Alzheimer's: Causes

Latest Research News

A two-year study which involved metabolic testing of 50 people, suggests that Alzheimer's disease consists of three distinct subtypes, each one of which may need to be treated differently. The finding may help explain why it has been so hard to find effective treatments for the disease.

The subtypes are:

  • Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased.
  • Non-inflammatory, in which these markers are not increased but other metabolic abnormalities (such as insulin resistance, hypovitaminosis D, and hyper-homocysteinemia) are present. This tends to affect slightly older individuals than the first subtype: 80s rather than 70s.
  • Cortical, which affects relatively young individuals (typically 50s- early 70s) and appears more widely distributed across the brain than the other subtypes, showing widespread cortical atrophy rather than marked hippocampal atrophy. It typically presents with language and number difficulties first, rather than memory loss. Typically, there is an impaired ability to hold onto a train of thought. It is often misdiagnosed, typically affects people without a family history of Alzheimer's, who do not have an Alzheimer's-related gene, and is associated with a significant zinc deficiency (Zinc is implicated in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling. Zinc deficiency is relatively common, and associated with increasing age.).

The cortical subtype appears to be fundamentally a different condition than the other two.

I note a study I reported on last year, that found different molecular structures of amyloid-beta fibrils in the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. That was a very small study, indicative only. However, I do wonder if there's any connection between these two findings. At the least, I think this approach a promising one.

The idea that there are different types of Alzheimer's disease is of course consistent with the research showing a variety of genetic risk factors, and an earlier study indicating at least two pathways to Alzheimer's.

It's also worth noting that the present study built on an earlier study, which showed that a program of lifestyle, exercise and diet changes designed to improve the body's metabolism reversed cognitive decline within 3-6 months in nine out of 10 patients with early Alzheimer's disease or its precursors. Note that this was a very small pilot program, and needs a proper clinical trial. Nevertheless, it is certainly very interesting.

http://www.eurekalert.org/pub_releases/2015-09/uoc--adc091615.php

Bredesen, D.E. 2015. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. AGING, 7 (8), 595-600. Full text at http://www.impactaging.com/papers/v7/n8/full/100801.html

Bredesen, D.E. 2014. Reversal of cognitive decline: A novel therapeutic program. AGING, Vol 6, No 9 , pp 707-717. Full text at http://www.impactaging.com/papers/v6/n9/full/100690.html

A post-mortem study of five Alzheimer's and five control brains has revealed the presence of iron-containing microglia in the subiculum of the Alzheimer's brains only. The subiculum lies within the hippocampus, a vital memory region affected early in Alzheimer's. None of the brains of those not diagnosed with Alzheimer's had the iron deposits or the microglia, in that brain region, while four of the five Alzheimer's brains contained the iron-containing microglia.

The microglia were mostly in an inflamed state. Growing evidence implicates brain inflammation in the development of Alzheimer's.

There was no consistent association between iron-laden microglia and amyloid plaques or tau in the same area.

Obviously, this is only a small study, and more research needs to be done to confirm the finding. However, this is consistent with previous findings of higher levels of iron in the hippocampi of Alzheimer's brain.

At the moment, we don't know how the iron gets into brain tissue, or why it accumulates in the subiculum. However, the researchers speculate that it may have something to do with micro-injury to small cerebral blood vessels.

This is an interesting finding that may lead to new treatment or prevention approaches if confirmed in further research.

http://www.eurekalert.org/pub_releases/2015-07/sumc-sss072015.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

[3620] Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, Li Z, Yuan SH, Zhang K, Goldstein LSB. The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells. Cell Reports [Internet]. 2013 ;5(4):974 - 985. Available from: http://www.cell.com/article/S2211124713006025/abstract

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

[3577] Hooli BV, Kovacs-Vajna ZM, Mullin K, Blumenthal MA, Mattheisen M, Zhang C, Lange C, Mohapatra G, Bertram L, Tanzi RE. Rare autosomal copy number variations in early-onset familial Alzheimer’s disease. Molecular Psychiatry [Internet]. 2014 ;19(6):676 - 681. Available from: http://www.nature.com/mp/journal/v19/n6/full/mp201377a.html

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

[3551] Armstrong A, Mattsson N, Appelqvist H, Janefjord C, Sandin L, Agholme L, Olsson B, Svensson S, Blennow K, Zetterberg H, et al. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimer’s Disease. NeuroMolecular Medicine [Internet]. 2014 ;16(1):150 - 160. Available from: http://link.springer.com/article/10.1007/s12017-013-8269-3

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

[3585] Lacoste B, Tong X-K, Lahjouji K, Couture R, Hamel E. Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice. Journal of Neuroinflammation [Internet]. 2013 ;10(1). Available from: http://www.jneuroinflammation.com/content/10/1/57/abstract

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

[3617] Wang L, Brier MR, Snyder AZ, et al. Cerebrospinal fluid aβ42, phosphorylated tau181, and resting-state functional connectivity. JAMA Neurology [Internet]. 2013 ;70(10):1242 - 1248. Available from: http://dx.doi.org/10.1001/jamaneurol.2013.3253

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

[3587] Lu J-X, Qiang W, Yau W-M, Schwieters C D, Meredith S C, Tycko R. Molecular Structure of β-Amyloid Fibrils in Alzheimer’s Disease Brain Tissue. Cell [Internet]. 2013 ;154(6):1257 - 1268. Available from: http://www.sciencedirect.com/science/article/pii/S0092867413010295

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

[3594] Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. Journal of Clinical Investigation [Internet]. 2013 ;123(12):5389 - 5400. Available from: http://www.jci.org/articles/view/70317

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

[3582] Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, Mayeux R, Duff KE, Small SA. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neuroscience [Internet]. 2014 ;17(2):304 - 311. Available from: http://www.nature.com/neuro/journal/v17/n2/full/nn.3606.html

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

[3612] Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, Monsell SE, Kukull WA, Trojanowski JQ. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain [Internet]. 2013 ;136(9):2697 - 2706. Available from: http://brain.oxfordjournals.org/content/136/9/2697

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

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

[3616] Wang X, Zhu M, Hjorth E, Cortés-Toro V, Eyjolfsdottir H, Graff C, Nennesmo I, Palmblad J, Eriksdotter M, Sambamurti K, et al. Resolution of inflammation is altered in Alzheimer's disease. Alzheimer's & Dementia [Internet]. 2014 . Available from: http://www.alzheimersanddementia.com/article/S1552-5260(14)00030-2/abstract?articleId=&articleTitle=&citedBy=false&isTabularSearchRequestOnSearchResultPage=no&medlinePmidWithoutMDLNPrefix=&overridingDateRestriction=&related=false&restrictdesc_author=&rest

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

[3623] Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgräfe K, Mandelkow E-M, et al. Neuronal activity regulates extracellular tau in vivo. The Journal of Experimental Medicine [Internet]. 2014 ;211(3):387 - 393. Available from: http://jem.rupress.org/content/211/3/387

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

[3625] Zhang J, Malik A, Choi HB, Ko RWY, Dissing-Olesen L, MacVicar BA. Microglial CR3 Activation Triggers Long-Term Synaptic Depression in the Hippocampus via NADPH Oxidase. Neuron [Internet]. 2014 ;82(1):195 - 207. Available from: http://www.cell.com/article/S0896627314000749/abstract

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

[3626] Zhang W, Thevapriya S, Kim PJ, Yu W-P, Shawn Je H, King Tan E, Zeng L. Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex. Nature Communications [Internet]. 2014 ;5. Available from: http://www.nature.com/ncomms/2014/140303/ncomms4330/full/ncomms4330.html

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/

[3323] Wang M, Yang Y, Wang C-J, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang X-J, Arnsten AFT. NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex. Neuron [Internet]. 2013 ;77(4):736 - 749. Available from: http://www.cell.com/neuron/abstract/S0896-6273(13)00038-X

I reported a few months ago on some evidence of a link between disturbed sleep and the development of Alzheimer’s. Now a mouse study adds to this evidence.

The mouse study follows on from an earlier study showing that brain levels of amyloid beta naturally rise when healthy young mice are awake and drop after they go to sleep, and that sleep deprivation disrupted this cycle and accelerated the development of amyloid plaques. This natural rhythm was confirmed in humans.

In the new study, it was found that this circadian rhythm showed the first signs of disruption as soon as Alzheimer’s plaques began forming in the mice’s brains. When the genetically engineered mice were given a vaccine against amyloid beta, the mice didn’t develop plaques in old age, the natural fluctuations in amyloid beta levels continued, and sleep patterns remained normal.

Research with humans in now underway to see whether patients with early markers of Alzheimer’s show sleep problems, and what the nature of these problems is.

Just to make it clear: the point is not so much that Alzheimer’s patients are more likely to have sleep problems, but that the sleep problems may in fact be part of the cause of Alzheimer’s disease development. The big question, of course, is whether you can prevent its development by attacking the dysfunction in circadian rhythm. (See more on this debate at Biomed)

Genetic analysis of 9,232 older adults (average age 67; range 56-84) has implicated four genes in how fast your hippocampus shrinks with age (rs7294919 at 12q24, rs17178006 at 12q14, rs6741949 at 2q24, rs7852872 at 9p33). The first of these (implicated in cell death) showed a particularly strong link to a reduced hippocampus volume — with average consequence being a hippocampus of the same size as that of a person 4-5 years older.

Faster atrophy in this crucial brain region would increase people’s risk of Alzheimer’s and cognitive decline, by reducing their cognitive reserve. Reduced hippocampal volume is also associated with schizophrenia, major depression, and some forms of epilepsy.

In addition to cell death, the genes linked to this faster atrophy are involved in oxidative stress, ubiquitination, diabetes, embryonic development and neuronal migration.

A younger cohort, of 7,794 normal and cognitively compromised people with an average age of 40, showed that these suspect gene variants were also linked to smaller hippocampus volume in this age group. A third cohort, comprised of 1,563 primarily older people, showed a significant association between the ASTN2 variant (linked to neuronal migration) and faster memory loss.

In another analysis, researchers looked at intracranial volume and brain volume in 8,175 elderly. While they found no genetic associations for brain volume (although there was one suggestive association), they did discover that intracranial volume (the space occupied by the fully developed brain within the skull — this remains unchanged with age, reflecting brain size at full maturity) was significantly associated with two gene variants (at loci rs4273712, on chromosome 6q22, and rs9915547, on 17q21). These associations were replicated in a different sample of 1,752 older adults. One of these genes is already known to play a unique evolutionary role in human development.

A meta-analysis of seven genome-wide association studies, involving 10,768 infants (average age 14.5 months), found two loci robustly associated with head circumference in infancy (rs7980687 on chromosome 12q24 and rs1042725 on chromosome 12q15). These loci have previously been associated with adult height, but these effects on infant head circumference were largely independent of height. A third variant (rs11655470 on chromosome 17q21 — note that this is the same chromosome implicated in the study of older adults) showed suggestive evidence of association with head circumference; this chromosome has also been implicated in Parkinson's disease and other neurodegenerative diseases.

Previous research has found an association between head size in infancy and later development of Alzheimer’s. It has been thought that this may have to do with cognitive reserve.

Interestingly, the analyses also revealed that a variant in a gene called HMGA2 (rs10784502 on 12q14.3) affected intelligence as well as brain size.

Why ‘Alzheimer’s gene’ increases Alzheimer’s risk

Investigation into the so-called ‘Alzheimer’s gene’ ApoE4 (those who carry two copies of this variant have roughly eight to 10 times the risk of getting Alzheimer’s disease) has found that ApoE4 causes an increase in cyclophilin A, which in turn causes a breakdown of the cells lining the blood vessels. Blood vessels become leaky, making it more likely that toxic substances will leak into the brain.

The study found that mice carrying the ApoE4 gene had five times as much cyclophilin A as normal, in cells crucial to maintaining the integrity of the blood-brain barrier. Blocking the action of cyclophilin A brought blood flow back to normal and reduced the leakage of toxic substances by 80%.

The finding is in keeping with the idea that vascular problems are at the heart of Alzheimer’s disease — although it should not be assumed from that, that other problems (such as amyloid-beta plaques and tau tangles) are not also important. However, one thing that does seem clear now is that there is not one single pathway to Alzheimer’s. This research suggests a possible treatment approach for those carrying this risky gene variant.

Note also that this gene variant is not only associated with Alzheimer’s risk, but also Down’s syndrome dementia, poor outcome following TBI, and age-related cognitive decline.

On which note, I’d like to point out recent findings from the long-running Nurses' Health Study, involving 16,514 older women (70-81), that suggest that effects of postmenopausal hormone therapy for cognition may depend on apolipoprotein E (APOE) status, with the fastest rate of decline being observed among HT users who carried the APOe4 variant (in general HT was associated with poorer cognitive performance).

It’s also interesting to note another recent finding: that intracranial volume modifies the effect of apoE4 and white matter lesions on dementia risk. The study, involving 104 demented and 135 nondemented 85-year-olds, found that smaller intracranial volume increased the risk of dementia, Alzheimer's disease, and vascular dementia in participants with white matter lesions. However, white matter lesions were not associated with increased dementia risk in those with the largest intracranial volume. But intracranial volume did not modify dementia risk in those with the apoE4 gene.

More genes involved in Alzheimer’s

More genome-wide association studies of Alzheimer's disease have now identified variants in BIN1, CLU, CR1 and PICALM genes that increase Alzheimer’s risk, although it is not yet known how these gene variants affect risk (the present study ruled out effects on the two biomarkers, amyloid-beta 42 and phosphorylated tau).

Same genes linked to early- and late-onset Alzheimer's

Traditionally, we’ve made a distinction between early-onset Alzheimer's disease, which is thought to be inherited, and the more common late-onset Alzheimer’s. New findings, however, suggest we should re-think that distinction. While the genetic case for early-onset might seem to be stronger, sporadic (non-familial) cases do occur, and familial cases occur with late-onset.

New DNA sequencing techniques applied to the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes (the three genes linked to early-onset Alzheimer's) has found that rare variants in these genes are more common in families where four or more members were affected with late-onset Alzheimer’s, compared to normal individuals. Additionally, mutations in the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene (both linked to frontotemporal dementia) were also found in some Alzheimer's patients, suggesting they had been incorrectly diagnosed as having Alzheimer's disease when they instead had frontotemporal dementia.

Of the 439 patients in which at least four individuals per family had been diagnosed with Alzheimer's disease, rare variants in the 3 Alzheimer's-related genes were found in 60 (13.7%) of them. While not all of these variants are known to be pathogenic, the frequency of mutations in these genes is significantly higher than it is in the general population.

The researchers estimate that about 5% of those with late-onset Alzheimer's disease have changes in these genes. They suggest that, at least in some cases, the same causes may underlie both early- and late-onset disease. The difference being that those that develop it later have more protective factors.

Another gene identified in early-onset Alzheimer's

A study of the genes from 130 families suffering from early-onset Alzheimer's disease has found that 116 had mutations on genes already known to be involved (APP, PSEN1, PSEN2 — see below for some older reports on these genes), while five of the other 14 families all showed mutations on a new gene: SORL1.

I say ‘new gene’ because it hasn’t been implicated in early-onset Alzheimer’s before. However, it has been implicated in the more common late-onset Alzheimer’s, and last year a study reported that the gene was associated with differences in hippocampal volume in young, healthy adults.

The finding, then, provides more support for the idea that some cases of early-onset and late-onset Alzheimer’s have the same causes.

The SORL1 gene codes for a protein involved in the production of the beta-amyloid peptide, and the mutations seen in this study appear to cause an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Such mutations were not found in the 1500 ethnicity-matched controls.

 

Older news reports on these other early-onset genes (brought over from the old website):

New genetic cause of Alzheimer's disease

Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases, mutations appear in the amyloid precursor protein (APP), causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. A genetic study of Alzheimer's patients younger than 70 has found genetic variations in the promoter that increases the gene expression and thus the formation of the amyloid precursor protein. The higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease.

Theuns, J. et al. 2006. Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.

http://www.eurekalert.org/pub_releases/2006-04/vfii-rda041906.php

Evidence that Alzheimer's protein switches on genes

Amyloid b-protein precursor (APP) is snipped apart by enzymes to produce three protein fragments. Two fragments remain outside the cell and one stays inside. When APP is produced in excessive quantities, one of the cleaved segments that remains outside the cell, called the amyloid b-peptides, clumps together to form amyloid plaques that kill brain cells and may lead to the development of Alzheimer’s disease. New research indicates that the short "tail" segment of APP that is trapped inside the cell might also contribute to Alzheimer’s disease, through a process called transcriptional activation - switching on genes within the cell. Researchers speculate that creation of amyloid plaque is a byproduct of a misregulation in normal APP processing.

[2866] Cao X, Südhof TC. A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60. Science [Internet]. 2001 ;293(5527):115 - 120. Available from: http://www.sciencemag.org/content/293/5527/115

http://www.eurekalert.org/pub_releases/2001-07/aaft-eta070201.php

Inactivation of Alzheimer's genes in mice causes dementia and brain degeneration

Mutations in two related genes known as presenilins are the major cause of early onset, inherited forms of Alzheimer's disease, but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides (the major components of amyloid plaques), it was thought that such mutations might cause Alzheimer’s by increasing brain levels of amyloid peptides. Accordingly, much effort has gone into identifying compounds that could block presenilin function. Now, however, genetic engineering in mice has revealed that deletion of these genes causes memory loss and gradual death of nerve cells in the mouse brain, demonstrating that the protein products of these genes are essential for normal learning, memory and nerve cell survival.

Saura, C.A., Choi, S-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B.S., Chattarji, S., Kelleher, R.J.III, Kandel, E.R., Duff, K., Kirkwood, A. & Shen, J. 2004. Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron, 42 (1), 23-36.

http://www.eurekalert.org/pub_releases/2004-04/cp-ioa032904.php

[2858] Consortium ENIGM-A (ENIGMA), Cohorts Heart Aging Research Genomic Epidemiology (charge). Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics [Internet]. 2012 ;44(5):545 - 551. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2237.html

[2909] Taal RH, Pourcain BS, Thiering E, Das S, Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nature Genetics [Internet]. 2012 ;44(5):532 - 538. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2238.html

[2859] Cohorts Heart Aging Research Genomic Epidemiology (charge), Consortium EGG (EGG). Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics [Internet]. 2012 ;44(5):539 - 544. Available from: http://www.nature.com/ng/journal/v44/n5/full/ng.2245.html

[2907] Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics [Internet]. 2012 ;44(5):552 - 561. Available from: http://www.nature.com/ng/journal/v44/n5/abs/ng.2250.html

[2925] Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature [Internet]. 2012 . Available from: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11087.html?WT.ec_id=NATURE-20120517

Kang, J. H., & Grodstein F. (2012).  Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.

Skoog, I., Olesen P. J., Blennow K., Palmertz B., Johnson S. C., & Bigler E. D. (2012).  Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.

[2728] Cruchaga C, Chakraverty S, Mayo K, Vallania FLM, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, et al. Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families. PLoS ONE [Internet]. 2012 ;7(2):e31039 - e31039. Available from: UR - http://dx.doi.org/10.1371/journal.pone.0031039,http://dx.doi.org/10.1371/journal.pone.0031039

Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039

[2897] Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular Psychiatry [Internet]. 2012 . Available from: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201215a.html

McCarthy, J. J., Saith S., Linnertz C., Burke J. R., Hulette C. M., Welsh-Bohmer K. A., et al. (2012).  The Alzheimer's associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiology of Aging. 33(7), 1485.e1-1485.e8 - 1485.e1-1485.e8

Another study adds to the evidence that changes in the brain that may lead eventually to Alzheimer’s begin many years before Alzheimer’s is diagnosed. The findings also add to the evidence that what we regard as “normal” age-related cognitive decline is really one end of a continuum of which the other end is dementia.

In the study, brain scans were taken of 137 highly educated people aged 30-89 (participants in the Dallas Lifespan Brain Study). The amount of amyloid-beta (characteristic of Alzheimer’s) was found to increase with age, and around a fifth of those over 60 had significantly elevated levels of the protein. These higher amounts were linked with worse performance on tests of working memory, reasoning and processing speed.

More specifically, across the whole sample, amyloid-beta levels affected processing speed and fluid intelligence (in a dose-dependent relationship — that is, as levels increased, these functions became more impaired), but not working memory, episodic memory, or crystallized intelligence. Among the elevated-levels group, increased amyloid-beta was significantly associated with poorer performance for processing speed, working memory, and fluid intelligence, but not episodic memory or crystallized intelligence. Among the group without elevated levels of the protein, increasing amyloid-beta only affected fluid intelligence.

These task differences aren’t surprising: processing speed, working memory, and fluid intelligence are the domains that show the most decline in normal aging.

Those with the Alzheimer’s gene APOE4 were significantly more likely to have elevated levels of amyloid-beta. While 38% of the group with high levels of the protein had the risky gene variant, only 15% of those who didn’t have high levels carried the gene.

Note that, while the prevalence of carriers of the gene variant matched population estimates (24%), the proportion was higher among those in the younger age group — 33% of those under 60, compared to 19.5% of those aged 60 or older. It seems likely that many older carriers have already developed MCI or Alzheimer’s, and thus been ineligible for the study.

The average age of the participants was 64, and the average years of education 16.4.

Amyloid deposits varied as a function of age and region: the precuneus, temporal cortex, anterior cingulate and posterior cingulate showed the greatest increase with age, while the dorsolateral prefrontal cortex, orbitofrontal cortex, parietal and occipital cortices showed smaller increases with age. However, when only those aged 60+ were analyzed, the effect of age was no longer significant. This is consistent with previous research, and adds to evidence that age-related cognitive impairment, including Alzheimer’s, has its roots in damage occurring earlier in life.

In another study, brain scans of 408 participants in the Mayo Clinic Study of Aging also found that higher levels of amyloid-beta were associated with poorer cognitive performance — but that this interacted with APOE status. Specifically, carriers of the Alzheimer’s gene variant were significantly more affected by having higher levels of the protein.

This may explain the inconsistent findings of previous research concerning whether or not amyloid-beta has significant effects on cognition in normal adults.

As the researchers of the first study point out, what’s needed is information on the long-term course of these brain changes, and they are planning to follow these participants.

In the meantime, all in all, the findings do provide more strength to the argument that your lifestyle in mid-life (and perhaps even younger) may have long-term consequences for your brain in old age — particularly for those with a genetic susceptibility to Alzheimer’s.

I commonly refer to ApoE4 as the ‘Alzheimer’s gene’, because it is the main genetic risk factor, tripling the risk for getting Alzheimer's. But it is not the only risky gene.

A mammoth genetic study has identified four new genes linked to late-onset Alzheimer's disease. The new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells, pointing to three new pathways that are critically related to the disease.

Genetic analysis of more than 11,000 people with Alzheimer's and a nearly equal number of healthy older adults, plus additional data from another 32,000, has identified MS4A, CD2AP, CD33, and EPHA1 genes linked to Alzheimer’s risk, and confirmed two other genes, BIN1 and ABCA7.

A second meta-analysis of genetic data has also found another location within the MS4A gene cluster which is associated with Alzheimer's disease. Several of the 16 genes within the cluster are implicated in the activities of the immune system and are probably involved in allergies and autoimmune disease. The finding adds to evidence for a role of the immune system in the development of Alzheimer's.

Another study adds to our understanding of how one of the earlier-known gene factors works. A variant of the clusterin gene is known to increase the risk of Alzheimer’s by 16%. But unlike the ApoE4 gene, we didn’t know how, because we didn’t know what the CLU gene did. A new study has now found that the most common form of the gene, the C-allele, impairs the development of myelin.

The study involved 398 healthy adults in their twenties. Those carrying the CLU-C gene had poorer white-matter integrity in multiple brain regions. The finding is consistent with increasing evidence that degeneration of myelin in white-matter tracts is a key component of Alzheimer’s and another possible pathway to the disease. But this gene is damaging your brain (in ways only detectible on a brain scan) a good 50 years before any clinical symptoms are evident.

Moreover, this allele is present in 88% of Caucasians. So you could say it’s not so much that this gene variant is increasing your risk, as that having the other allele (T) is protective.

[2257] Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet [Internet]. 2011 ;43(5):436 - 441. Available from: http://dx.doi.org/10.1038/ng.801

Antunez, C. et al. 2011. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Medicine,  3:33 doi:10.1186/gm249
Full text available at http://genomemedicine.com/content/3/5/33/abstract

[2254] Braskie MN, Jahanshad N, Stein JL, Barysheva M, McMahon KL, de Zubicaray GI, Martin NG, Wright MJ, Ringman JM, Toga AW, et al. Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults. The Journal of Neuroscience [Internet]. 2011 ;31(18):6764 - 6770. Available from: http://www.jneurosci.org/content/31/18/6764.abstract

A new study finds out why curcumin might help protect against dementia, and links two factors associated with Alzheimer’s and Parkinson’s diseases: DNA damage by reactive oxygen species (ROS), and excessive levels of copper and iron in parts of the brain. It turns out that high levels of copper or iron help generate large numbers of ROS and interfere with DNA repair.

While small amounts of iron and copper are vital, these are normally bound by proteins. However, when there’s too much, it can overwhelm the proteins and the result is "free" iron or copper ions circulating in the blood, able to initiate chemical reactions that produce reactive oxygen species. Moreover, the free copper and iron also interferes with the activity of two enzymes that repair DNA, NEIL1 and NEIL2.

However, the curry spice curcumin binds to iron and copper and was extremely effective in protecting the NEIL enzymes from the metals.

Hegde, M.L., Hegde, P.M. , Rao, K.S.J. & Mitra, S. 2011. Oxidative Genome Damage and Its Repair in Neurodegenerative Diseases: Function of Transition Metals as a Double-Edged Sword. Journal of Alzheimer's Disease , 25 (1), 183-198.

More evidence that vascular disease plays a crucial role in age-related cognitive impairment and Alzheimer’s comes from data from participants in the Alzheimer's Disease Neuroimaging Initiative.

The study involved more than 800 older adults (55-90), including around 200 cognitively normal individuals, around 400 people with mild cognitive impairment, and 200 people with Alzheimer's disease. The first two groups were followed for 3 years, and the Alzheimer’s patients for two. The study found that the extent of white matter hyperintensities (areas of damaged brain tissue typically caused by cardiovascular disease) was an important predictor of cognitive decline.

Participants whose white matter hyperintensities were significantly above average at the beginning of the study lost more points each year in cognitive testing than those whose white matter hyperintensities were average at baseline. Those with mild cognitive impairment or Alzheimer's disease at baseline had additional declines on their cognitive testing each year, meaning that the presence of white matter hyperintensities and MCI or Alzheimer's disease together added up to even faster and steeper cognitive decline.

The crucial point is that this was happening in the absence of major cardiovascular events such as heart attacks, indicating that it’s not enough to just reduce your cardiovascular risk factors to a moderate level — every little bit of vascular damage counts.

Carriers of the so-called ‘Alzheimer’s gene’ (apoE4) comprise 65% of all Alzheimer's cases. A new study helps us understand why that’s true. Genetically engineered mice reveal that apoE4 is associated with the loss of GABAergic interneurons in the hippocampus. This is consistent with low levels of GABA (produced by these neurons) typically found in Alzheimer’s brains. This loss was associated with cognitive impairment in the absence of amyloid beta accumulation, demonstrating it is an independent factor in the development of this disease.

The relationship with the other major characteristic of the Alzheimer’s brain, tau tangles, was not independent. When the mice’s tau protein was genetically eliminated, the mice stopped losing GABAergic interneurons, and did not develop cognitive deficits. Previous research has shown that suppressing tau protein can also prevent amyloid beta from causing memory deficits.

Excitingly, daily injections of pentobarbital, a compound that enhances GABA action, restored cognitive function in the mice.

The findings suggest that increasing GABA signaling and reducing tau are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

Inflammation in the brain appears to be a key contributor to age-related memory problems, and it may be that this has to do with the dysregulation of microglia that, previous research has shown, occurs with age. As these specialized support cells in the brain do normally when there’s an infection, with age microglia start to produce excessive cytokines, some of which result in the typical behaviors that accompany illness (sleepiness, appetite loss, cognitive deficits and depression).

Now new cell and mouse studies suggests that the flavenoid luteolin, known to have anti-inflammatory properties, apparently has these benefits because it acts directly on the microglial cells to reduce their production of inflammatory cytokines. It was found that although microglia exposed to a bacterial toxin produced inflammatory cytokines that killed neurons, if the microglia were first exposed to luteolin, the neurons lived. Exposing the neuron to luteolin had no effect.

Old mice fed a luteolin-supplemented diet for four weeks did better on a working memory test than old mice on an ordinary diet, and restored levels of inflammatory cytokines in their brains to that of younger mice.

Luteolin is found in many plants, including carrots, peppers, celery, olive oil, peppermint, rosemary and chamomile.

Low levels of DHA, an omega-3 fatty acid, have been found in the brains of those with Alzheimer's disease, but the reason has not been known. A new study has found that lower levels of DHA in the liver (where most brain DHA is manufactured) were correlated with greater cognitive problems in the Alzheimer’s patients. Moreover, comparison of postmortem livers from Alzheimer’s patients and controls found reduced expression of a protein that converts a precursor acid into DHA, meaning the liver was less able to make DHA from food.

The findings may explain why clinical trials in which Alzheimer's patients are given omega-3 fatty acids have had mixed results. They also suggest that it might be possible to identify at-risk persons using specific blood tests, and perhaps delay the development of Alzheimer’s with a chemically enhanced form of DHA.

Findings from the long-running Religious Orders Study, from 354 Catholic nuns and priests who were given annual cognitive tests for up to 13 years before having their brains examined post-mortem, has revealed that even the very early cognitive impairments we regard as normal in aging are associated with dementia pathology. Although pathology in the form of neurofibrillary tangles, Lewy bodies, and cerebral infarctions were all associated with rapid decline, they were also associated with “normal” mild impairment. In the absence of any of these lesions, there was almost no cognitive decline.

Previous research has shown that white matter lesions are very common in older adults, and mild cognitive impairment is more likely in those with quickly growing white matter lesions; importantly, the crucial factor appears to be the rate of growth, not the amount of lesions. This new study extends the finding, suggesting that any age-related cognitive impairment reflects the sort of brain pathology that ultimately leads to dementia (if given enough time). It suggests that we should be more proactive in fighting such damage, instead of simply regarding it as normal.

It’s been suggested before that Down syndrome and Alzheimer's are connected. Similarly, there has been evidence for connections between diabetes and Alzheimer’s, and cardiovascular disease and Alzheimer’s. Now new evidence shows that all of these share a common disease mechanism. According to animal and cell-culture studies, it seems all Alzheimer's disease patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is characteristic of all the cells in people with Down syndrome. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in Alzheimer's. It now appears that amyloid protein is interfering with the microtubule transport system inside cells, essentially creating holes in the roads that move everything, including chromosomes, around inside the cells. Incorrect transportation of chromosomes when cells divide produces new cells with the wrong number of chromosomes and an abnormal assortment of genes. The beta amyloid gene is on chromosome 21; thus, having three copies produces extra beta amyloid. The damage to the microtubule network also interferes with the receptor needed to pull low-density lipoprotein (LDL — the ‘bad’ cholesterol) out of circulation, thus (probably) allowing bad cholesterol to build up (note that the ‘Alzheimer’s gene’ governs the low-density lipoprotein receptor). It is also likely that insulin receptors are unable to function properly, leading to diabetes.

While everyone agrees that amyloid-beta protein is part of the problem, not everyone agrees that amyloid plaques are the cause (or one of them) of Alzheimer’s. Other forms of amyloid-beta have been pointed to, including floating clumps called oligomers or ADDLs. A new study, using mice engineered to form only these oligomers, and never any plaques, throughout their lives, provides more support for this theory. Mice that never developed plaques were just as impaired by the disease as mice with both plaques and oligomers, and when a gene that converted oligomers into plaques was added to the mice, the mice were no more impaired than they had been before. This may explain why treatments aimed at removing plaques have not been successful, and offers a new approach to the treatment of Alzheimer’s.

Older news items (pre-2010) brought over from the old website

Role of fatty acids in Alzheimer's disease

Fatty acids are rapidly taken up by the brain and incorporated into phospholipids, a class of fats that form the membrane or barrier that shields the content of cells from the external environment. Now genetically engineered mice have revealed that there is a striking increase in arachidonic acid and related metabolites in the hippocampus. Removal or reduction of the enzyme that releases this acid prevented memory deficits in the Alzheimer mice. It’s thought that the acid causes too much excitation.

Sanchez-Mejia, R.O. et al. 2008. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nature Neuroscience, 11, 1311-1318.

http://www.eurekalert.org/pub_releases/2008-10/gi-gsi101408.php

Support for view of Alzheimer's as form of diabetes

Research in the last few years has raised the possibility that Alzheimer’s memory loss could be due to a third form of diabetes. A new study clarifies the connection between insulin and Alzheimer’s. It seems that the toxic protein ADDL, found in the brains of individuals with Alzheimer’s, removes insulin receptors from nerve cells, rendering those neurons insulin resistant. The findings suggest that some existing drugs now used to treat diabetic patients may be useful for Alzheimer’s treatment.

Zhao,W-Q. et al. 2007. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB Journal, published online ahead of print August 24.

http://www.eurekalert.org/pub_releases/2007-09/nu-dst092607.php

Link between size of hippocampus and progression to Alzheimer's

A study of 20 older adults with mild cognitive impairment has found that the hippocampus was smaller in those who developed into Alzheimer's during the 3 year period.

Apostolova, L.G. et al. 2006. Conversion of Mild Cognitive Impairment to Alzheimer Disease Predicted by Hippocampal Atrophy Maps. Archives of Neurology, 63, 693-699.

http://www.eurekalert.org/pub_releases/2006-05/uoc--rml050406.php

Post-mortem brain studies reveal features of mild cognitive impairment

Autopsies have revealed that the brains of patients with mild cognitive impairment display pathologic features that appear to place them at an intermediate stage between normal aging and Alzheimer's disease. For instance, the patients had begun developing neurofibrillary tangles, but the number of plaques was similar to that in healthy patients. All patients with mild cognitive impairment had abnormalities in their temporal lobes, which likely caused their cognitive difficulties, and many also had abnormalities in other areas that did not relate to the features of Alzheimer's disease. In a second study, of 34 patients with mild cognitive impairment who had progressed to clinical dementia before their deaths, 24 were diagnosed (post-mortem) with Alzheimer’s, and 10 with other types of dementia. As in the other study, all patients had abnormalities in their temporal lobes.

Petersen, R.C. et al. 2006. Neuropathologic Features of Amnestic Mild Cognitive Impairment. Archives of Neurology, 63, 665-672.

Jicha, G.A. et al. 2006. Neuropathologic Outcome of Mild Cognitive Impairment Following Progression to Clinical Dementia. Archives of Neurology, 63, 674-681.

http://www.eurekalert.org/pub_releases/2006-05/jaaj-pbs050406.php

Neurons can produce apolipoprotein E

Apolipoprotein E has been known to be synthesized in the brain in support cells such as astrocytes, microglia, and ependymal layer cells. Controversial for the last decade has been the question of whether or not neurons can produce apoE. Using a unique mouse model, researchers have now demonstrated that neurons can produce apoE, but only in response to injury to the brain.

Xu, Q. et al. 2006. Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus. Journal of Neuroscience, 26, 4985-4994.

http://www.eurekalert.org/pub_releases/2006-05/gi-gsp051006.php

Protein identified as cause of memory loss

Researchers have identified a substance in the brain that is proven to cause memory loss, giving drug developers a target for creating drugs to treat memory loss in people with dementia. The substance is a form of the amyloid-beta protein that is distinct from plaques and has been given the name Ab*56. Ab*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

Lesné, S. et al. 2006. A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440, 352-357.

http://www.eurekalert.org/pub_releases/2006-03/uom-uom_1031306.php

Reduced insulin in the brain triggers Alzheimer's degeneration

By depleting insulin and its related proteins in the brain, researchers have replicated the progression of Alzheimer's disease – including plaque deposits, neurofibrillary tangles, impaired cognitive functioning, cell loss and overall brain deterioration – in an experimental animal model. Brain deterioration was not related to the pancreas, raising the possibility that Alzheimer's is a neuroendocrine disorder, or a Type 3 diabetes.

Lester-Coll, N. et al. 2006. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. Journal of Alzheimer’s Disease, 9(1)

http://www.eurekalert.org/pub_releases/2006-03/l-rii031606.php

Pin1 enzyme key in preventing onset of Alzheimer's disease

An enzyme called Pin1, previously shown to prevent the formation of the tangles characteristic of Alzheimer's brains, has now been shown to also play a pivotal role in guarding against the development of the plaques that are also characteristic of Alzheimer's. These findings establish a direct link between amyloid plaques and tau tangles, and provide further evidence that Pin1 (prolyl isomerase) is essential to protect individuals from age-related neurodegeneration.

Pastorino, L. et al. 2006. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production Nature, 440, 528-534.

http://www.eurekalert.org/pub_releases/2006-03/hms-nrs032006.php

Link between APOE and memory neurotransmitter

A new link in the complex chain of Alzheimer’s development has been found. It’s been found that receptors that bind apolipoprotein E (APOE) and those that bind glutamate are in fact connected, separated only by a small protein. It may be that inefficient or high levels of APOE are clogging these binding sites, preventing glutamate from activating the processes necessary to form memories. It may also be that the APOE4 variant — associated with Alzheimer's — is less efficient at removing lipid debris in the brain than is APOE2 or APOE3.

Hoe, H-S. et al. 2006. Apolipoprotein E Receptor 2 Interactions with the N-Methyl-D-aspartate Receptor. Journal of Biological Chemistry, 281, 3425-3431.

http://www.eurekalert.org/pub_releases/2006-02/gumc-nrr020906.php

Two pathways lead to Alzheimer's disease

Mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer's disease, has been categorized into two sub-types on the basis of differing symptoms. Those with the amnesic subtype (MCI-A) have memory impairments only, while those with the multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, and mild or no memory loss. Both sub-types progress to Alzheimer's disease at the same rate. A new imaging technique has now revealed that these types do in fact have different pathologies. The hippocampus of patients with MCI-A was not significantly different from that of Alzheimer's patients (who show substantial shrinkage), but the hippocampus of those with MCI-MCD was not significantly different from that of the healthy controls.

Becker, J.T., Davis, S.W., Hayashi, K.M., Meltzer, C.C., Toga, A.W., Lopez, O.L., Thompson, P.M., for the Imaging Methods and Analysis in Geriatrics Research Group. 2006. Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment. Archives of Neurology, 63, 97-101.

http://www.eurekalert.org/pub_releases/2006-01/uopm-tpf010606.php

Key genetic risk for Alzheimer's linked to myelin breakdown

Myelin, the fatty insulation coating the brain's internal wiring, builds up in childhood, and breaks down as we age. Myelin is critical for speedy communication between neurons. A new study supports a growing body of evidence that myelin breakdown is a key contributor to the onset of Alzheimer disease later in life. Moreover, it has also revealed that the severity and rate of myelin breakdown in healthy older individuals is associated with ApoE status. Thus both age, the most important risk factor for Alzheimer disease, and ApoE status, the second-most important risk factor, seem to act through the process of myelin breakdown.

Bartzokis, G., Lu, P.H., Geschwind, D.H., Edwards, N., Mintz, J. & Cummings, J.L. 2006. Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia. Archives of General Psychiatry, 63, 63-72.

http://www.eurekalert.org/pub_releases/2006-01/uoc--isl122805.php

Study links Alzheimer's and Down’s syndrome

New research suggests the cognitive problems observed in Alzheimer’s are related to defects in the machinery controlling neuronal connections — PAK enzyme signaling pathways. PAK (p21-activated kinase) enzymes form a family that includes two members (PAK1 and PAK3) that play critical roles in learning and memory. Humans with genetic loss of PAK3 have severe mental retardation. The study reveals that both PAK1 and PAK3 are abnormally distributed and reduced in Alzheimer patients, and that beta-amyloid was directly involved in PAK signaling deficits. The finding suggests therapies designed to address the PAK defect could treat cognitive problems in both patient populations.

Zhao, L. et al. 2006. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nature Neuroscience, 9, 234–242.

http://www.eurekalert.org/pub_releases/2006-01/uoc--sid012506.php

New technique finds higher levels of creatine in Alzheimer’s brains

Creatine is involved in the maintaining the energy balance in the brain, but creatine, being small and very soluble, is difficult to detect. A new study has now succeeded in detecting creatine in situ, in brain tissue, and has found relatively large deposits in the hippocampus of Alzheimer’s brains. The finding suggests an overlooked aspect of energy disturbance in Alzheimer's disease, but further research is needed to understand it.
Gallant, M. et al. 2006. Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue. Journal of Biological Chemistry, 281, 5-8.
http://www.eurekalert.org/pub_releases/2005-12/uow-iar122105.php

More light on apoE4 and Alzheimer’s

A mutant form of a protein that transports cholesterol, apolipoprotein E (apoE) has long been recognized as a causative factor for Alzheimer's disease, but exactly how has been unclear. 299 amino acids are associated with apoE4, but new research has now found which of these amino acids are toxic. These toxic fragments all reside in the mitochondria (the “energy powerhouse” of the cell). The finding suggests a new therapeutic approach, involving blocking interaction of apoE4 fragments with the mitochondria.

Ye, S. et al. 2005. Apolipoprotein (apo) E4 enhances amyloid peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target. Proceedings of the National Academy of Science, 102 (51), 18700-18705.

http://www.eurekalert.org/pub_releases/2005-12/gi-gsl121405.php

p25 only good in small doses

Elevated levels of a key brain regulatory enzyme called Cdk5 and an associated regulatory protein called p25 have been found in the brains of Alzheimer’s patients. A new mouse study has found that switching on p25 in the hippocampus for only two weeks actually enhanced learning and memory compared to normal mice; however mice in which p25 had been switched on for six weeks showed impaired learning and memory. These mice also showed significant brain atrophy and loss of hippocampal neurons. The two-week pulse of p25 did not cause neurodegeneration and had long-lasting effects on enhancing memory. The researchers suggest that p25 might be produced to compensate for the loss of Cdk5 activity during aging, however chronically high levels lead to neuronal cell death. The findings are consistent with several recent studies suggesting that in the development of Alzheimer’s, compensatory mechanisms that initially enhance neuroplasticity eventually become maladaptive when chronically activated.

Fischer, A., Sananbenesi, F., Pang, P.T., Lu, B. & Tsai, L-H. 2005. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron, 48, 825–838.

http://www.eurekalert.org/pub_releases/2005-12/cp-aje120505.php

“Default” brain activity implicated in Alzheimer's disease

Here’s an unexpected finding: imaging of the brains of 764 adults of various ages has revealed that the regions that are active when people are in “default mode” — not concentrating on anything in particular, just musing to yourself — are the same regions that develop plaques in Alzheimer’s. They also found that, when asked to concentrate on a specific task, individuals with Alzheimer’s showed increased activity in these posterior cortical regions, rather than the decreased activity seen in young, healthy adults. The researchers speculate that dementia may in fact be a consequence of normal cognitive function — a possibility that hasn’t heretofore been considered. The findings raise the hope of developing methods to detect precursors of the disease long before it develops.

Buckner, R.L. et al. 2005. Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory. Journal of Neuroscience, 25, 7709-7717.

http://www.eurekalert.org/pub_releases/2005-08/hhmi-bai082405.php

How Alzheimer's impacts important brain cell function

Researchers have found that synaptic proteins, proteins involved in brain cell communications, decrease in the brains of Alzheimer's patients compared to healthy brains from people in the same age range. The decrease in the frontal cortex was more severe than in other portions of the brain. They also found synaptic protein levels were even lower in the brains of patients in the early stages of Alzheimer's disease, suggesting that the loss of these proteins happens very early in the disease process. The reduction of synaptic proteins may be caused by mitochondrial dysfunction, a well-documented occurrence in Alzheimer's.

Reddy, P.H., Mani, G., Park, B.S., Jacques, J., Murdoch, G., Whetsell, W.Jr., Kaye, J. & Manczak, M. 2005. Differential loss of synaptic proteins in Alzheimer’s disease: Implications for synaptic dysfunction Journal of Alzheimer's Disease, 7(2),103-117.

http://www.eurekalert.org/pub_releases/2005-04/ohs-ord040605.php

Research clarifies how Alzheimer's medicines work

New research clarifies how cholinesterase inhibitors alleviate mild-to-moderate Alzheimer's. When scientists chemically blocked receptors for an important neurotransmitter called acetylcholine, even healthy young people found it significantly harder to learn and remember – especially in the face of interference. Cholinesterase inhibitors slow the breakdown of acetylcholine. The finding also helps explain why Parkinson's disease, dementia due to multiple strokes, multiple sclerosis and schizophrenia, are all also associated with memory problems — all these conditions, like Alzheimer’s, are associated with lower levels of acetylcholine in the brain.

Atri, A., Norman, K.A., Nicolas, M.M., Cramer, S.C., Hasselmo, M.E., Sherman, S., Kirchhoff, B.A., Greicius, M.D., Breiter, H.C. & Stern, C.E. 2004. Central Cholinergic Receptors Impairs New Learning and Increases Proactive Interference in a Word Paired-Associate Memory Task. Behavioral Neuroscience, 118 (1).

http://www.eurekalert.org/pub_releases/2004-02/apa-rch020904.php

Why diet, hormones, exercise might delay Alzheimer’s

A theory that changes in fat metabolism in the membranes of nerve cells play a role in Alzheimer's has been supported in a recent study. The study found significantly higher levels of ceramide and cholesterol in the middle frontal gyrus of Alzheimer's patients. The researchers suggest that alterations in fats (especially cholesterol and ceramide) may contribute to a "neurodegenerative cascade" that destroys neurons in Alzheimer's, and that the accumulation of ceramide and cholesterol is triggered by the oxidative stress brought on by the presence of the toxic beta amyloid peptide. The study also suggests a reason for why antioxidants such as vitamin E might delay the onset of Alzheimer's: treatment with Vitamin E reduced the levels of ceramide and cholesterol, resulting in a significant decrease in the number of neurons killed by the beta amyloid and oxidative stress.

Cutler, R.G., Kelly, J., Storie, K., Pedersen, W.A., Tammara, A., Hatanpaa, K., Troncoso, J.C. & Mattson, M.P. 2004. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. PNAS, 101, 2070-5.

http://www.eurekalert.org/pub_releases/2004-02/aaft-nsm021004.php

Late-life Alzheimer's begins in midlife

A new model of human brain aging identifies midlife breakdown of myelin, a fatty insulation with very high cholesterol content that wraps tightly around axons (part of the neurons) and enables messages to pass along the “wiring” of the brain speedily, as a possible key to the onset of Alzheimer's disease later in life. Imaging studies and examination of brain tissue shows that the brain's wiring develops until middle age and then begins to decline as the breakdown of myelin triggers a destructive domino affect. It is suggested that genetic factors coupled with the brain's own developmental process of increasing cholesterol and iron levels in middle age help degrade the myelin. The complex connections that take the longest to develop and allow humans to think at their highest level are among the first to deteriorate as the brain's myelin breaks down in reverse order of development. The model suggests that the best time to address the inevitability of myelin breakdown is when it begins, in middle age. Possible preventive therapies include cholesterol- and iron-lowering medications, anti-inflammatory medications, diet and exercise programs and possibly hormone replacement therapy designed to prevent menopause rather than simply ease the symptoms. Education and cognitively stimulating activities may also stimulate the production of myelin.

Bartzokis, G. 2003. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiology of Aging, 25(1), 5-18.

http://www.eurekalert.org/pub_releases/2003-12/uoc--mbc122303.php

A nicotine by-product implicated in Alzheimer’s

A previously unrecognized chemical process has been discovered, by which a chemical called nornicotine, naturally present in tobacco and produced as a metabolite of nicotine, permanently and irreversibly modifies proteins in the body. These modified proteins interact with other chemicals in the body to form a variety of compounds known as advanced glycation endproducts. Advanced glycation endproducts have previously been implicated in numerous diseases including diabetes, cancer, atherosclerosis, and Alzheimer’s disease.

Dickerson, T.J. & Janda, K.D. 2002. A previously undescribed chemical link between smoking and metabolic disease. Proc. Natl. Acad. Sci. USA, 99 (23), 15084-15088.

http://www.eurekalert.org/pub_releases/2002-10/sri-aka102402.php