alzheimers causes

Alzheimer's disease consists of 3 distinct subtypes

  • A very small study points to three subtypes of Alzheimer's disease, each of which seems to be associated with:
    • different physiological abnormalities
    • different causes and risk factors
    • different symptoms / progression
    • different age-onsets.
  • This suggests that effective treatments need to be tailored to the subtype.

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.


Bredesen, D.E. 2015. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. AGING, 7 (8), 595-600. Full text at

Bredesen, D.E. 2014. Reversal of cognitive decline: A novel therapeutic program. AGING, Vol 6, No 9 , pp 707-717. Full text at

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Inflamed iron-containing cells found in Alzheimer's brains

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.



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Inflammation in Alzheimer's

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

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.

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Cell Death

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

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 .

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Amyloid-beta Proteins

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.

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New biomarkers for early Alzheimer's diagnosis

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.


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Blocking inflammation receptor helps Alzheimer's mice

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.


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Brain network decay detected in early Alzheimer's

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.


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Individual differences in Alzheimer's molecular structure

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.


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