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The Relationship between Copper and Alzheimer's Disease


I've been reading up about the research concerning the etiological factors behind Alzheimer's and I came across two papers - "Studies on Copper induced stability changes in DNA fragment (GCA ATC TAA TCC CTA): Relevance to Alzheimer's disease" and "Copper interactions with DNA of chromatin and its role in neurodegenerative disorders." The issue I'm having is that the papers suggest that copper causes the DNA's double helix to unwind in some parts, and it causes it to coil more tightly in others (the fluorescence and circular dichroism research supports the latter).

My question is this: do high concentrations of copper cause DNA to unwind or coil more tightly?

If you could provide any help, I'd be very grateful, as I feel like I'm be missing something obvious.


I found your second reference online, which says

Hydrogen bonds are disrupted by the process of partial unwinding which induces structural changes such as loosening of base-base interaction, base tilting and destabilization of the DNA double helix leading to DNA denaturation [17]. The destabilization was due to most probable binding sites in DNA such as Cu2+ to N7 of guanine and N3 of cytosine in line with our present results and with the predictions of Eichhorn and Clark [18], [19].

With this in hand, we can Read The Friendly References. #18 is on PMC and gets the first look - they say "perhaps the structure is"

The other references are less helpful for me right now - #17 is a paper from 1971 that's not online and never will be, and #19 talks about histone H1 blocking the copper interaction.

Now what I see here is only unwinding, and is dependent (as proposed) on the presence of G-C base pairs in the sequence. So far from what I've seen, this is based at interactions at around 0.1 mM in in vitro studies, so I feel like it is possible a physiological situation could involve a completely different mechanism.

After writing the above, I found the other paper in Young Scientists Journal - it is quite a remarkable thing to consider. The author is a 12th-grade student from Panama who was doing (among other things) a circular dichroism study and molecular docking with Discovery Studio 3.5. Statistics is lacking and the experiments aren't very well integrated, and the model from the software, which doesn't agree with the image above (it doesn't bind a ring nitrogen in the cytosine), doesn't seem to be tested by the lab data. Despite the sophistication of the software I'm afraid I'm about as skeptical as I was the first time. Still, there is some Ph.D.-level thought there, using some methods that American undergraduates rarely access, conducted by a university in Panama with support from an Indian research institute. Educationally, fascinating.

But I don't see much support for the interpretation in that paper that the DNA coils more tightly. The fluorescence experiment suggests a competition between copper and ethidium bromide, but knowing what actually happens is another story. The CD study… well, some shifts are identified, one one way and one the other, but I don't see how they prove the DNA is coiling more. But maybe I'm missing something!


The Relationship between Copper and Alzheimer's Disease - Biology

Hypotheses for the pathogenesis of Alzheimer’s disease (AD) were described.

Metal-based hypothesis in neurodegeneration is strategic to identifying therapeutic alternatives for AD.

The significance of exploring metal chelation to ensure metal homeostasis and oxidative damage is highlighted.

Multifunctional metal chelating agents appear as credible alternatives to managing AD.

Limiting factors in metal chelation therapy of AD are discussed.


Scientists Find Unusual Form of Iron and Copper in Brains of Alzheimer's Patients

A group of scientists say they’ve made a surprising and potentially very important discovery in the brains of two people with Alzheimer’s disease: traces of a particular form of iron and copper deep inside deposits of amyloid plaque, a key marker of the fatal disease. The find raises more questions about how Alzheimer’s develops and may one day point to a new avenue of detecting or treating the underlying dysfunction that causes it.

Iron and copper are elements found in tiny amounts throughout the body, including in the brain. They can serve many important functions, such as being parts of enzymes crucial to our healthy function. Both can come in different oxidation states when they’re part of a compound, meaning they lose or gain electrons. Because some forms of these elements can be dangerous to us, triggering chemical reactions that damage cells, the body usually does a good job of regulating which kinds of iron and copper should be present in our system at any one time.

The regulation of these metals doesn’t seem to work so great in the brains of people with Alzheimer’s disease, though. Those with the disorder develop deposits of misfolded amyloid beta and tau, which are called plaques and tangles, respectively. And some evidence has suggested that toxic forms of iron and copper can be found inside these plaques.

To better understand this possible link, researchers in the UK, Germany, and the U.S. collaborated for a new study, published Wednesday in Science Advances. They used a type of X-ray imaging to analyze the specific chemical composition of plaques taken from the brains of two deceased donors with severe Alzheimer’s. They then found elemental and metallic nanoparticles of iron and copper in the cores of these plaques, meaning that the elements had no oxidation—no electrons missing or added.

Though some species of bacteria, fungi, and plants are known to produce these sorts of metals, it’s the first time this kind of iron and copper has been documented in human tissue, according to the authors. And it may help explain how plaques damage the brain.

“The metallic forms of iron and copper we observed have distinctly different chemical and magnetic properties from their less reactive oxide forms, in which iron and copper are predominately stored in the human body,” senior author Neil Telling, a professor of biomedical nanophysics at Keele University in the UK, told Gizmodo in an email. “The surfaces of metallic copper and iron are highly unstable and readily react with their surroundings, with potential to cause damage to brain cells.”

Of course, potential discoveries like this have to be further studied and validated by other researchers before they should be accepted as true. Even if this is a genuine find, there are many unanswered questions. It’s not yet confirmed, for instance, whether these metals can only be found in the brains of Alzheimer’s patients. Beyond that, their exact origin is still a mystery, though past research from Telling’s team and others does suggest that amyloid plaques can trigger chemical reactions capable of converting less reactive forms of these elements into something more dangerous. Some studies have also raised the possibility that amyloid plaques may be protecting us from these toxic metals, Telling noted, so the relationship between all these factors may be more complicated than we think.

In any case, Telling and his team plan to keep digging further into this. And should this area continue to show promise, it could very well lead to new directions in understanding Alzheimer’s and other neurological disorders linked to rogue proteins, such as Parkinson’s disease.

“This line of research could ultimately lead to new treatments that target metals as well as the amyloid proteins currently under consideration,” he said. “The existence of tiny magnetic iron particles within plaques could also help with diagnosis and to monitor disease progression, as they could in principle be detected by MRI scanners.”


The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease

This study aimed to evaluate the concentrations of copper, iron, and selenium in elderly people with Alzheimer disease (AD), comparing the same parameters in a paired group of healthy people, in order to verify if the amount of these metals may influence the cognitive impairment progression. Patients’ cognitive impairment was evaluated by Clinical Dementia Rating (CDR). The elementary quantification of erythrocytes was performed by inductively coupled plasma mass spectrometry technique. The statistical analyses were carried out by SPSS software 20.0 version, employing Shapiro-Wilk, Wilcoxon, Kruskall-Wallis, and Spearman correlation tests, considering significant results of p < 0.05. The sample was composed of 34% (n = 11) of women and 66% (n = 21) of men in each group. The AD group was characterized by a higher concentration of copper (p < 0.0001) and iron (p < 0.0001) however, there is no significant difference in selenium level. The analyses of the metal levels in different stages of AD were not significant in CDR-1, however in CDR-2 and CDR-3, elevated levels of copper and iron were observed in CDR-3 patients, the level of selenium was lower (p < 0.008) compared to that of healthy controls. Patients with Alzheimer disease studied present increase in biometal blood levels, especially of copper and iron, and such increase can be different according to the disease stage and can cause more impairment cognitive functions in AD.

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Copper Ion Toxicity in AD

The key event in AD is the formation of fibrils and plaques in AD patients’ brain. Plaques are mainly made of β-amyloid peptide, the natural peptide that is produced in the brain and exists at nanomolar concentration levels in cerebrospinal fluid (CSF) and serum (Masters et al., 1985 Vigo-Pelfrey et al., 1993). On the other hand, a high concentration of trace metals, including copper, is observed in amyloid plaques (Miller et al., 2006). Interestingly, some data show that copper distribution in the brain does not correspond to β-amyloid plaques distribution in TASTPM mice model (Torres et al., 2016) with plaque pathology but not appreciable neuronal loss (Howlett et al., 2004). Copper is a necessary trace metal in nervous system development since disruption of its homeostasis leads to neurodegenerative disorders like Menkes and Wilson’s diseases (Waggoner et al., 1999). Cu 2+ ions bind to β-amyloid peptides with high affinity (Atwood et al., 2000 Sarell et al., 2009 Barritt and Viles, 2015 Mital et al., 2015 Drew, 2017) and increase the proportions of β-sheet and α-helix structures in amyloid peptides, which can be responsible for β-amyloid aggregation (Dai et al., 2006). Various concentrations of Cu 2+ ions enhance fibril formation while binding of copper ions to β-amyloid noticeably increases its toxicity for cells (Dai et al., 2006 Sarell et al., 2010). In addition, substoichiometric concentrations of Cu 2+ are more toxic to cells (Sarell et al., 2010).

Fibril formation is highly pH-dependent and Cu 2+ ions cause it to occur at physiological pH. However, the formation of amorphous aggregates dominates in acidic conditions (Jun et al., 2009 Sarell, 2010 Lv et al., 2013). In a proton-rich environment, β-amyloid (Aβ40) possesses two copper binding sites, and its second bound Cu 2+ ion causes the formation of amorphous aggregates by preventing the conformational transition of β-amyloid into amyloid fibrils (Jun et al., 2009).

The production of Reactive Oxygen Species (ROS) is a key factor in β-amyloid toxicity toward neurons, which is dependent on metal ion redox properties. Copper ions in complex with β-amyloid fibrils produce hydrogen peroxide, in the presence of biological reducing agents (Parthasarathy et al., 2014). When the ratio of copper to peptide increases, hydrogen peroxide levels and the production of hydroxyl radicals increase, and the morphology of aggregates changes from fibrillar to amorphous (Mayes et al., 2014). Although previous studies have presented ROS as fatal molecules provoking neurodegeneration, the accumulated evidence shows that some ROS act as essential molecules in processes underlying cognition and memory formation (Klann, 1998 Yermolaieva et al., 2000 Knapp and Klann, 2002a,b Kamsler and Segal, 2003, 2004 Hu et al., 2006 Kishida and Klann, 2007). On the other hand, some results imply that the copper-amyloid complex produces fewer ROS than free copper ions (Nakamura et al., 2007). According to in vitro data, oligomeric and fibrillar forms of β-amyloid inhibit H2O2 generation at higher concentrations of Cu 2+ . In addition, the fibrillar form generates less H2O2 than the oligomeric form (Fang et al., 2010).

Copper toxicity in AD brains is attributed to the oxidized form of copper ions, i.e., Cu 2+ , (Brewer, 2015 Greenough et al., 2016). In contrast, other data show that copper ions are only transported in their reduced form, i.e., Cu 1+ , (Macreadie, 2008). Some studies suggest that Cu 2+ bypasses the liver (Brewer, 2015). Otherwise, some data show that the removal of Cu 1+ from β-amyloid, hinders the formation of oligomers and prevents ROS production (Atrián-Blasco et al., 2015). A study of the affinity of the soluble copper-binding domain of the β-amyloid peptide for Cu 1+ shows that it binds to β-amyloid stronger than Cu 2+ suggesting Cu 1+ is the relevant in vivo oxidation state (Feaga et al., 2011). Both Cu 1+ and Cu 2+ inhibit β-amyloid degradation by insulin-degrading enzyme, but Cu 1+ cations act as irreversible inhibitors (Grasso et al., 2011). Copper ion by reduction from Cu 2+ to Cu 1+ protects proteins against free radicals (Deloncle and Guillard, 2014).

A meta-analysis (Schrag et al., 2011) and subsequent studies (James et al., 2012 Szabo et al., 2016) demonstrated that the concentration of total copper is decreased in the brain of AD patients, while the concentration of labile copper is increased in the most affected regions of the AD brain (James et al., 2012). In addition, AD cortical tissues (James et al., 2012) and the cortex of mice with Traumatic Brain Injury show an elevated binding capacity for Cu 2+ (Peng et al., 2015). Another study shows that in APP sw/0 mouse model of AD, which shows parenchymal plaques but no neuronal loss (Elder et al., 2010 Sasaguri et al., 2017), unlike in the control mouse in which the metal accumulates in the capillaries, copper ions accumulate in brain parenchyma. These ions could bind to β-amyloid and stimulate β-sheet conformation, aggregation, and toxicity (Singh et al., 2013).

In the 𠇊myloid cascade hypothesis,” plaque formation is a main event in AD pathology but it is sometimes preceded by neurodegeneration, and plaque clearance by immunization of AD patients does not prevent disease progression (Chui et al., 1999 Oddo et al., 2003 Holmes et al., 2008 Bayer and Wirths, 2010 Bittner et al., 2012 Wright et al., 2013 Xie et al., 2013 Jung et al., 2015). Moreover, some studies show that senile plaques exist in cognitively normal people (Jack et al., 2010 Sperling et al., 2011 Swerdlow, 2011 Esparza et al., 2013) and, despite an equivalent plaque presence, the concentration of brain amyloid oligomers is higher in AD patients than in normal cases. The “Toxic oligomers hypothesis” explains these events by suggesting that small, diffusible oligomers are responsible for toxicity, and not the amyloid plaques (Naylor et al., 2008 Sarell, 2010). The oligomers derived from cell culture have unusually high chemical stability and resist degradation into monomers by various degrading agents, supporting the existence of covalent cross-links between the oligomers (Podlisny et al., 1995 Walsh et al., 2002 Lesné et al., 2006 Naylor et al., 2008). Based on in vitro experiments, Cu 2+ binding to β-amyloid can lead to the formation of dityrosine-linked dimers of β-amyloids found in AD (Atwood et al., 2004 Haeffner et al., 2005 Bush and Tanzi, 2008 Streltsov et al., 2008 Al-Hilaly et al., 2013). In the presence of Cu 2+ , the dimer conformation changes from parallel to anti-parallel and is stabilized by the occupied copper binding sites (Hane et al., 2013). However, the same authors showed later that Cu 2+ at nanomolar concentrations has no effect on peptide–peptide affinity in the amyloid dimer (Hane et al., 2016). Other authors have demonstrated that binding of Cu 2+ ions induces structural changes in the amyloid dimer resulting in N-termini interactions within it (Lv et al., 2013). The mutant dimer that is unable to produce cross-links provides supporting evidence for the toxicity of Cu 2+ cross-linked dimers because the mutant dimer’s properties are the same as those of the wild type dimer except that it has no neurotoxicity (Barnham, 2004 Figure 1). In addition, other studies suggest that the toxicity of the cross-linked dimer is due to enhanced membrane binding (Ciccotosto et al., 2004).

FIGURE 1. The role of copper in β-amyloid neurotoxicity in AD. (A) Copper binding to β-amyloid peptides leads to the formation of dityrosine-linked β-amyloid dimers, which resist degradation into monomers and have neurotoxic properties. (B) Mutant β-amyloids (Tyr to Ala) in the presence of copper ions have no toxicity effect on neurons and degrade to monomers by degrading agents.

Elimination of Cu 2+ from β-amyloid prevents amyloid aggregation in vitro (Wu et al., 2008 Behbehani et al., 2012), and promotes β-amyloid degradation, and prevents H2O2 formation. Hence, it also decreases cell mortality (Wu et al., 2008). Because of these positive effects of copper elimination, some studies have targeted copper chelators as suitable drugs (Moret et al., 2006 Geng et al., 2012 Nguyen et al., 2014 Savelieff et al., 2014 Hauser-Davis et al., 2015 Hung et al., 2015 Yang et al., 2016). However, the most recently published review on copper chelation therapy states that the results in human clinical trials are discouraging (Drew, 2017), even though some authors have refuted this interpretation (Squitti et al., 2017a). Furthermore, studies in Tg2576 mouse model of AD, which shows parenchymal plaques but no neuronal loss (Elder et al., 2010 Sasaguri et al., 2017), show that although the use of chelator helps to prevent AD, it is inefficient in AD treatment suggesting that systemic copper removal is useful only in the early stages of the disease (Quinn et al., 2010). Interestingly, there is some evidence that making changes in brain copper uptake in the primary stages can have a considerable effect on amyloid pathology (Lang et al., 2013).

Until 2012, a number of ambiguous results published previously fueled a debate about copper levels in AD patients. Overall, six meta-analyses have been carried out in the last 6 years to evaluate copper concentrations in AD in different biological matrices (serum, plasma, and cerebrospinal fluid). These meta-analyses, combining data collected from studies published between 1984 and 2017 (Bucossi et al., 2011 Ventriglia et al., 2012 Schrag et al., 2013 Squitti et al., 2014a Wang et al., 2015 Li et al., 2017), provide unequivocal results: total copper (Bucossi et al., 2011 Ventriglia et al., 2012 Schrag et al., 2013 Squitti et al., 2014a Wang et al., 2015 Li et al., 2017) and 𠇏ree” copper (Squitti et al., 2014a) are higher in the serum–plasma of AD patients in comparison with healthy controls. More specifically, the large stand most recent meta-analysis (total pool of subjects analyzed: 2128 AD vs. 2889 healthy controls) includes a total of 35 studies: 18 report an increase, 14 no difference, and one a decrease in values of copper in the serum–plasma in AD compared to healthy controls (Li et al., 2017). Three additional studies appeared after the publication of this consensus result (Guan et al., 2017 Pu et al., 2017 Talwar et al., 2017), reporting increased concentrations of Cu 2+ in AD patients vs. controls.

Recent studies have contributed to unraveling further the initial controversy, demonstrating that the increased concentration of serum copper in AD can be explained by the increased concentrations of the plasma fraction of the 𠇏ree” copper pool in the blood, which is detected in only 50�% of AD patients (Squitti et al., 2016 Szabo et al., 2016 Tecchio et al., 2016 Talwar et al., 2017). An older study also indicated that serum copper concentration rises in a special type of AD (González et al., 1999). Some studies have proposed a genetic basis for this AD subtype as an explanation of this observation (González et al., 1999 Liu et al., 2013 Squitti et al., 2013, 2017b Mercer et al., 2017).


Article information

Copper inducing Aβ42 rather than Aβ40 nanoscale oligomer formation is the key process for Aβ neurotoxicity

L. Jin, W. Wu, Q. Li, Y. Zhao and Y. Li, Nanoscale, 2011, 3, 4746 DOI: 10.1039/C1NR11029B

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The Relationship between Copper and Alzheimer's Disease - Biology

In 1942, Dr. H. W. Bennetts dissected 21 cattle known to have died of "falling disease". This was the name given to the sudden, inexplicable death that struck herds of cattle in certain regions of Australia. Dr. Bennett believed the disease was linked to copper deficiency. He found that 19 of the 21 cattle had abnormal hearts, showing atrophy and abnormal connective tissue infiltration (fibrosis) of the heart muscle (1).

In 1963, Dr. W. F. Coulson and colleagues found that 22 of 33 experimental copper-deficient pigs died of cardiovascular disease. 11 of 33 died of coronary heart disease, the quintessential modern human cardiovascular disease. Pigs on a severely copper-deficient diet showed weakened and ruptured arteries (aneurysms), while moderately deficient pigs "survived with scarred vessels but demonstrated a tendency toward premature atherosclerosis" including foam cell accumulation (2). Also in 1963, Dr. C. R. Ball and colleagues published a paper describing blood clots in the heart and coronary arteries, heart muscle degeneration, ventricular calcification and early death in mice fed a lard-rich diet (3).

This is where Dr. Leslie M. Klevay enters the story. Dr. Klevay suspected that Ball's mice had suffered from copper deficiency, and decided to test the hypothesis. He replicated Ball's experiment to the letter, using the same strain of mice and the same diet. Like Ball, he observed abnormal clotting in the heart, degeneration and enlargement of the heart muscle, and early death. He also showed by electrocardiogram that the hearts of the copper-deficient mice were often contracting abnormally (arrhythmia).

But then the coup de grace : he prevented these symptoms by supplementing the drinking water of a second group of mice with copper (4). In the words of Dr. Klevay: "copper was an antidote to fat intoxication" (5). I believe this was his tongue-in-cheek way of saying that the symptoms had been misdiagnosed by Ball as due to dietary fat, when in fact they were due to a lack of copper.

Since this time, a number of papers have been published on the relationship between copper intake and cardiovascular disease in animals, including several showing that copper supplementation prevents atherosclerosis in one of the most commonly used animal models of cardiovascular disease (6, 7, 8). Copper supplementation also corrects abnormal heart enlargement-- called hypertrophic cardiomyopathy-- and heart failure due to high blood pressure in mice (9).

  • Heart attacks (myocardial infarction)
  • Blood clots in the coronary arteries and heart
  • Fibrous atherosclerosis including smooth muscle proliferation
  • Unstable blood vessel plaque
  • Foam cell accumulation and fatty streaks
  • Calcification of heart tissues
  • Aneurysms (ruptured vessels)
  • Abnormal electrocardiograms
  • High cholesterol
  • High blood pressure

The second reason you may not have heard of the theory is due to a lab assay called copper-mediated LDL oxidation. Researchers take LDL particles (from blood, the same ones the doctor measures as part of a cholesterol test) and expose them to a high concentration of copper in a test tube. Free copper ions are oxidants, and the researchers then measure the amount of time it takes the LDL to oxidize. Yet questions have been raised about the relevance of this method to human cardiovascular disease, because studies have shown that the amount of time it takes copper to oxidize LDL in a test tube doesn't predict how much oxidized LDL you'll actually find in the bloodstream of the person you took the LDL from ( 10 , 11).

The fact that copper is such an efficient oxidant has led some researchers to propose that copper oxidizes LDL in human blood, and therefore dietary copper may contribute to heart disease (oxidized LDL is likely a central player in heart disease). The problem with this theory is that there are virtually no free copper ions in human serum. Then there's the fact that supplementing humans with copper actually reduces the susceptibility of red blood cells to oxidation (by copper in a test tube, unfortunately), which is difficult to reconcile with the idea that dietary copper increases oxidative stress in the blood (13).

The third reason you may never have heard of the theory is more problematic. Several studies have found that a higher level copper in the blood correlates with a higher risk of heart attack (14, 15). At this point, I could hang up my hat, and declare the animal experiments irrelevant to humans. But let's dig deeper.

Nutrient status is sometimes a slippery thing to measure. As it turns out, serum copper isn't a good marker of copper status. In a 4-month trial of copper depletion in humans, blood copper stayed stable, while the activity of copper-dependent enzymes in the blood declined (16). These include the important copper-dependent antioxidant, superoxide dismutase. As a side note, lysyl oxidase is another copper-dependent enzyme that cross-links the important structural proteins collagen and elastin in the artery wall, potentially explaining some of the vascular consequences of copper deficiency. Clotting factor VIII increased dramatically during copper depletion, perhaps predicting an increased tendency to clot. Even more troubling, three of the 12 women developed heart problems during the trial, which the authors felt was unusual:

The other reason to be skeptical of the association between blood copper and heart attack risk is that inflammation increases copper in the blood (18, 19). Blood copper level correlates strongly with the marker of inflammation C-reactive protein (CRP) in humans, yet substantially increasing copper intake doesn't increase CRP (20, 21). This suggests that elevated blood copper is likely a symptom of inflammation, rather than its cause, and presents a possible explanation for the association between blood copper level and heart attack risk.

Only a few studies have looked at the relationship between more accurate markers of copper status and cardiovascular disease in humans. Leukocyte copper status, a marker of tissue status, is lower in people with cardiovascular disease (22, 23). People who die of heart attacks generally have less copper in their hearts than people who die of other causes, although this could be an effect rather than a cause of the heart attack (24). Overall, I find the human data lacking. It would be useful to see more studies examining liver copper status in relation to cardiovascular disease, as the liver is the main storage organ for copper. Until we have more human data, it will remain unclear whether copper deficiency is a significant contributor to cardiovascular disease.

According to a 2001 study, the majority of Americans may have copper intakes below the USDA recommended daily allowance (25), many substantially so. This problem is exacerbated by the fact that copper levels in food have declined in industrial nations over the course of the 20th century, something I'll discuss in the next post.


A complex link between body mass index and Alzheimer's

Though obesity in midlife is linked to an increased risk for Alzheimer's disease, new research suggests that a high body mass index later in life doesn't necessarily translate to greater chances of developing the brain disease.

In the study, researchers compared data from two groups of people who had been diagnosed with mild cognitive impairment -- half whose disease progressed to Alzheimer's in 24 months and half whose condition did not worsen.

The researchers zeroed in on two risk factors: body mass index (BMI) and a cluster of genetic variants associated with higher risk for Alzheimer's disease.

Their analysis showed that a higher genetic risk combined with a lower BMI was associated with a higher likelihood for progression to Alzheimer's, and that the association was strongest in men.

The finding does not suggest people should consider gaining weight in their later years as a preventive effort -- instead, researchers speculate that lower BMI in these patients was likely a consequence of neurodegeneration, the progressive damage to the brain that is a hallmark of Alzheimer's. Brain regions affected by Alzheimer's are also involved in controlling eating behaviors and weight regulation.

"We don't want people to think they can eat everything they want because of this lower BMI association," said senior study author Jasmeet Hayes, assistant professor of psychology at The Ohio State University.

"We know that maintaining a healthy weight and having a healthy diet are extremely important to keeping inflammation and oxidative stress down -- that's a risk factor that is modifiable, and it's something you can do to help improve your life and prevent neurodegenerative processes as much as possible," she said. "If you start to notice rapid weight loss in an older individual, that could actually be a reflection of a potential neurodegenerative disease process."

The study was published online recently in the Journals of Gerontology: Series A.

Previous research has found a link between obesity and negative cognitive outcomes, but in older adults closer to the age at which Alzheimer's disease is diagnosed, the results have been mixed, Hayes said. And though a variant to the gene known as APOE4 is the strongest single genetic risk factor for Alzheimer's, it explains only about 10 to 15% of overall risk, she said.

Hayes has focused her research program on looking at multiple risk factors at the same time to see how they might interact to influence risk -- and to identify health behaviors that may help reduce the risk.

"We're trying to add more and more factors. That is my goal, to one day build a more precise and better model of the different combinations of risk factors," said Hayes, also an investigator in Ohio State's Chronic Brain Injury Initiative. "Genetic risk is important, but it really explains only a small part of Alzheimer's disease, so we're really interested in looking at other factors that we can control."

For this study, the research team obtained data from the Alzheimer's Disease Neuroimaging Initiative, compiling a sample of 104 people for whom BMI and polygenic risk scores were available. Fifty-two individuals whose mild cognitive impairment (MCI) had progressed to Alzheimer's in 24 months were matched against demographically similar people whose MCI diagnosis did not change over two years. Their average age was 73.

Statistical analysis showed that individuals with mild cognitive impairment who had both a lower BMI and higher genetic risk for Alzheimer's were more likely to progress to Alzheimer's disease within 24 months compared to people with a higher BMI.

"We think there's interaction between the genetics and lower BMI, and having both of these risk factors causes more degeneration in certain brain regions to increase the likelihood of developing Alzheimer's disease," said Jena Moody, a graduate student in psychology at Ohio State and first author of the paper.

The effect of the BMI-genetic risk interaction was significant even after taking into account the presence of beta-amyloid and tau proteins in the patients' cerebrospinal fluid -- the core biomarkers of Alzheimer's disease.

The relationship between low BMI and high genetic risk and progression to Alzheimer's was stronger in males than in females, but a larger sample size and additional biological data would be needed to expand on that finding, the researchers said.

Because brain changes can begin long before cognitive symptoms surface, a better understanding of the multiple risk factors for Alzheimer's could open the door to better prevention options, Moody said.

"If you can identify people at higher risk before symptoms manifest, you could implement interventions and prevention techniques to either slow or prevent that progression from happening altogether," she said.

To date, scientists have suggested preventive steps include maintaining a healthy weight and diet and participating in activities that reduce inflammation and promote neurofunctioning, such as exercise and mentally stimulating activities.

"We're finding again and again how important inflammation is in the process," Hayes said. "Especially in midlife, trying to keep that inflammation down is such an important aspect of maintaining a healthy lifestyle and preventing accelerated aging."

This work was supported by the National Institute on Aging and Ohio State's Chronic Brain Injury Initiative.

Additional co-authors include Kate Valerio, Alexander Hasselbach, Sarah Prieto and Scott Hayes of Ohio State and Mark Logue of Boston University and the VA Boston Healthcare System.


New insights into Alzheimer's disease

A new study by Florida State University researchers may help answer some of the most perplexing questions surrounding Alzheimer's disease, an incurable and progressive illness affecting millions of families around the globe.

FSU Assistant Professor of Psychology Aaron Wilber and graduate student Sarah Danielle Benthem showed that the way two parts of the brain interact during sleep may explain symptoms experienced by Alzheimer's patients, a finding that opens up new doors in dementia research. It is believed that these interactions during sleep allow memories to form and thus failure of this normal system in a brain of a person with Alzheimer's disease may explain why memory is impaired.

The study, a collaboration among the FSU Program in Neuroscience, the University of California, Irvine, and the University of Lethbridge in Alberta, Canada, was published online in the journal Current Biology and will appear in the publication's July 6 issue.

"This research is important because it looks at possible mechanisms underlying the decline of memory in Alzheimer's disease and understanding how it causes memory decline could help identify treatments," Benthem said.

Wilber and Benthem's study, based on measuring brain waves in mouse models of the disease, gave researchers a number of new insights into Alzheimer's including how the way that two parts of the brain -- the parietal cortex and the hippocampus -- interact during sleep may contribute to symptoms experienced by Alzheimer's patients, such as impaired memory and cognition, and getting lost in new surroundings.

The team had examined a phenomenon known as memory replay -- the playing back of activity patterns from waking experience in subsequent sleep periods -- in a mouse model of Alzheimer's disease as a potential cause of impaired spatial learning and memory.

During these memory replay periods, they found that the mice modeling aspects of Alzheimer's Disease in humans had impaired functional interactions between the hippocampus and the parietal cortex.

The hippocampal formation is crucial for the storage of "episodic" memories -- a type of long-term memory of a past experience -- and is thought to be important for assisting other parts of the brain in extracting generalized knowledge from these personal experiences.

"Surprisingly, a better predictor of performance and the first impairment to emerge was not 'memory replay' per se, but was instead the relative strength of the post-learning coupling between two brain regions known to be important for learning and memory: the hippocampus and the parietal cortex," Wilber said.


Watch the video: 7ο Μοριοδοτούμενο Σεμινάριο: Νόσος Alzheimer (January 2022).