of Aβ and tau for therapeutic intervention, the way might be paved for personalized medicine and more-targeted treatment strategies.

Wnt And Alzheimer's Disease

Promoting Wnt signaling against Alzheimer’s.  Abstract:

This Editorial highlights an article in the current issue by Tapia-Rojas and Inestrosa suggesting that attenuation of Wnt signalling may be a triggering factor for the pathogenesis of Alzheimer disease (AD) in the J20 mouse model of AD. Their study utilises Wnt signalling inhibitors that operate at different points in the signalling pathway. The molecular changes of several key Wnt signaling components are examined, along with a thorough analysis of both the amyloid and tau based pathologies in the mouse brain. Studies focusing on inhibition of Wnt signalling in AD mice have the potential to provide much needed information regarding the pathological mechanisms by which attenuated Wnt signalling impacts on AD.

A Judicious Update: Alzheimer’s Disease

By ADEAR: "Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging." - http://www.nia.nih.gov/NR/rdonlyres/A01D12CE-17E3-4D3D-BCEF-9ABC4FF91900/0/TANGLES_HIGH.JPG, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4476425

Here is a review of possible therapies for Alzheimer’s disease.  Current drugs have not been very successful; what may be needed are more direct treatments against the more direct molecular/cell causes of the disease, with effective blood-brain barrier delivery of these therapies being a major hurdle that needs to be overcome.  Abstract:

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of β-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and-2 genes. AD progresses through accumulation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Aβ deposition and phosphorylated tau (p-tau) are useful core biomarkers in the cerebrospinal fluid (CSF) of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Aβ and p-tau. Failure of biologics or compounds to cross the blood-brain barrier (BBB) in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression.

Aging And Dementia Links

Aging and dementia has common links, including the mitochondrial α-F1 -ATP synthase (ATP5A), which can be a target for the Alzheimer's disease drug candidate J147.  The mTOR signaling pathway is involved with this; abstract:

Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α-F1 -ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.

Janus-Faced Wnt Signaling

Deregulated Wnt signaling leads to certain types of cancer, particularly colorectal cancer.  But Wnt signaling is two-faced, Janus-faced, and certain neurological diseases are characterized by the opposite problem: repression of Wnt signaling.  There, inhibition of Wnt signaling enhances disease in a mouse model of Alzheimer’s.

More On Mitochondria And Alzheimer's Disease

It has been shown that the stimulation of certain mitochondrial functions can increase the fitness and lifespan of a worm model of Alzheimer's disease and also reduce amyloid aggregation (that has been associated with Alzheimer's disease) in a variety of model systems, including mice. These findings may lead to anti-Alzheimer's therapeutics.  Abstract:

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.

APOE4 And Late-onset Alzheimer Disease

This link is to another paper showing an association between APOE4 and late-onset Alzheimer disease.  Understanding how the APOE4 gene variant enhances risk for this disease can help in the discover of novel therapeutic approaches.  Abstract:

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Diabetes Drugs Against Alzheimer’s Disease

Some findings of interest, relevant sections:

Studies in a mouse model of Alzheimer’s disease (AD) have shown how a drug that was originally developed to treat diabetes demonstrates what researchers in the U.K. and China call “clear promise” as a treatment for AD and other neurodegenerative disorders in humans. The studies, led by Christian Hölscher, Ph.D., at the U.K.’s Lancaster University, confirmed that AD mice treated using a triple-receptor agonist (TA) showed “significantly reversed memory loss,” as well as reduced neuroinflammation and oxidative stress, lower amyloid plaque load in the brain, and increased levels of brain-derived neurotropic factor (BDNF), a key growth factor that protects synaptic function… 

…Type 2 diabetes mellitus (T2DM) is a known risk factor for AD, and this association has motivated scientists to investigate whether antidiabetic drugs might also be effective against AD. Studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which have antidiabetic properties, can play a neuroprotective role in the brain and have demonstrated promising effects in animal models of AD. 

  Prof. Holscher’s team turned to a triple-receptor agonist that activates GIP-1, GIP, and glucagon receptors…The results showed that a daily injection of TA reversed memory loss in AD mice, which was assessed in a spatial water maze test. The drug also reduced levels of the mitochondrial proapoptotic signaling molecule BAX, increased the antiapoptotic signaling molecule Bcl-2, and boosted levels of BDNF. Levels of synaptophysin were also elevated, which the researchers say demonstrates protection against the synaptic loss that is seen in AD…

 

 …“Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus,” the authors write. “The results demonstrate for the first time that the novel GLP-1/GIP/Gcg receptor agonist has clear neuroprotective effects in the APP/PS1 mouse model of AD.” 

Given the “impressive” preclinical data demonstrating the neuroprotective properties of GLP-1, GIP, and glucagon receptor agonists, clinical trials are now under way to investigate the neuroprotective effects of the GLP-1 receptor agonists extendin-4 (Byetta®, Bydureon®) and liraglutide (Victoza®) in patients with AD or with Parkinson's disease, the authors note. “A pilot study testing the GLP-1 analogue liraglutide in AD patients showed promising results.”

That sounds like a very promising advance in the field of Alzheimer’s therapy, and also underscores the relationship between that disease and metabolic disorders.

Alzheimer's Disease-Cancer Link

First described case of Alzheimer's disease. By Unknown - Unknown, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1595297

Sometimes serious diseases have interesting co-morbidities.  Having one disease may increase or decrease your risk of getting the other.  Such co-morbidities exist between some nervous system diseases and some forms of cancer.  Not surprisingly, Alzheimer’s disease and brain cancer are positively linked, which may be due to common changes in immune function affecting brain cells, while Alzheimer’s and lung cancer are negatively associated.  It seems that changes in the mitochondria – “the powerhouse of the cell” – that increase the risk of Alzheimer’s decrease the risk of lung cancer and vice versa.  Studying the mechanisms behind such correlations can lead to new therapies for these diseases.  From the article:

Alzheimer’s disease, lung cancer, and brain cancer—all devastating, all leading public health challenges—have been thought to harbor connections at the molecular level, connections that could explain curious co-morbidities. Specifically, in cases of Alzheimer’s disease, the risk of developing lung cancer is decreased, and the risk of developing glioblastoma, a kind of brain tumor, is increased…

…“A functional analysis of the sets of deregulated genes points to the immune system, up-regulated in both Alzheimer’s disease and glioblastoma, as a potential link between these two diseases,” wrote the article’s author. “Mitochondrial metabolism is regulated oppositely in Alzheimer’s disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases.”

The authors of the current paper emphasized that they intended to explain previously published findings that overexpressed genes in central nervous system diseases (Alzheimer's disease, Parkinson's disease, and schizophrenia) were underexpressed in cancer (lung, colon, and prostate), and vice versa. Understanding the molecular bases of these processes, the authors suggested, could provide valuable information regarding the study of the causes of each disease and the possible design of new therapeutic strategies (drug repositioning).

Grapes Against Alzheimer's Disease

By Fir0002 - Own work, GFDL 1.2, https://commons.wikimedia.org/w/index.php?curid=135219

Another benefit of grapes, relevant sections from article:

Chances are that you already like the taste of grapes. If you're looking for another reason to eat them, though, then how about this … a recent study conducted by the University of California, Los Angeles indicates that consuming them helps protect against Alzheimer's disease.

It was discovered that while the placebo group exhibited significant metabolic decline in regions of the brain that are affected by the early stages of Alzheimer's, the grape powder group maintained a healthy level of metabolic activity in those areas. What's more, the grape group also "showed beneficial changes in regional brain metabolism that correlated to improvements in cognition and working memory performance."

This effect is likely due to the known antioxidant and anti-inflammatory properties of the polyphenols. It is believed that they reduce oxidative stress in the brain, while also promoting blood flow within it and maintaining levels of a chemical that boosts memory.

Therefore, here we see more evidence that dietary choices can have profound impacts on human health and the course of even some of the most serious diseases.