Aricept

Most of the (few) approved Alzheimer’s drugs are cholinesterase inhibitors — that is, they stop the breakdown of the neurotransmitter acetylcholine. A new study explains why they help. It appears they allow signals to enter the brain with more precision and less background noise.

The study involved 13 healthy young adults, some of whom were given the cholinesterase inhibitor galantamine, before listening to a series of modulating tones while focusing on a simple concentration task. The patterns of neural activity demonstrated by those on the drug most closely fit a model in which the signals coming into the brain were sharpened. This was something of a surprise, since it has been generally assumed that the effects would be most pronounced in the ‘higher-order’ processing regions.

The findings are an interesting reminder of the importance of sensory perception for optimal cognition. It should be noted, though, that this sharpening of the signal did occur in an environment in which the stimuli were predictable.

http://www.eurekalert.org/pub_releases/2013-05/vt-taf050713.php

Because long-term cognitive decline can occur in some older adults after undergoing surgery, there has been some concern that exposure to anesthesia may be associated with increased dementia risk. It is therefore pleasing to report that data from the very large, long-running Mayo Clinic Study, the Rochester Epidemiology Project, has found that receiving general anesthesia for procedures after age 45 is not a risk factor for developing dementia.

http://www.eurekalert.org/pub_releases/2013-05/mc-nlb042913.php

Late-life depression is associated with an increased risk for all-cause dementia, Alzheimer’s disease, and, most predominantly, vascular dementia, a new study shows.

A new meta-analysis extends previous research showing a link between depression and Alzheimer’s disease to late-life depression and dementia. The analysis of 23 studies concluded that those with late-life depression were significantly more likely to develop dementia (1.85 times more likely), and that the risk of developing vascular dementia was significantly greater than that of developing Alzheimer’s (2.52 vs 1.65).

Late-life depression is estimated to affect 15% of older adults (65+) in the U.S. It has been associated to social isolation, as well as poorer health.

Interestingly, another recent study has explored the difficulties of disentangling major depression and early Alzheimer’s in older adults, given the overlap in symptoms. The study, involving 120 older depressed patients, found that tests of episodic memory were most predictive of Alzheimer’s (as compared to other cognitive tests, for example, in executive function).

http://www.futurity.org/health-medicine/late-life-depression-may-boost-dementia-risk/ (Press release, 1st study)

http://newoldage.blogs.nytimes.com/2013/05/01/does-depression-contribute-to-dementia/ (Commentary, 1st study)

I’ve been happily generous with cinnamon on my breakfast ever since the first hints came out that cinnamon might help protect against Alzheimer’s (it’s not like it’s an ordeal to add cinnamon!). Now a new study has revealed why. Two compounds found in cinnamon —cinnamaldehyde and epicatechin —appear to help prevent tau tangles (one of the characteristics of Alzheimer’s).

Cinnamaldehyde protects tau from oxidative stress, by binding to two residues of an amino acid called cysteine on the tau protein. This protects the cysteine residues from changing in ways that contribute to the development of Alzheimer’s.

Epicatechin is a powerful antioxidant that I have mentioned before. Found in a number of foods, including blueberries, chocolate, and red wine, it similarly responds to oxidation by sequestering reactive byproducts such as the cysteine residues.

The findings also help explain previous research showing cinnamon’s beneficial effects in managing blood glucose and other problems associated with diabetes. Higher glucose levels lead to oxidative stress.

Given the early stage of the research, the researchers do caution against eating more than typical amounts of cinnamon – but there’s surely no harm in including it in your daily diet, and it may well do some good!

http://www.futurity.org/top-stories/can-cinnamon-prevent-alzheimer%e2%80%99s-tangles/

Last year, a cancer drug, Bexarotene, was touted as a potential treatment for Alzheimer’s disease. However, four independent studies have now failed to replicate the most dramatic result of the original study: a claim that the drug could clear half the amyloid plaques in a mere 72 hours.

Still, two of the studies confirmed findings that the drug reduced levels of amyloid-beta, and one showed improved cognition in mice.

The inconsistencies suggest more research is needed. The drug is now being tested in humans.

http://www.nature.com/news/studies-cast-doubt-on-cancer-drug-as-alzheimer-s-treatment-1.13058

We know that the E4 variant of the APOE gene greatly increases the risk of developing Alzheimer’s disease, but the reason is a little more mysterious. It has been thought that it makes it easier for amyloid plaques to form because it produces a protein that binds to amyloid beta. However, a new study shows that APOE and amyloid beta don’t bind together in cerebrospinal fluid and in fluids present outside cells grown in dishes, making it unlikely that they are binding together in the brain.

Mouse and cell culture experiments suggest instead that the APOE protein may be blocking a pathway that normally helps degrade amyloid beta — both APOE and amyloid beta seem to compete to bind to an astrocyte receptor. Previous work has shown that astrocytes can degrade amyloid beta.

The findings suggest that therapeutic strategies that target APOE need to be redirected.

http://www.futurity.org/health-medicine/sticky-questions-about-role-of-alzheimer%e2%80%99s-gene/

A new study adds to growing evidence of a link between sleep problems and Alzheimer’s. The interesting thing is that this association – between sleep apnea and Alzheimer’s biomarkers — wasn’t revealed until the data was separated out according to BMI.

Those with sleep apnea and a BMI under 25 showed several Alzheimer’s biomarkers (increased levels of tau in the cerebrospinal fluid, greater atrophy of the hippocampus, glucose hypometabolism in regions vulnerable to Alzheimer’s). This (with the exception of glucose hypometabolism in the mediotemporal lobe only) was not found in those with sleep apnea and a higher BMI.

The study involved 68 healthy older adults (average age 71), of whom 18 had normal breathing, 33 mild sleep apnea, and 17 moderate-severe apnea. Those in the latter group tended to have higher BMIs.

Some 10-20% of middle-aged adults in the U.S. have sleep apnea, and this jumps dramatically in those over 65 (30-60%), where the link to obesity is much smaller. The researchers suggest that early preclinical Alzheimer’s damage might be a reason, and plan follow-up research to assess what impact CPAP therapy for sleep apnea has on the Alzheimer’s biomarkers.

Those interested in the relationship between poor sleep and later development of Alzheimer’s might also like to read a Guardian article on the subject.

http://www.eurekalert.org/pub_releases/2013-05/ats-sft051413.php

Osorio, R.S. et al. 2013. Sleep-Disordered Breathing, Aging And Risk For Alzheimer's Disease In Cognitively Normal Subjects. Abstract 38456. Presented at the ATS 2013 International Conference.

Analysis of data from 418 older adults (70+) has found that carriers of the ‘Alzheimer’s gene’, APOEe4, were 58% more likely to develop mild cognitive impairment compared to non-carriers. However, ε4 carriers with MCI developed Alzheimer’s at the same rate as non-carriers. The finding turns prevailing thinking on its head: rather than the gene increasing the risk of developing Alzheimer’s, it appears that it increases the risk of MCI — and people with MCI are the main source of new Alzheimer’s diagnoses.

In this regard, it’s worth noting that the cognitive effects of this gene variant have been demonstrated in adults as young as the mid-20s.

The finding points to the benefit of genetic testing for assessing your likelihood of cognitive impairment rather than dementia — and using this knowledge to build habits that fight cognitive impairment.

http://www.futurity.org/health-medicine/genetic-test-fails-to-show-alzh…

A study involving nearly 6,000 African American older adults has found those with a specific gene variant have almost double the risk of developing late-onset Alzheimer’s disease compared with African Americans who lack the variant. The size of the effect is comparable to that of the ‘Alzheimer’s gene’, APOE-e4.

The gene (ABCA7) is involved in the production of cholesterol and lipids. It also affects the transport of several important proteins, including amyloid precursor protein, which is involved in the production of amyloid-beta.

The finding suggests that lipid metabolism may be a more important pathway in Alzheimer’s disease in African Americans than in whites. Cholesterol and lipid imbalances are more common in African Americans.

The gene does not seem to be a significant risk factor for whites, adding more weight to the idea that there are multiple pathways to the disease, and showing that the genetic underpinnings may vary among different populations (although it should be noted that other genes linked to Alzheimer’s risk in white populations were also significant for this group).

http://www.futurity.org/health-medicine/gene-tied-to-double-alzheimers-risk-in-african-americans/

New findings support a mathematical model predicting that the slow, steady firing of neurons in the dorsolateral prefrontal cortex that maintains visual representations in working memory relies on a class of NMDA receptors known as NR2B receptors. Blocking these receptors abolished persistent firing among pyramidal Delay cells.

Earlier studies have shown these types of NMDA receptors are often altered in patients with schizophrenia. They also seem to be altered in Alzheimer’s patients. The findings suggest that this may be one cause of cognitive deficits in those with schizophrenia and Alzheimer’s.

Ketamine, an anesthetic often abused as a street drug, also blocked these receptors, explaining at least in part why ketamine abuse can produce schizophrenia-like symptoms.

https://www.futurity.org/health-medicine/brains-sketch-pad-goes-blank-in-schizophrenia/

Data from 70 older adults (average age 76) in the Baltimore Longitudinal Study of Aging has found that those who reported poorer sleep (shorter sleep duration and lower sleep quality) showed a greater buildup of amyloid-beta plaques.

http://www.eurekalert.org/pub_releases/2013-10/tjnj-lsa101813.php

Studies linking head trauma with increased risk and earlier age of onset for Alzheimer's disease have yielded contradictory results. Now a population-based study involving 448 healthy older adults (70+) and 141 seniors with mild cognitive impairment has found that a history of head trauma was associated with higher levels of amyloid-beta plaques (a marker for Alzheimer’s) in those with MCI, but not in the cognitively normal. Similar rates of self-reported head trauma were found in the two groups (17% and 18%, respectively).

http://www.eurekalert.org/pub_releases/2013-12/aaon-acr122013.php

A gene linked to Alzheimer's has been linked to brain changes in childhood. This gene, SORL1, has two connections to Alzheimer’s: it carries the code for the sortilin-like receptor, which is involved in recycling some molecules before they develop into amyloid-beta; it is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway.

Brain imaging of 186 healthy individuals (aged 8-86) found that, even among the youngest, those with a specific variant of SORL1 showed a reduction in white matter connections. Post-mortem brain tissue from 269 individuals (aged 0-92) without Alzheimer's disease, found that the same SORL1 variant was linked to a disruption in the process by which the gene translated its code to become the sortilin-like receptor, and this was most prominent during childhood and adolescence. Another set of post-mortem brains from 710 individuals (aged 66-108), of whom the majority had mild cognitive impairment or Alzheimer's, found that the SORL1 risk gene was linked with the presence of amyloid-beta.

It may be that, for those carrying this gene variant, lifestyle interventions may be of greatest value early in life.

http://www.eurekalert.org/pub_releases/2013-12/cfaa-arg120313.php

A new study shows that a combination of inflammation and hypoxia activates microglia in a way that persistently weakens the connection between neurons, contributing to brain damage in conditions such as stroke and Alzheimer's disease.

http://www.eurekalert.org/pub_releases/2014-03/uobc-scb031214.php

Blocking a receptor involved in inflammation in the brains of mice with severe Alzheimer’s produced marked recovery in blood flow and vascular reactivity, a dramatic reduction in toxic amyloid-beta, and significant improvements in learning and memory.

The receptor was the bradykinin B1 receptor (B1R), and the finding confirms a role of B1R, and neuroinflammation, in the development of Alzheimer’s. It also points to a new target for therapy.

http://www.eurekalert.org/pub_releases/2013-06/mu-bor061713.php

Analysis of brain scans and cognitive scores of 64 older adults from the NIA's Baltimore Longitudinal Study of Aging (average age 76) has found that, between the most cognitively stable and the most declining (over a 12-year period), there was no significant difference in the total amount of amyloid in the brain, but there was a significant difference in the location of amyloid accumulation. The stable group showed relatively early accumulation in the frontal lobes, while the declining group showed it in the temporal lobes.

http://www.eurekalert.org/pub_releases/2013-07/uops-pop071513.php

A study involving 74 older adults (70+), of whom 3 had mild dementia, 33 were cognitively normal and 38 had mild cognitive impairment, has found that high levels of "good" cholesterol and low levels of "bad" cholesterol correlated with lower levels of the amyloid-beta plaques in the brain (a hallmark of Alzheimer's disease).

http://www.eurekalert.org/pub_releases/2013-12/uoc--hga122613.php

A new study involving 96 older adults initially free of dementia at the time of enrollment, of whom 12 subsequently developed mild Alzheimer’s, has clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads.

Specifically, it begins in the lateral entorhinal cortex (LEC), a gateway to the hippocampus. Over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular the parietal cortex. It’s thought that it spreads by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

Mouse models comparing the effects of elevated levels of tau in the LEC with elevated levels of APP, and with elevated levels of both, found that LEC dysfunction occurred only in the mice with high levels of both tau and APP. The LEC normally accumulates tau, making it more vulnerable to the accumulation of APP.

http://www.eurekalert.org/pub_releases/2013-12/cumc-ssw121713.php

Analysis of 40 spinal marrow samples, 20 of which belonged to Alzheimer’s patients, has identified six proteins in spinal fluid that can be used as markers for Alzheimer's. The analysis focused on 35 proteins that are associated with the lysosomal network — involved in cleaning and recycling beta amyloid. None of the six proteins had previously been linked to Alzheimer’s.

http://www.eurekalert.org/pub_releases/2013-10/lu-ast102313.php

A study involving 206 spousal and adult children caregivers of dementia sufferers (mostly Alzheimer’s) has found that about 84% of caregivers reported a clinically significant burden. Three factors were significant contributors to the burden:

• the direct impact of providing care on the caregiver’s life
• guilt
• frustration or embarrassment.

Caregiver depression and age predicted the first two factors. Caregivers' satisfaction with their relationship with the patient and patients' functional independence also predicted the direct impact of caregiving upon caregivers' lives. Patients' behavioral problems and caregivers' relationship satisfaction predicted frustration/embarrassment.

Caregiver burden has been found to be associated with poorer physical health, and increased rates of emotional distress and depression. This study shows that caregiver burden has several dimensions, each with its own predictors. The finding suggests that caregivers may benefit from interventions tailored to their specific subtype of burden.

http://www.eurekalert.org/pub_releases/2013-07/l-rhc071813.php

An Italian study has found that a significant percentage of Alzheimer’s patients suffer from Obstructive Sleep Apnea Syndrome. This respiratory disorder, which causes people to temporarily stop breathing during their sleep, affects cerebral blood flow, promoting cognitive decline. The finding adds to evidence that detecting and treating OSA early is important for preventing cognitive decline and dementia.

http://www.eurekalert.org/pub_releases/2013-10/ip-apn100813.php

Buratti, L. et al. 2013. Vascular Impairment in Alzheimer’s Disease: The Role of Obstructive Sleep Apnea. Journal of Alzheimer's Disease, 38 (2), 445-53.

A French study has predicted with 90% accuracy which patients with mild cognitive impairment would receive a clinical diagnosis of Alzheimer's disease within the following two years. The best neurological predictors were cortical thickness in two brain regions (the right anterior cingulate and middle frontal gyri), and the best cognitive predictors were deficits in both free recall and recognition episodic memory. Combining these measures achieved the highest accuracy.

http://www.eurekalert.org/pub_releases/2013-12/uom-amt120213.php

Peters, F., Villeneuve, S. & Belleville, S. 2014. Predicting Progression to Dementia in Elderly Subjects with Mild Cognitive Impairment Using Both Cognitive and Neuroimaging Predictors. Journal of Alzheimer's Disease, 38 (2) 307-318.

A brain imaging study of 162 healthy babies (2-25 months) has found that those who carried the ApoE4 gene (60 of the 162) tended to have increased brain growth in areas in the frontal lobe, and decreased growth in several areas in the middle and rear of the brain (precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions) — areas that tend to be affected in Alzheimer’s disease.

While this does not mean that those children are destined to develop Alzheimer’s, the findings do suggest brains of ApoE4 carriers tend to develop differently from those of non-carriers, and perhaps these early changes provide a “foothold” for the development of Alzheimer’s pathologies.

http://www.futurity.org/irregular-brain-growth-babies-risk-alzheimers/

A study involving genetically engineered fruit flies adds to our understanding of why sleep and bioclock disruptions are common in those with Alzheimer's disease. People with Alzheimer's often have poor biological rhythms — periods of sleep become shorter and more fragmented, resulting in periods of wakefulness at night and snoozing during the day. It has been thought that Alzheimer’s destroys the biological clock, but this new study indicates that the clock is still working — however, it’s being ignored by other parts of the brain.

http://www.eurekalert.org/pub_releases/2014-02/uoc-swu022514.php

Analysis of 1,821 Alzheimer’s brains has found that 11% of them actually suffered from a variant called hippocampal sparing Alzheimer’s. This subtype has been neither well recognized nor treated appropriately, but is now revealed to be relatively common.

The variant often produces symptoms that are substantially different from the most commonly known form of Alzheimer’s (e.g., frequent and sometimes profane angry outbursts, feelings that their limbs do not belong to them and are controlled by an "alien" unidentifiable force, or visual disturbances in the absence of eye problems), and because their memory is often little affected, they’re often misdiagnosed — often with frontotemporal dementia, or corticobasal syndrome. The problem mostly affects males, and at a much younger age than normal for Alzheimer’s. Correct diagnosis is particularly important because there is evidence that some Alzheimer’s drugs may work better with this variant than they do with the normal form.

The study was presented at the annual meeting of the American Academy of Neurology in Philadelphia, May 2014.

http://www.eurekalert.org/pub_releases/2014-05/mc-afo050114.php

Analysis of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative has revealed a genetic mutation (rs4728029) that’s associated with people who develop Alzheimer’s pathology but don’t show clinical symptoms in their lifetime. The gene appears to be related to an inflammatory response in the presence of phosphorylated tau. In other words, some people’s brains react to phosphorylated tau with a ‘bad’ inflammatory response, while others don’t.

http://www.eurekalert.org/pub_releases/2014-05/vumc-vs050214.php

Creating amyloid-beta requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments (beta-secretase or BACE). Both APP and BACE are common in the brain, so why don’t we all get Alzheimer’s?

Cultured hippocampal neurons and tissue from human and mouse brains have now revealed that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, ensuring the two proteins don’t have much contact with each other. However, in conditions promoting greater production of amyloid-beta protein (an increase in neuronal electrical activity), the convergence of APP and BACE also increases.

The findings not only add to our understanding of how Alzheimer’s gets started, but also suggests a possible therapeutic target: molecules that can physically keep APP and BACE-1 apart.

http://www.eurekalert.org/pub_releases/2013-08/uoc--wdw080213.php

http://www.alzforum.org/news/research-news/neural-activity-tips-endosomal-balance-hastens-amyloid-pathology

A study involving mice lacking a master clock gene called Bmal1 has found that as the mice aged, their brains showed patterns of damage similar to those seen in Alzheimer's disease and other neurodegenerative disorders. Many of the injuries seemed to be caused by free radicals. Several key antioxidant enzymes, which usually neutralize and help clear free radicals from the brain, have been found to peak in the middle of the day in healthy mice, but not in these mice lacking Bmal1. It may be that, without this daily increase, free radicals remain in the brain longer, causing more damage.

The finding may help explain the connection between sleep problems and Alzheimer’s.

http://www.eurekalert.org/pub_releases/2013-11/wuso-bc112513.php

Data from two longitudinal studies of older adults (a nationally representative sample of older adults, and the Alzheimer’s Disease Neuroimaging Initiative) has found that a brief cognitive test can distinguish memory decline associated with healthy aging from more serious memory disorders, years before obvious symptoms show up.

Moreover, the data challenge the idea that memory continues to decline through old age: after excluding the cognitively impaired, there was no evidence of further memory declines after the age of 69.

The data found that normal aging showed declines in recollective memory (recalling a word or event exactly) but not in reconstructive memory (recalling a word or event by piecing it together from clues about its meaning, e.g., recalling that “dog” was presented in a word list by first remembering that household pets were presented in the list). However, declines in reconstructive memory were reliable predictors of future progression from healthy aging to mild cognitive impairment and Alzheimer’s.

http://www.futurity.org/memory-test-mistakes-can-flag-trouble-sooner/

A study, involving 371 patients with mild cognitive impairment, has found that those with depressive symptoms had higher levels of amyloid-beta, particularly in the frontal cortex and the anterior and posterior cingulate gyrus (both involved in mood disorders such as depression).

The findings suggest that late-life depression could be a major risk factor for developing Alzheimer's faster than others.

http://www.eurekalert.org/pub_releases/2014-06/sonm-dit060814.php

Brendel, M. et al. 2014. Subsyndromal late life depression is associated with amyloid accumulation in mild cognitive impairment. Presented at the Society of Nuclear Medicine and Molecular Imaging's 2014 Annual Meeting, June 7, 2014, St. Louis, Missouri.

Following on from the evidence that Alzheimer’s brains show higher levels of metals such as iron, copper, and zinc, a mouse study has found that amyloid plaques in Alzheimer’s-like brains with significant neurodegeneration have about 25% more copper than those with little neurodegeneration. This is consistent with a human study showing very high levels of copper in Alzheimer’s plaques.

Iron, though doubled in Alzheimer’s brains compared to controls, was not significantly different as a function of neurodegeneration, and zinc showed very little difference.

The findings suggest that the cellular control of copper is altered in some way in Alzheimer’s brains, while the increase in oxidized iron suggests it might be useful as a biomarker for the early diagnosis of Alzheimer’s.

http://www.eurekalert.org/pub_releases/2013-08/ip-elo082113.php

Cognitive testing for dementia has a problem in that low scores on some tests may simply reflect a person's weakness in some cognitive areas, or the presence of a relatively benign form of mild cognitive impairment (one that is not going to progress to dementia). A 2008 study found that one of every six healthy adults scored poorly on two or more of 10 tests in a brief cognitive battery. Following this up, the same researchers now show that a more holistic view might separate those who are on the path to dementia from those who are not.

Data from 395 clinical patients (aged 60+) and 135 healthy older adults has revealed that, while the cognitively normal produce a pattern of scores on 13 cognitive tests that fits a bell-shaped curve, those experiencing some level of dementia produce a more skewed pattern. Increasingly lower scores and degree of positive skew was also associated with worsening dementia.

http://www.futurity.org/lopsided-cognition-may-predict-early-alzheimers/

http://www.eurekalert.org/pub_releases/2013-11/jhm-jhr111113.php

Understanding a protein's role in familial Alzheimer's disease

Genetic engineering of human induced pluripotent stem cells has revealed very specifically how a key mutated protein is involved in familial Alzheimer's. Familial Alzheimer’s is a subset of early-onset Alzheimer's disease that is caused by inherited gene mutations.

The study looked at presenilin 1 (PS1), a protein that catalyzes gamma-secretase, an enzyme that splits amyloid precursor protein (APP), creating amyloid-beta. About 20% of the time, these cuts result in potentially harmful amyloid-beta fragments. What this study has found is that mutations in PS1 double the frequency of these bad cuts. Such PS1 mutations are the most common cause of familial Alzheimer’s disease.

http://www.eurekalert.org/pub_releases/2013-11/uoc--uap111413.php

Rare genomic mutations linked to familial Alzheimer's

Mutations in three genes – amyloid precursor protein (APP) and presenilins 1 and 2 – account for around half of all cases of early-onset familial Alzheimer's. A new study has now implicated 10 copy-number variants (duplications or deletions creating a change in the number of copies of a gene), which were found in affected members of 10 families with early-onset Alzheimer's. Notably, different genomic changes were identified in each family.

Genetic data from 261 families with at least one member who developed Alzheimer's before the age of 65 found that two families had CNVs that included the well-established APP gene, but 10 others had CNVs not previously associated with Alzheimer's (although two, CHMP2B and MAPT, have been associated with frontotemporal dementia).

CNVs are now thought to have a greater impact on genomic diversity than do single-nucleotide changes (single-nucleotide polymorphisms, SNPs, are the most common type of genetic variation, involving a change in a single nucleotide: A, G, T, C).

http://www.eurekalert.org/pub_releases/2013-06/mgh-rgm061713.php

Tau protein stabilizes structures that transport supplies from the center of the cell to the extremities, but sometimes some tau is not bound to these microtubules and instead clumps together into neurofibrillary tangles — one of the hallmarks of Alzheimer's disease, and also linked to other neurodegenerative disorders. A new study supports the theory that ‘bad’ tau travels to different brain regions via the synapses — that is, it’s secreted with the signals passing between neurons.

http://www.eurekalert.org/pub_releases/2014-02/wuso-bca022514.php

More evidence for early changes in the eye in Alzheimer’s disease comes from a study involving both rats and postmortem human retinas. Changes were found in the retinal pigment epithelial layer (which harbors the supportive cells located in the back of the eye) and in the thickness of the choroidal layer that has blood vessels providing nutrients to the retina.

The finding is consistent with growing evidence that glaucoma is a neurodegenerative disorder similar to Alzheimer’s.

http://www.eurekalert.org/pub_releases/2014-03/cmc-vie031714.php

http://www.eurekalert.org/pub_releases/2013-11/gumc-cte110113.php

Analysis of data from more than 8,000 people, most of them older than 60, has revealed that, among the 5,000 people initially tested cognitively normal, carrying one copy of the “Alzheimer’s gene” (ApoE4) only slightly increased men’s risk of developing MCI or Alzheimer’s — but nearly doubled women’s risk (healthy men with APOE4 were 27% more likely to develop MCI or Alzheimer’s compared to those without the gene, while female carriers had an 81% greater risk).

Among the 2,200 who were initially diagnosed with mild cognitive impairment, women were more likely to progress to Alzheimer’s (116% greater risk vs 64% for men), but the difference wasn’t significant. However, it was significant when only comparing carriers of 2 copies of the common ApoE3 variant with carriers of one ApoE3 copy and one ApoE4 copy (there are three variants of the ApoE gene: E3 is the most common; E4 is the ‘bad’ one; E2 is actually protective). Analysis of imaging and biomarker data from 1,000 patients confirmed the gender difference.

A gender difference was first suggested in a 1997 paper, but the research had never been followed up until recently. The current study was preceded by a 2012 imaging study, that found that female ApoE4 carriers had brain connectivity significantly different from normal, while male carriers’ brains were little different than normal.

While it’s not known why there should be such differences, biomarkers suggested that the increased female risk has something to do with tau pathology. Previous research has also indicated that ApoE4 interacts with estrogen.

The finding suggests why Alzheimer’s is so much more common in women — not just because they tend to live longer, but because they are, indeed, more at risk. It also tells us that research referencing the ApoE gene should separate by gender.

http://www.eurekalert.org/pub_releases/2014-04/sumc-gvp040814.php

http://www.the-scientist.com/?articles.view/articleNo/39704/title/Sex-Biased-Alzheimer-s-Variant/

New research helps explain the role of amyloid-beta plaques in the development of Alzheimer's, by finding that the prion protein known to bind strongly to small aggregates of amyloid-beta peptides, also attaches to large fibrillar clumps of amyloid-beta. However, it doesn’t break them down into smaller, more harmful pieces, as has been suggested. This suggests that prion-protein-based compounds might be a useful means of treatment, to stop these smaller pieces from forming.

http://www.eurekalert.org/pub_releases/2014-04/acs-tut042314.php

The first detailed characterization of the molecular structures of amyloid-beta fibrils that develop in the brains of those with Alzheimer's disease suggests that different molecular structures of amyloid-beta fibrils may distinguish the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. A comparison of amyloid-beta fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage found different molecular structures, confirming cell research showing that amyloid-beta fibrils grown in a dish have different molecular structures depending on the specific growth conditions.

Obviously, this is a very small study, and will need to be confirmed across more patients. However, it’s important for indicating that structural variations may correlate with variations in Alzheimer’s, and that structure-specific amyloid imaging agents may need to be used.

http://www.eurekalert.org/pub_releases/2013-09/cp-aps090513.php

Comparison of the EEGs of 27 healthy older adults, 27 individuals with mild Alzheimer's and 22 individuals with moderate cases of Alzheimer’s, has found statistically significant differences across the three groups, using an algorithm that dissects brain waves of varying frequencies.

In particular, delta modulation of the beta frequency band reliably discriminated between healthy controls and mild Alzheimer’s, and disappeared with an increase in disease severity (from mild to moderate). Increase in disease severity was also marked by the appearance of delta modulation of the theta band.

It’s hoped that the algorithm can be used not only to help detect Alzheimer’s disease early, but also to monitor its progression. The algorithm has been shared on the NeuroAccelerator.org online data analysis portal, to enable it to be used by researchers around the world.

http://www.eurekalert.org/pub_releases/2013-08/i-tae082913.php

An Indian study involving 648 dementia patients, of whom 391 were bilingual, has found that, overall, bilingual patients developed dementia 4.5 years later than the monolingual ones. There was no additional advantage to speaking more than two languages.

The effect remained after factors such as education, sex, occupation, and urban vs. rural dwelling, had been accounted for. The finding is consistent with previous research, and is not only the largest study so far on the subject, but the first to show the effect also applies to illiterate people who had not attended school. Moreover, the effect was found in three different types of dementia: frontotemporal, vascular, and Alzheimer’s disease.

http://www.eurekalert.org/pub_releases/2013-11/uoe-sas110613.php

http://www.psmag.com/health/evidence-bilingualism-delays-onset-dementia-69595/

The hippocampus is damaged early in Alzheimer’s, while the thalamus is generally unaffected until the late stages. Brain imaging of the hippocampus and the thalamus in 31 patients with Alzheimer's and 68 healthy controls has revealed increased levels of iron in the hippocampus of those with Alzheimer’s, but not in the thalamus. Moreover, this increased iron was associated with tissue damage in patients with Alzheimer's but not in the healthy older individuals.

The findings support the view that iron accumulation is a factor in the development of Alzheimer's disease. It’s theorized that the buildup of tau and amyloid-beta is a response to the destruction of myelin. Myelin, and the oligodendrocytes that produces it, have the highest levels of iron of any cells in the brain.

http://www.eurekalert.org/pub_releases/2013-08/uoc--uss082013.php

Raven, E.P. 2013. Increased Iron Levels and Decreased Tissue Integrity in Hippocampus of Alzheimer’s Disease Detected in vivo with Magnetic Resonance Imaging. Journal of Alzheimer’s Disease, 37 (1), 127-136

Initial findings from an analysis of cerebrospinal fluid taken between 1995 and 2005 from 265 middle-aged healthy volunteers, of whom 75% had a close family member with Alzheimer’s disease, has found that the ratios of phosphorylated tau and amyloid-beta could predict mild cognitive impairment more than five years before symptom onset — the more tau and less amyloid-beta, the more likely MCI will develop. The rate of change in the ratio over time was also predictive — the more rapidly the ratio of tau to amyloid-beta went up, the more likely the eventual development of MCI.

The drop in amyloid-beta is thought to be because it is getting trapped in the plaques characteristic of Alzheimer’s.

http://www.futurity.org/spinal-fluid-test-may-predict-alzheimers/

11 new genetic susceptibility factors for Alzheimer’s identified

The largest international study ever conducted on Alzheimer's disease (I-GAP) has identified 11 new genetic regions that increase the risk of late-onset Alzheimer’s, plus 13 other genes yet to be validated. Genetic data came from 74,076 patients and controls from 15 countries.

Eleven genes for Alzheimer's disease have previously been identified.

Some of the newly associated genes confirm biological pathways already known to be involved, including the amyloid (SORL1, CASS4 ) and tau (CASS4 , FERMT2 ) pathways. The role of the immune response and inflammation (HLA-DRB5/DRB1 , INPP5D , MEF2C ) already implied by previous work (CR1, TREM2) is reinforced, as are the importance of cell migration (PTK2B), lipid transport and endocytosis (SORL1 ). New hypotheses have also emerged related to hippocampal synaptic function (MEF2C , PTK2B), the cytoskeleton and axonal transport (CELF1 , NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).

All this reinforces the idea that there are several paths to Alzheimer's, and no single treatment approach is likely to be successful.

http://www.eurekalert.org/pub_releases/2013-10/bumc-eng102513.php

ADAM10 mutations increase risk of Alzheimer's

Mouse studies have found that two mutations in a gene called ADAM10 (which codes for an enzyme involved in processing the amyloid precursor protein) impaired the folding of the gene, resulting in an increase in toxic amyloid-beta, and reduced neurogenesis in the hippocampus. Previous research had found that either of these mutations was associated with an increased risk of Alzheimer’s in seven families with the late-onset form of the disease.

The finding suggests that increasing ADAM10 activity might be a potential therapeutic approach.

http://www.eurekalert.org/pub_releases/2013-09/mgh-sct092413.php

TREM2 gene variant has dramatic effect on brain atrophy

Back in January 2013, a study (initially involving 2261 Icelanders, but then repeated on data from the U.S., Norway, the Netherlands, and Germany) reported on a rare genetic variant (TREM2) that nearly trebled Alzheimer’s risk. The variant was found in 0.46% of controls aged 85+. Carriers (aged 85-100) without Alzheimer’s also had poorer cognitive function than non-carriers.

TREM2 is thought to have an anti-inflammatory role, and so it’s thought that this rare mutation reduces its effectiveness.

In a more recent study, brain scans of 478 older adults (average age 76), of whom 100 had Alzheimer's, 221 had MCI and 157 were healthy controls, found that those carrying the TREM2 mutation lost 1.4-3.3% more of their brain tissue than non-carriers, and twice as fast. The loss appeared to be concentrated in the temporal lobe and hippocampus. Those carrying the TREM2 mutation may develop the disease three years earlier than expected.

http://www.eurekalert.org/pub_releases/2013-10/uosc-gml101513.php

Rajagopalan, P., Hibar, D.P., & Thompson, P.M. (2013). TREM2 and neurodegenerative disease. The New England Journal of Medicine, 369(16), 1564-1567. Published online Oct. 16, 2013; doi:10.1056/NEJMc1306509

Analyses of cerebrospinal fluid from 15 patients with Alzheimer's disease, 20 patients with mild cognitive impairment, and 21 control subjects, plus brain tissue from some of them, has found that those with Alzheimer’s had lower levels of a particular molecule involved in resolving inflammation. These ‘specialized pro-resolving mediators’ regulate the tidying up of the damage done by inflammation and the release of growth factors that stimulate tissue repair. Lower levels of these molecules also correlated with a lower degree of cognitive function.

The pro-resolving molecules identified so far are derivatives of omega-3 fatty acids, providing support for the idea that dietary supplements of these may provide benefit.

http://www.eurekalert.org/pub_releases/2014-02/ki-irf021414.php

Wang, X., Zhu, M., Hjorth, E., Cortés-Toro, V., Eyjolfsdottir, H., Graff, C., … Schultzberg, M. (2014). Resolution of inflammation is altered in Alzheimer’s disease. Alzheimer’s & Dementia. Retrieved from http://www.alzheimersanddementia.com/article/S1552-5260(14)00030-2/abst…

A three-year study involving 152 adults aged 50 and older, of whom 52 had been recently diagnosed with mild cognitive impairment and 31 were diagnosed with Alzheimer's disease, has found that those with mild or no cognitive impairment who initially had amyloid-beta plaques showed greater cognitive decline than those whose brain scans were negative for plaques. Moreover, 35% of plaque-positive participants who started with MCI progressed to Alzheimer's, compared to 10% without plaque, and they were more than twice as likely to be started on cognitive-enhancing medication.

The fact that 90% of those with MCI but no plaque didn’t progress to Alzheimer's (within the three-year period) points to the value of using PET imaging to identify patients unlikely to decline, who can be reassured accordingly. The finding also points to the importance of plaque buildup in cognitive decline.

http://www.eurekalert.org/pub_releases/2014-03/dumc-pdi030514.php

Two studies indicate that young people carrying the “Alzheimer’s gene” (ApoE4) do not have the pathological changes found later in life. The first study, involving 1412 adolescents, found no differences in hippocampal volume or asymmetry as a function of gene status. The second study, involving 173 young adults (average age, 28 ± 7.6 years), found no difference in plasma concentrations of amyloid-beta peptides.

http://www.eurekalert.org/pub_releases/2014-04/ip-neo040614.php

A new function has been found for the amyloid precursor protein (APP), which may help explain how it goes awry in Alzheimer's disease. It appears that APP (which is involved in the creation of amyloid-beta), also helps control the growth and maturation of newborn brain cells, by regulating a specific microRNA (microRNA-574-5p) that normally promotes neurogenesis.

http://www.eurekalert.org/pub_releases/2014-04/s-nrd041814.php

An analysis of the anatomical connectivity in the brains of 15 people with Alzheimer's disease, 68 with mild cognitive impairment and 28 healthy older individuals, has found several measures showed disease effects:

• widespread network disruptions
• decreases in network nodes
• neural fiber path length
• decreased signaling efficiency
• increased asymmetry in the proportions of fibers that connect the left and right cortical regions

http://www.eurekalert.org/pub_releases/2013-08/mali-wgw082213.php

Analysis of mitochondrial DNA (mtDNA) in the cerebrospinal fluid has found that both symptomatic Alzheimer’s patients and asymptomatic patients at risk of Alzheimer’s showed a significant decrease in levels of circulating cell-free mtDNA in the CSF. Patients with frontotemporal dementia did not display this.

Moreover, this potential biomarker occurred at least a decade before signs of dementia manifested, preceding the appearance of amyloid-beta and tau — suggesting not simply that it might be used as a very early sign of developing Alzheimer’s, but that the pathological process of Alzheimer's disease starts earlier than previously thought.

http://www.eurekalert.org/pub_releases/2013-08/cg-nbc081213.php

A study involving 97 healthy older adults (65-89) has found that those with the “Alzheimer’s gene” (APOe4) who didn’t engage in much physical activity showed a decrease in hippocampal volume (3%) over 18 months. Those with the gene who did exercise showed no change in the size of their hippocampus, nor did those without the gene, regardless of exercise. Physical activity was classified as low if the participant reported two or fewer days per week of low intensity activity, such as no activity, slow walking or light chores. Physical activity was classified as high if the participant reported three or more days/week of moderate to vigorous activity

The finding suggests that those with the risky gene will benefit most from regular exercise — indeed, this is as yet the only known means to counteract hippocampal shrinkage.

http://www.eurekalert.org/pub_releases/2014-04/uom-pak042214.php

The jugular venous reflux (JVR) occurs when the pressure gradient reverses the direction of blood flow in the veins, causing blood to leak backwards into the brain. A small pilot study has found an association between JVR and white matter changes in the brains of patients with Alzheimer’s disease and those with mild cognitive impairment. This suggests that cerebral venous outflow impairment might play a role in the development of white matter changes in those with Alzheimer’s.

JVR occurs when the internal jugular vein valves don’t open and close properly, which occurs more frequently in the elderly. The study involved 12 patients with Alzheimer’s disease, 24 with MCI, and 17 age-matched controls. Those with severe JVR were more likely to have hypertension, more and more severe white matter changes, and tended to have higher cerebrospinal fluid volumes.

Further research is needed to validate these preliminary findings.

http://www.futurity.org/vascular-changes-neck-may-alzheimers-role/

http://www.eurekalert.org/pub_releases/2013-11/uab-aav112513.php

Chung, C-P. et al. 2013. Jugular Venous Reflux and White Matter Abnormalities in Alzheimer’s Disease: A Pilot Study. Journal of Alzheimer’s Disease, 39 (3), 601-609.

New research supports the classification system for preclinical Alzheimer’s proposed two years ago. The classification system divides preclinical Alzheimer's into three stages:

Stage 1: Levels of amyloid beta begin to decrease in the spinal fluid. This indicates that the substance is beginning to form plaques in the brain.

Stage 2: Levels of tau protein start to increase in the spinal fluid, indicating that brain cells are beginning to die. Amyloid beta levels are still abnormal and may continue to fall.

Stage 3: In the presence of abnormal amyloid and tau biomarker levels, subtle cognitive changes can be detected by neuropsychological testing.

Long-term evaluation of 311 cognitively healthy older adults (65+) found 31% with preclinical Alzheimer’s, of whom 15% were at stage 1, 12% at stage 2, and 4% at stage 3. This is consistent with autopsy studies, which have shown that around 30% of cognitively normal older adults die with some preclinical Alzheimer's pathology in their brain. Additionally, 23% were diagnosed with suspected non-Alzheimer pathophysiology (SNAP), 41% as cognitively normal, and 5% as unclassified.

Five years later, 2% of the cognitively normal, 5% of those with SNAP, 11% of the stage 1 group, 26% of the stage 2 group, and 56% of the stage 3 group had been diagnosed with symptomatic Alzheimer's.

http://www.eurekalert.org/pub_releases/2013-09/wuso-apt092313.php

A new U.S. study suggests that Alzheimer's disease and other dementias are markedly under-reported on death certificates and medical records. Death certificates tend to only provide an immediate cause, such as pneumonia, and don’t mention the underlying condition that provoked it.

The study involved 2,566 older adults (65+; mean age 78) who received annual testing for dementia. The death rate was more than four times higher for those aged 75-84 who had been diagnosed with Alzheimer’s, and nearly three times higher in those with Alzheimer’s aged 85+. More than one-third of all deaths in those age groups were attributable to Alzheimer's disease. Median time from Alzheimer’s diagnosis to death was 3.8 years.

All this translates into an estimated mortality rate from Alzheimer's that is five to six times higher than the accepted number (derived from death certificates), which has put Alzheimer’s as the 6^th leading cause of death.

http://www.eurekalert.org/pub_releases/2014-03/aaon-sad022614.php

A new discovery helps explain why the “Alzheimer’s gene” ApoE4 is such a risk factor. It appears that ApoE4 causes a dramatic reduction in SirT1, an "anti-aging protein" that is targeted by resveratrol (present in red wine). This reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) was processed. Moreover, there was evidence that ‘bad’ tau and amyloid-beta could be prevented by increasing SirT1.

http://www.eurekalert.org/pub_releases/2013-10/bifa-mar101613.php

A five-year study involving 525 older adults (70+) found 46 had Alzheimer’s or aMCI and a further 28 went on to develop the conditions. The blood levels of 10 specific lipids predicted with more than 90% accuracy whether an individual would go on to develop either Alzheimer’s or aMCI within 2-3 years. The researchers speculate that the lower lipid levels could be an early indication that brain cells are beginning to lose their integrity and break down.

The continual failures in human clinical trials of promising therapies has led to a growing belief that once the cognitive symptoms of the Alzheimer’s have emerged, it may be too late to slow or reverse the neurological damage. However, treatments begun early enough may be more effective. This is why early diagnosis of Alzheimer’s risk is so critical.

http://www.futurity.org/blood-test-predicts-alzheimers-risk/

http://www.theguardian.com/science/2014/mar/09/blood-test-could-detect-early-signs-dementia

http://www.eurekalert.org/pub_releases/2014-03/gumc-bti030314.php

Analysis of data from 237 patients with mild cognitive impairment (mean age 79.9) has found that, compared to those carrying the ‘normal’ ApoE3 gene (the most common variant of the ApoE gene), the ApoE4 carriers showed markedly greater rates of shrinkage in 13 of 15 brain regions thought to be key components of the brain networks disrupted in Alzheimer’s.

http://www.eurekalert.org/pub_releases/2014-01/rson-gva010714.php

Brain scans of 10 persons with Down syndrome but no dementia, 10 persons with Down syndrome and dementia, and 10 healthy controls, have revealed a linear correlation between cognitive ability and compromised white matter connections in the frontal lobes among those with Down syndrome. Those with higher cognitive ability and motor skill coordination had healthier white matter integrity, and those with additional dementia showed the most deterioration.

Adults with Down Syndrome are known to be at high risk of developing Alzheimer’s after age 40.

http://www.eurekalert.org/pub_releases/2014-04/uok-nrs040714.php

A multi-year study involving 207 healthy older adults, in which their spinal fluids were repeatedly sampled and their brains repeatedly scanned, has found that disruptions in the default mode network emerges about the same time as chemical markers of Alzheimer’s appear in the spinal fluid (decreased amyloid-beta and increased tau protein). The finding suggests not only that amyloid-beta and tau pathology affect default mode network integrity early on, but that scans of brain networks may be an equally effective and less invasive way to detect early disease.

The greatest decrease in functional connectivity was found between the posterior cingulate and medial temporal regions. This decrease was not attributable to age or structural atrophy in these regions.

http://www.eurekalert.org/pub_releases/2013-08/wuso-bnd081913.php

A pilot study involving 94 older adults, of whom 18 had Alzheimer’s, 24 had MCI, 26 other dementias, and 26 were healthy controls, has found those with Alzheimer’s were significantly less able to detect the smell of peanut butter. Peanut butter was chosen because of its purity and accessibility (not because there's something special about its smell!).

The test was undertaken by the patient closing eyes and mouth and blocking one nostril, while the clinician held a ruler next to the open nostril and moved 14g of peanut butter in an open jar up the ruler one centimeter at a time, as the patient breathed out. Those in the early stages of Alzheimer’s disease showed a dramatic difference in detecting odor between the left and right nostril. The average distance at which the peanut butter was detected was 5.1 cm for the left nostril, compared to 17.4 cm for the right. The difference between these (12.4 cm) compares to an average 4.8 cm for other dementias, 1.9 for MCI, and 0 for healthy controls.

Of the 24 patients with MCI, only 10 patients showed a left nostril impairment, suggesting that this may be an indication of who will go on to develop Alzheimer’s.

http://www.futurity.org/can-peanut-butter-smell-test-confirm-alzheimers/

Analysis of 5715 cases from the National Alzheimer's Coordinating Center (NACC) database has found that nearly 80% of more than 4600 Alzheimer's disease patients showed some degree of vascular pathology, compared with 67% of the controls, and 66% in the Parkinson's group. The link was especially strong for younger patients with Alzheimer’s.

The findings support the view that early management of vascular risk factors, such as high blood pressure and cholesterol, and adopting a 'heart healthy' diet as well as exercise and other lifestyles in midlife, may delay or prevent the onset of dementia due to Alzheimer's.

http://www.eurekalert.org/pub_releases/2013-07/uops-pss070913.php

Data from 848 adults of all ages has found that brain volume in the default mode network declined in both healthy and pathological aging, but the greatest decline occurred in Alzheimer’s patients and in those who progressed from mild cognitive impairment to Alzheimer’s disease. Reduced brain volumes in these regions were associated with declines in cognitive ability, the presence of Alzheimer’s biomarkers in the cerebrospinal fluid, and with carrying the “Alzheimer’s gene”, the APOE4 allele.

The findings support the idea that neurodegeneration spreads through networks of connected brain regions, in a disease specific manner.

http://www.futurity.org/faster-brain-shrinkage-flag-alzheimers/

A study involving 254 people with dementia living at home has found that 99% of people with dementia and 97% of their caregivers had one or more unmet needs, 90% of which were safety-related. More than half of the patients had inadequate meaningful daily activities at a senior center or at home, one-third still needed a dementia evaluation or diagnosis, and more than 60% needed medical care for conditions related or unrelated to their dementia.

Unmet needs were significantly greater in those with higher cognitive function, in those with more depression, and those with lower income. Caregivers with less education and more symptoms of depression also had significantly more unmet needs.

Previous research has shown that greater unmet needs among people with dementia are predictive of nursing home placement and death. Caregiver stress also predicts nursing home admission for people with dementia.

The findings suggests that routine assessments of patient and caregiver care needs coupled with simple fixes in basic medical and supportive services and safety (such as, grab bars in the bathroom, carpets safely tacked down to prevent falls, and — a very American one — guns locked away) could go a long way toward keeping those with dementia from ending up in a nursing or assisted-living facility.

http://www.eurekalert.org/pub_releases/2013-12/jhm-lah121913.php