Alzheimer's: Causes

About these topic collections

I’ve been reporting on memory research for over ten years and these topic pages are simply collections of all the news items I have made on a particular topic. They do not pretend to be in any way exhaustive! I cover far too many areas within memory to come anywhere approaching that. What I aim to do is provide breadth, rather than depth. Outside my own area of cognitive psychology, it is difficult to know how much weight to give to any study (I urge you to read my blog post on what constitutes scientific evidence). That (among other reasons) is why my approach in my news reporting is based predominantly on replication and consistency. It's about the aggregate. So here is the aggregate of those reports I have at one point considered of sufficient interest to discuss. If you know of any research you would like to add to the collection, feel free to write about it in a comment (please provide a reference).

Latest news

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.

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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).

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A mouse study shows that sleep deprivation and aggregation of amyloid beta go hand in hand, and may be key players on the road to Alzheimer’s.

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)

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A round-up of genetic news. Several genes are linked to smaller brain size and faster brain atrophy in middle- & old age. The main Alzheimer's gene is implicated in leaky blood vessels, and shown to interact with brain size, white matter lesions, and dementia risk. Some evidence suggests early-onset Alzheimer's is not so dissimilar to late-onset Alzheimer's.

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.

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.

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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.

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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.

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Full text available at

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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

New genetic studies implicate myelin development, the immune system, inflammation, and lipid metabolism as critical pathways in the development of 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.

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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

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Research with genetically engineered mice shows why the apoE4 gene is so strongly associated with Alzheimer’s, and points to strategies for countering its effects.

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.

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A finding that the livers of Alzheimer’s patients have an impaired ability to make the omega-3 fatty acid DHA may suggest a new approach.

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.

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New evidence suggests that Down syndrome, Alzheimer's, diabetes, and cardiovascular disease, all share a common disease mechanism.

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.

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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. A new study provides convincing evidence that floating clumps called oligomers or ADDLs are the real problem.

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.

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

Why and how plaques form

Progress toward a drug that could actually stop Alzheimer’s

Amyloid plaques, characteristic of Alzheimer’s, are created when the amyloid precursor protein is cut into pieces incorrectly, which is governed by the γ-secretase complex. Acting on this complex is problematic however, as it is also involved in the regulation of a number of other essential proteins. New research with mouse models has now found that the complex assumes a different shape and function according to the tissue in which the secretase is active, and that they can specifically target the relevant variant, Aph1B γ-secretase, thus reducing formation of the plaques without any harmful side effects. The finding raises hopes for a drug that, for the first time, will succeed in stopping or even preventing Alzheimer's disease. However, many years of further research and development will be needed before such a drug will reach marketable status.

Serneels, L. et al. 2009. γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease. Science, Published Online March 19.

Paradoxical finding may shed new light on memory loss

Following a previous study, in which genetically engineered mice were prevented from getting Alzheimer’s by blocking a single site of cleavage of amyloid precursor protein (APP), studies of brain tissue from Alzheimer’s patients were found to have clearly more of this cleavage process than people of the same age who do not have the disease. However, much younger people without Alzheimer’s displayed as much as ten times the amount of the same cleavage event. The researchers now believe that normal memory loss is hyper-activated in Alzheimer’s, pointing to Alzheimer’s as a disorder affecting the plasticity, the ability to make and break memories, of the brain. Rather than the problem lying with the buildup of A-beta, the researchers suggest the problem lies in the downstream signaling of A-beta.

Banwait, S. et al. 2008. C-terminal cleavage of the amyloid-ß protein precursor at Asp664: a switch associated with Alzheimer's disease. Journal of Alzheimer’s Disease, 13 (1), 1-16.

Progression of Alzheimer's disease revealed

A new imaging agent is giving researchers information never before available about how and where Alzheimer’s progresses in the brain. Results suggest that amyloid plaques deposit sequentially, first appearing in the cingulate cortex/precuneus and frontal cortex areas, then progressing to the parietal and temporal cortex and caudate, and finally reaching the occipital cortex and sensory-motor cortex. These findings may explain why memory and judgment are often the brain functions first affected in Alzheimer's disease.

Klunk & Mathis 2005. Can In Vivo Amyloid Imaging with Pittsburgh Compound-B Tell Us Anything About the Time Course of Amyloid Deposition in Alzheimer's Disease. Paper presented at the 35th Annual Meeting of the Society for Neuroscience, Nov. 12-16, in Washington, D.C.

New light on how amyloid beta accumulation leads to long-term memory loss

A study using genetically engineered mice has shed new light on why the damage to brain tissue seen in Alzheimer’s leads to the loss of long-term memories. It seems that the accumulation of amyloid-beta peptides can deplete key proteins in the hippocampus, and this process can be worsened by increased activity of an enzyme called Fyn. The conversion of new information into long-term memories requires proteins (such as Arc and Fos) that help strengthen the synapses between specialized neurons in the hippocampus. Fyn is located at the synapses, where it regulates the activity of several memory-related proteins; increases in Fyn activity significantly increase the susceptibility of the hippocampal granule cells to the amyloid beta-induced depletion of memory proteins.

Palop, J.J., Chin, J., Bien-Ly, N., Massaro, C., Yeung, B.Z., Yu, G-Q. & Mucke, L. 2005. Vulnerability of Dentate Granule Cells to Disruption of Arc Expression in Human Amyloid Precursor Protein Transgenic Mice. Journal of Neuroscience, 25, 9686-9693.

Chin, J., Palop, J.J., Puoliväli, J., Massaro, C., Bien-Ly, N., Gerstein, H., Scearce-Levie, K., Masliah, E. & Mucke, L. 2005. Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease. Journal of Neuroscience, 25, 9694-9703.

New light on why plaques form

Alzheimer's disease is characterized by an increasing deposit of the amyloid-β protein in the brain, which collect to form aggregations called 'plaques'. New research has unraveled how certain plaques are formed. It seems the plaques attach primarily to blood vessels, which show clear structural damage, leading to leakage between the blood vessels and the brain. Under normal circumstances, the blood vessels transport excess amyloid-β protein away from the brain. The findings suggest new treatment approaches.

Kumar-Singh, S., Pirici, D., McGowan, E., Serneels, S., Ceuterick, C., Hardy, J., Duff, K., Dickson, D. & Van Broeckhoven, C. 2005. Dense-Core Plaques in Tg2576 and PSAPP Mouse Models of Alzheimer’s Disease Are Centered on Vessel Walls. American Journal of Pathology, 167, 527-543.

Finding an Alzheimer's switch

One prominent theory of the cause of Alzheimer's involves the so-called "amyloid beta protein cascade," in which a protein called APP is clipped into shorter pieces by enzymes known as secretases. If the portion of APP clipped by the beta form of secretase is further clipped by a third form, gamma secretase, the resulting fragments are amyloid beta peptides, A-beta 40 and A-beta 42. A-beta 42 in particular is toxic and causes the formation of amyloid plaques. A new study has uncovered an unsuspected subunit of gamma-secretase, the protein CD147, which apparently regulates the production of the toxic peptides that cause amyloid plaques. CD147 is expressed in many tissues and has many functions besides its role in tumor invasion, including reproduction, inflammation, and protein transport and sorting within cells. It also has a role in neural function: when the CD147 gene is deleted in mice, the result is defective nervous system development, loss of working memory, spatial learning deficits, and disorientation — behaviors remarkably suggestive of Alzheimer's disease. Future research will attempt to uncover exactly how CD147 prevents excessive production of A-beta 42 peptides, and what causes it to fail.

Zhou, S., Zhou, H., Walian, P.J. & Jap, B.K. 2005. CD147 is a regulatory subunit of the ã-secretase complex in Alzheimer's disease amyloid â-peptide production. Proceedings of the National Academy of Sciences, Published online before print May 12, 2005, 10.1073/pnas.0502768102.

Beta amyloid accumulation shown to be trigger for onset of Alzheimer's

A study using genetically engineered mice has determined that early beta amyloid accumulation within neurons is the trigger for the onset of memory decline in Alzheimer's. The study found that decline in long-term memory retention began with the buildup of beta amyloid in neurons of the hippocampus, amygdala and cerebral cortex regions of the mice's brains, although the plaques and tangles characteristic of Alzheimer’s had not yet developed. When the beta amyloid was cleared away, the memory impairments disappeared; the reemergence of beta amyloid inside the neurons marked again the onset of memory problems.

Billings, L.M., Oddo, S., Green, K.N., McGaugh, J.L. & LaFerla, F.M. 2005. Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice. Neuron, 45(5), 675-688.

Progress toward a more targeted treatment of Alzheimer's disease

A major role in the process by which plaques develop is played by γ-secretase, an enzyme that cuts proteins in a particular place. Sometimes the γ-secretase cleavage goes wrong, causing the creation of a by-product that sticks together and precipitates (plaques). Although γ-secretase is divided into several entities, it’s been assumed that the complex acts as a homogeneous unit. However, new research has found that γ-secretase's various sub-units exhibit very diverse, tissue-specific activity. The findings should make it possible to develop medicines that are targeted on a single sub-unit and thereby have a much more specific action, with fewer unwanted side-effects.

Serneels, L. et al. 2005. Differential contribution of the three Aph1 genes to g-secretase activity in vivo. Proceedings of the National Academy of Sciences, 102, 1719-1724; published online before print January 21 2005

Certain antibodies might clear amyloid-beta proteins from brain

New research in mice may explain why certain antibodies could slow or reverse changes in the brain that are characteristic of Alzheimer’s disease. The study used an antibody that targets a particular region on the amyloid-beta protein. Animals injected with the antibody over a period of months developed fewer amyloid plaques in the brain than did control animals. It appears that the antibody draws amyloid-beta out of the brain and into the blood as a clearance mechanism. "Our work is distinguished from previous research in that we have discovered that this particular antibody can be administered into the bloodstream and need not necessarily gain access to the brain and directly attack amyloid plaque to be effective in reducing plaques. Thus, our work suggests a new mechanism by which certain anti-amyloid antibodies could be useful in preventing or treating Alzheimer’s." The research team now is working to understand the detailed mechanism of how the antibody exerts its effect. The research has potential implications for both diagnosis and treatment of Alzheimer’s disease.

DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease, Proceedings of the National Academy of Sciences Early Edition, 2(27), July 3, 2001.

Amyloid plaques follow oxidative damage to brain cells

Research into the causes of Alzheimer's Disease shows that amyloid plaques develop while the illness is taking over the brain but still not clinically evident. Accordingly, the most common scientific belief holds that those plaques contribute to or cause the oxidative damage and inflammation that occur and, ultimately, destroy brain cells. Now, a mouse-model study at the University of Pennsylvania School of Medicine has demonstrated that oxidative damage precedes the plaques. This finding is likely to have significant implications for treatment. "We know Vitamin E, which is an anti-oxidant, can temporarily slow the progression of AD for some patients. What we don't yet know is what will happen if we suppress, reduce or delay oxidative stress over the long run."

Praticò, D., Uryu, K., Leight, S., Trojanoswki, J. Q., & Lee, V. M.-Y. (2001). Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis. The Journal of Neuroscience, 21(12), 4183–4187. Retrieved from

Scientists begin to unravel cause of blocked memory in Alzheimer's

Researchers at the National Institute of Environmental Health Sciences have found that a protein found in patients with Alzheimer's disease can disrupt brain signals and therefore may contribute to the memory losses of Alzheimer's disease. It appears the characteristic plaques found in the brains of Alzheimer's patients may not be the result of the disease but a cause. It is thought that the major protein of these plaques, beta-amyloid peptide, binds to a receptor in the brain, thus blocking the signals thought to be involved in learning and memory.

Pettit, D. L., Shao, Z., & Yakel, J. L. (2001). β-Amyloid1–42 Peptide Directly Modulates Nicotinic Receptors in the Rat Hippocampal Slice. The Journal of Neuroscience, 21(1), RC120–RC120. Retrieved from

Increased production of protein alpha1-antichymotrypsin found to strongly increase plaque deposits

The protein alpha1-antichymotrypsin can double the accumulation of amyloid plaque in the brains of mice, suggesting a possible new target for therapy in humans. Alpha1-antichymotrypsin (ACT) is a serin protease inhibitor, or serpin, that normally prevents enzymes known as proteases from digesting proteins. Scientists have known for some time that production of ACT is increased in the brains of patients with Alzheimer's disease, but its role has not been understood. The current study, conducted in genetically engineered mice, reveals that increased production of ACT in the brain strongly increases the build-up of amyloid proteins. It is not yet clear exactly how it does this.

Mucke, L., Yu, G.-Q., McConlogue, L., Rockenstein, E. M., Abraham, C. R., & Masliah, E. (2000). Astroglial Expression of Human α1-Antichymotrypsin Enhances Alzheimer-like Pathology in Amyloid Protein Precursor Transgenic Mice. The American Journal of Pathology, 157(6), 2003–2010. doi:10.1016/S0002-9440(10)64839-0

Enzyme found essential for nerve cells to form amyloid plaques

Scientists at Johns Hopkins have demonstrated that a specific enzyme, beta-secretase, is essential for nerve cells to form amyloid plaques, whose over-abundance is characteristic of Alzheimer's. It is one of two enzymes implicated in plaque formation. The other is gamma-secretase. "We're really encouraged by possible therapeutic implications because scientists are already designing small molecules capable of crossing the brain's blood-brain barrier." The molecules could, in theory, be fine-tuned to inhibit such enzymes as beta-secretase.

The research was presented at the annual meeting of the Society for Neuroscience in New Orleans.

Accumulation of plaque may occur because of a decrease in the molecule involved in removing it

While the excess of amyloid plaque deposits have long been recognized as a hallmark of Alzheimer's disease, it has not been known whether the problem occurs because of an over-production, or because of a failure to remove them. A study involving mice found that blood vessels are responsible for removing the beta amyloid protein in healthy brain tissue. In particular, a protein known as LRP-1 (low density lipoprotein receptor-related protein), rapidly shuttles beta amyloid out of the brain and across the blood-brain barrier to the body, which breaks it down into harmless waste products. Not only did the researchers find that removal of amyloid from the brain slowed dramatically when LRP-1 was blocked, but they also showed that healthy middle-aged mice had fewer LRP-1 molecules and shuttled amyloid out of their brains at only half the rate as young mice. It is speculated that healthy young people normally can handle the load of removing amyloid, but that plaques can occur when the LRP-1 system becomes less efficient and the body faces other challenges related to aging, such as decreased circulation. It's also possible that the protein begins accumulating more quickly, overwhelming the removal system.


Biosensor reveals new information about ADDLs

A new method using nanoscale optical biosensors allows researchers to detect and estimate the size and structure of ADDLs in cerebrospinal fluid. It’s believed that only ADDLs of a certain size cause problems for neurons in the early stages of Alzheimer’s disease. It is hoped that eventually this technology will help us diagnose Alzheimer’s accurately in living people, and aid our understanding of how ADDLs are involved in Alzheimer’s.

Haes, A.J., van Duyne, R.P., Klein, W.L. & Chang, L. 2005. The paper, ANYL 396, was presented at 9:00 a.m., Wednesday, Aug. 31, during the "New Frontiers in Ultrasensitive Analysis: Nanobiotech, Single Molecule Detection, and Single Cell Analysis" symposium.

Findings show how toxic proteins rob Alzheimer's patients of memory

Researchers have discovered a molecular mechanism that could explain why the brain damage in early Alzheimer's disease results in memory loss and not other symptoms such as loss of balance or tremors. Toxic proteins called "amyloid ß-derived diffusible ligands" (ADDLs) — first discovered last year — have been found to specifically attack and disrupt synapses, rather than the neurons themselves. By so doing they damage the neuron’s ability to communicate with other neurons. Moreover, the ADDLs target specific synapses — those where there is a gene linked to memory that is normally expressed. The attack disrupts the normal expression of the gene. The finding brings hope that the damage is reversible. ADDls are a form of amyloid beta, but differ from the better-known amyloid fibrils known as plaques, that are a hallmark of Alzheimer’s.

Lacor, P.N., Buniel, M.C., Chang, L., Fernandez, S.J., Gong, Y., Viola, K.L., Lambert, M.P., Velasco, P.T., Bigio, E.H., Finch, C.E., Krafft, G.A. & Klein, W.L. 2004. Synaptic Targeting by Alzheimer's-Related Amyloid {beta} Oligomers. Journal of Neuroscience, 24, 10191-10200.

New toxic protein found

New research has found up to 70 times more small, soluble aggregated proteins called "amyloid b-derived diffusible ligands" (ADDLs) in the brain tissue of individuals with Alzheimer's disease compared to that of normal individuals. This supports a recent theory in which ADDLs accumulate at the beginning of Alzheimer's disease and block memory function by a process predicted to be reversible. ADDLs have the ability to attack the memory-building activity of synapses, points of communication where neurons exchange information, without killing neurons. While both are a form of amyloid beta, ADDLs differ significantly from the amyloid fibrils (plaques) that are diagnostic of Alzheimer's. ADDLs are much, much smaller than fibrils. Unlike fibrils, ADDLs are soluble and diffuse between brain cells until they find vulnerable synapses. The discovery of ADDLs may help explain the poor correlation between plaques and neurological deficits.

Gong, Y. et al. 2003. Alzheimer's disease-affected brain: Presence of oligomeric A β ligands (ADDLs) suggests a molecular basis for reversible memory loss. PNAS, 100, 10417-10422.

Amyloid beta production

Amyloid beta can disrupt neural communication without clumping

Two separate studies have found that minute clumps of amyloid beta (not accumulated into plaque) severely disrupt neurotransmission and inhibit delivery of key proteins in Alzheimer's. One study found that the particles activate an enzyme, CK2, which in turn disrupts the "fast axonal transport" system inside the neuron, while the other found that activation of CK2 blocks neurotransmission at the synapse. It’s suggested that disruptions in the fast axonal transport system are probably key elements in the pathogenesis of Alzheimer's and other adult-onset neurodegenerative diseases, such as Parkinson's and ALS. A prior study also found that activation of another enzyme, GSK3, also disrupts the fast axonal transport system. The new findings suggest the possibility of designing a drug to protect the fast axonal transport system.

Pigino, G. et al. 2009. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. PNAS, 106 (14), 5907-5912.

Moreno, H. et al. 2009. Synaptic transmission block by presynaptic injection of oligomeric amyloid beta. PNAS, 106 (14), 5901-5906. Full text at

Why stroke and hypertension may increase risk of Alzheimer's

New findings of the presence of beta amyloid in the brain of a mouse that overproduces a protein called p25 may help explain the occurrence of sporadic Alzheimer's (the more common form of the disease) and also why stroke and high blood pressure increase the likelihood of developing Alzheimer's. Researchers are now testing potential compounds to halt, or even prevent, the complex cascade of events caused by the presence of p25 that lead to neurodegeneration. The work may also suggest an intervention after stroke to lower or prevent additional risk of Alzheimer's.

The report was presented on June 15 at the annual meeting of the American Society for Biochemistry and Molecular Biology (ASBMB)/8th International Union of Biochemistry and Molecular Biology Conference (IUBMB) in Boston.

Gene targeting prevents memory loss in Alzheimer's disease model

A new mouse study presents new evidence that beta-amyloid is directly responsible for causing the memory loss seen in Alzheimer's, and provides compelling evidence for the therapeutic potential of inhibiting an enzyme, beta-secretase (BACE1), required for the production of beta-amyloid. The mice were genetically engineered to lack the enzyme.

Ohno, M., Sametsky, E.A., Younkin, L.H., Oakley, H., Younkin, S.G., Citron, M., Vassar, R. & Disterhoft, J.F. 2004. BACE1 Deficiency Rescues Memory Deficits and Cholinergic Dysfunction in a Mouse Model of Alzheimer's Disease. Neuron, 41, 27-33.

Neuron death

Study links Alzheimer's disease to abnormal cell division

Neurons affected by Alzheimer’s and many other neurodegenerative diseases often start to divide before they die. A new mouse study shows that this abnormal cell division starts long before amyloid plaques or other markers of the disease appear, suggesting a new approach to therapy for Alzheimer's. The findings also shed new light on the theory that the accumulation of amyloid beta in the brain causes the neuron death in Alzheimer’s, indicating that micro-molecular aggregates (tiny clumps made up of several amyloid beta molecules) rather than amyloid plaques may trigger the disease.

Yang, Y., Varvel, N.H., Lamb, B.T. & Herrup, K. 2006. Ectopic cell cycle events link human Alzheimer's disease and APP transgenic mouse models. The Journal of Neuroscience, 26 (3), 775-784.

Abnormal cell division possible precursor of Alzheimer's

A study of genetically engineered mice sheds more light on the causes of Alzheimer’s. The study looked at what the reasons for neuron death apart from neurofibrillary tangles; they found an abnormal type of cell division occurring in tau proteins that may activate a cascade of abnormal events.

Andorfer, C., Acker, C.M., Kress, Y., Hof, P.R., Duff, K. & Davies, P. 2005. Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms. Journal of Neuroscience, 25, 5446-5454.

Nerve cell death in Alzheimer's is caused by a failed attempt at cell division

Researchers have uncovered a key piece of missing evidence in the proof that nerve cell death in Alzheimer's disease is caused by a failed attempt at cell division. They have found a significant number of brain cells in Alzheimer's patients with extra copies of chromosomes, showing attempts at cell division in cells that are not supposed to divide. This effort to divide may be the cause of the nerve degeneration and dementia in Alzheimer's disease. "It's almost as if Alzheimer's disease were a novel form of cancer." Cancer is characterized by uncontrolled cell division. In this study, scientists found uncontrolled cell division, arrested in the midst of the process, is the likely cause of the nerve cell destruction. It is speculated that the plaques which are a hallmark of Alzheimer's disease brain cells trigger an inflammatory response in the brain, and that this response brings with it proteins that trigger cell division. This finding may signal a new approach to the treatment of Alzheimer's, trying to prevent signals for the inflammatory response from reaching the cells or to prevent the cells from responding to the signals to divide.

Yang, Y., Geldmacher, D. S., & Herrup, K. (2001). DNA Replication Precedes Neuronal Cell Death in Alzheimer’s Disease. The Journal of Neuroscience, 21(8), 2661–2668. Retrieved from

Overproduction of the brain chemical galanin might contribute to cognitive decline

Overproduction of the brain chemical galanin during the early stages of Alzheimer’s may have an negative effect on the brain and contribute to the cognitive decline of patients, according to a study involving transgenic (mutated) mice. The study suggests the overproduction of galanin might be a response to the deterioration of brain cells ( people with Alzheimer's have twice as much galanin in certain areas of the brain as peers who die of something else). While initially galanin might be beneficial, as the disease progresses, the overexpression of galanin may become its own problem, contributing to cognitive decline. It seems that the memory loss that occurs with Alzheimer's may be caused by the combination of cell death and excess galanin. It may be that a drug that blocks galanin would slow or reverse the mental damage caused by the disease.

Steiner, R. A., Hohmann, J. G., Holmes, A., Wrenn, C. C., Cadd, G., Juréus, A., … Crawley, J. N. (2001). Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer’s disease. Proceedings of the National Academy of Sciences, 98(7), 4184–4189. doi:10.1073/pnas.061445598 .


Evidence challenges inflammation theory for Alzheimer's

Although it has long been theorized that inflammation plays a role in the development of Alzheimer’s, repeated studies have failed to find consistent evidence that anti-inflammatory drugs are helpful. Now a brain tissue study reveals that supporting brain cells called microglia are not activated in the presence of tau tangles in the brains of Alzheimer’s patients, as has been predicted, and as would be the case if there were inflammation. Instead, microglia are degenerating. It’s suggested that it is this loss of microglia that contributes to the loss of neurons, and thus to the development of dementia. The next step is to find out why the microglia are dying.

Streit, W.J. et al. 2009. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathologica, Published online ahead of print.

Blood inflammation plays role in Alzheimer's disease

Data from the Framingham Heart Study has found that those with the highest amount of cytokines (protein messengers that trigger inflammation) in their blood were more than twice as likely to develop Alzheimer's disease as those with the lowest amount of cytokines, providing further evidence that inflammation plays a role in the development of Alzheimer's disease.

Tan, Z.S. et al. 2007. Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. Neurology, 68, 1902-1908.

Alzheimer's disease linked to early inflammation

A new study of dementia in identical twins suggests that exposure to inflammation early in life quadruples one's risk of developing Alzheimer's disease. The study involved sifting the 20,000 participants in the Swedish Twin Registry for the 109 "discordant" pairs where only one twin had been diagnosed with dementia. Answers to health questions in the survey enabled the researchers to build a crude indicator of periodontal disease, measured indirectly by teeth lost or loose. Because this is not a direct measure of inflammation, the results need to be confirmed, but they do suggest that an inflammatory burden early in life, as represented by chronic gum disease, may have severe consequences later. The study also found that mental activities at age 40 did not seem to lower the risk of developing Alzheimer's, and the level of education was not a large factor once genes were taken into account (nevertheless, those with less high school and college education had 1.6 times the risk of dementia). Previous studies have shown that Alzheimer's is strongly genetic: If one twin has the disease, his or her identical twin has a 60% chance of developing it.

The study was presented at the first Alzheimer's Association International Conference on Prevention of Dementia, to be held June 18-21 in Washington, D.C.

Antibody detection in Alzheimer's may improve diagnosis, treatment

A study has found that people with Alzheimer’s disease have three to four times more antibodies to RAGE (receptor for advanced glycation end products) and beta amyloid — both major players in Alzheimer’s — than their healthy counterparts. The ability to measure these specific antibody levels could lead to a method for very early diagnosis. The finding may also point to a new treatment approach. The study supports the theory that autoimmunity and resulting inflammation play a big role in Alzheimer’s.

Mruthinti, S., Buccafusco, J.J., Hill, W.D., Waller, J.L., Jackson, T.W., Zamrini, E.Y. & Schade, R.F. 2004. Autoimmunity in Alzheimer’s disease: increased levels of circulating IgGs binding Ab and RAGE peptides. Neurobiology of Aging, 25 (8), 1023-1032.

A new hypothesis about Alzheimer's

A new theory about the cause of Alzheimer's disease has been proposed. According to this theory, Alzheimer’s arises as a consequence of inflammation, which creates abnormal metabolites out of normal brain molecules. These abnormal metabolites then modify "amyloid beta" proteins in the brain and cause them to misfold, thus accumulating into the fibrils and plaques characteristic of the disease. The inflammation process that creates these metabolites can be triggered by numerous stimuli, including infections that precede the onset of Alzheimer's disease by a significant amount of time — perhaps years. Traumatic head injuries, for example, are a major risk factor for later developing Alzheimer's disease. Inflammation is increasingly seen as playing a role in neurodegenerative diseases.

Zhang, Q., Powers, E.T., Nieva, J., Huff, M.E., Dendle, M.A., Bieschke, J., Glabe, C.G., Eschenmoser, A., Wentworth, P.Jr., Lerner, R.A. & Kelly, J.W. 2004. Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proceedings of the National Academy of Sciences, 101 (14), 4752-7.


Gene variation linked to earlier onset of Alzheimer's symptoms

Another genetic variation has been found for Alzheimer’s disease. Unlike the ‘Alzheimer’s gene’ APOe4, which is linked to the rare early-onset form, this gene variant is linked to early presentation in people afflicted with the more common, late-onset form. Rather than increasing the risk of Alzheimer’s, the gene increases the vulnerability of carriers to the effects of amyloid plaques, so that symptoms become evident earlier. The gene codes for the tau protein found in neurofibrillary tangles. Previous studies have had inconsistent results, but the new study has dealt with previous difficulties.

Kauwe, J.S.K. et al. 2008. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proceedings of the National Academy of Sciences, 105 (23), 8050-8054.

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.

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.

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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.


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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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.

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.

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.

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.

Concussions increase chance of age-related cognitive impairment

A study involving retired National Football League players found that they had a 37% higher risk of Alzheimer's than other U.S. males of the same age. Some 60.8% of the retired players reported having sustained at least one concussion during their professional playing career, and 24% reported sustaining three or more concussions. Those with three or more concussions had a five-fold greater chance of having been diagnosed with mild cognitive impairment and a three-fold prevalence of reported significant memory problems compared to those players without a history of concussion. As the study was based on self-reported answers to the health questions, further studies are needed to confirm the findings, but it does seem likely that head injuries earlier in life increase the chance of developing dementia or mild cognitive impairment.

Guskiewicz, K.M., Marshall, S.W., Bailes, J., McCrea, M., Cantu, R.C., Randolph, C. & Jordan, B.D. 2005. Association between Recurrent Concussion and Late-Life Cognitive Impairment in Retired Professional Football Players. Neurosurgery, 57(4), 719-726.

“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.

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.

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).

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.

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.

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.