Alzheimer's Disease

Alzheimer's Disease

Alzheimer's disease currently affects one in 10 people over age 65 and nearly half of those over age 85.

More than 19 million Americans say they have a family member with the disease, and 37 million say they know somebody affected with Alzheimer's.

In the United States, the average lifetime cost per Alzheimer patient is US$174,000. (These figures are from the U.S. Alzheimer's Association).

Resources:

For information about Alzheimer's, see the Alzheimer's Disease Education and Referral (ADEAR) Center's website (www.alzheimers.org). ADEAR is run by the National Institute on Aging (one of the US Government's National Institutes of Health).

Other useful resources include:

The Alzheimer Research Forum: "A scientific knowledge base on Alzheimer disease, with research news, expert commentaries, and databases for peer-reviewed articles, drugs, research reagents, grants, jobs, conferences, and more."
www.alzforum.org

Cognitive Neurology and Alzheimer's Disease Center at Northwestern University
http://www.brain.northwestern.edu/mdad/index.html

Medline Plus
http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html

Links to national organizations that offer support:

http://www.alz.org/ Site of the U.S. Alzheimer’s Association.

http://www.alzheimers.org.uk/ Site of the U.K. Alzheimer's Society

http://www.alzheimer.ca/ Site of the Canadian Alzheimer's Association

http://www.alzheimers.org.au/ Site of the Australian Alzheimer's Association

www.alzheimers.org.nz Site of Alzheimer's New Zealand

Some articles of interest:

a good introduction from the Harvard Mahoney Neuroscience Newsletter:

http://www.med.harvard.edu/publications/On_The_Brain/Volume2/Special/SPAlz.html

Montessori for Alzheimer's patients

Movement with Meaning

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How dementia risk varies among ethnic groups

  • A very large U.S. study looking at ethnic differences in dementia risk, has found that African-Americans show the highest rates of dementia, followed by blacks and American Indian/Alaska Natives, then Latinos and whites, with Asian-Americans having the lowest rates.

A study involving 14 years of health records from more than 274,000 Northern Californians has assessed the relative dementia risk of six different ethnicities.

The average annual rate of dementia was:

  • 26.6 cases per 1,000 for blacks
  • 22.2 cases per 1,000 for American Indians/Alaskan Natives
  • 19.6 cases per 1,000 for Latinos and Pacific Islanders
  • 19.3 cases per 1,000 for whites
  • 15.2 cases per 1,000 for Asian Americans.

But this is an annual rate, not particularly useful at a practical level. How do these numbers convert to lifetime risk? Statistical calculations estimate that among those who reach age 65 dementia-free, the following percentages of each ethnicity will develop dementia in the next 25 years:

  • 38% of blacks
  • 35% of American Indians/Alaskan Natives
  • 32% of Latinos
  • 30% of whites
  • 28% of Asian Americans
  • 25% of Pacific Islanders (this is probably the least reliable number, given the small number of Pacific Islanders in the sample).

The study population included 18,778 African-Americans, 4543 American Indians/Alaskan Natives, 21,000 Latinos, 206,490 white Americans, 23,032 Asian-Americans, and 440 Pacific Islanders.

http://www.eurekalert.org/pub_releases/2016-02/kp-lsf021016.php

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Cognitive Tests

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

Effective new cognitive screening test for detection of Alzheimer's

A new cognitive test for detecting Alzheimer's has been developed, and designed to be suitable for non-specialist use. The TYM ("test your memory") involves 10 tasks including ability to copy a sentence, semantic knowledge, calculation, verbal fluency and recall ability. It has been tested on 540 healthy individuals and 139 patients with diagnosed Alzheimer's or mild cognitive impairment. Healthy controls completed the test in an average time of five minutes and gained an average score of 47 out of 50, compared to 45 for those with mild cognitive impairment, 39 for those with non-Alzheimer dementias and 33 for those with Alzheimer’s. Among controls, the average score was not affected by age until after 70, when it showed a small decline. There were no gender or geographical background differences in performance. The TYM detected 93% of patients with Alzheimer's, compared to only 52% by the widely used mini-mental state examination.

Brown, J. et al. 2009. Self administered cognitive screening test (TYM) for detection of Alzheimer’s disease: cross sectional study. BMJ, 338:b2030, doi: 10.1136/bmj.b2030
Full text available here.

Early identification of dementia increasingly difficult

A study comparing nondemented 70-year-olds examined in the early 1970s with nondemented 70-year-olds examined in the year 2000 has revealed that those who were examined in 2000 scored much higher on non-memory cognitive tests than those examined 30 years earlier — indicating that such tests can no longer be used to predict future dementia. Moreover, although memory loss was a predictor for later development of dementia, it wasn’t conclusive —not everybody with poor memory developed dementia. This was particularly true of the very old (85 year olds).

Sacuiu, S.F. 2009. Prodromal Cognitive Signs of Dementia. Doctoral thesis from Sahlgrenska Academy, University of Gothenburg. http://gupea.ub.gu.se/dspace/handle/2077/19395

http://www.eurekalert.org/pub_releases/2009-05/uog-eio_1052009.php

Degree of test variability improves dementia diagnosis

A study of nearly 900 older adults has found that the degree of variability in performance across neuropsychological tests, measured within a person, improved the prediction of dementia above and beyond one's level of performance on each test alone.

Holtzer, R. et al. 2008. Within-Person Across-Neuropsychological Test Variability and Incident Dementia. JAMA, 300(7), 823-830.

http://www.eurekalert.org/pub_releases/2008-08/aeco-set081908.php

New criterion may improve identification of dementia risk in highly educated older adults

A shift in the cutoff point on the widely used cognitive screening tool, the mini-mental state examination (MMSE), is suggested for highly educated older adults, in order to more effectively assess the risk of dementia.

Bryant, S.E. et al. 2008. Detecting Dementia With the Mini-Mental State Examination in Highly Educated Individuals. Archives of Neurology, 65 (7), 963-967.

http://www.eurekalert.org/pub_releases/2008-07/jaaj-ncm071008.php

New 'everyday cognition' scale tracks how older adults function in daily life

A new, carefully validated questionnaire called Everyday Cognition (ECog) has been developed by seven psychologists. The 39-question screening tool is designed to enable mild functional problems in older adults to be quickly and easily identified. The questionnaire needs to be filled out by someone who knows an older adult well, such as a spouse, adult child, or close friend. It looks at everyday function in seven key cognitive domains: memory, language, semantic (factual) knowledge, visuospatial abilities, planning, organization and divided attention. The test has been shown to be sensitive to early changes present in Mild Cognitive Impairment, and unlike other cognitive tests, does not appear to be strongly influenced by education level. The test even differentiated between people diagnosed with mild impairment in memory only and those mildly impaired in several areas.

Farias, S.T. et al. 2008. The Measurement of Everyday Cognition (ECog): Scale Development and Psychometric Properties. Neuropsychology, 22 ( 4), 531-544.

http://www.eurekalert.org/pub_releases/2008-07/apa-nc062408.php

Simple test predicts 6-year risk of dementia

A 14-point index combining medical history, cognitive testing, and physical examination — a simple test that can be given by any physician — has been found to predict a person’s risk for developing dementia within six years with 87% accuracy. As measured by the index, the risk factors for developing dementia are an age of 70 or older, poor scores on two simple cognitive tests, slow physical functioning on everyday tasks such as buttoning a shirt or walking 15 feet, a history of coronary artery bypass surgery, a body mass index of less than 18, and current non-consumption of alcohol. The results do need to be validated in other populations — for example, they have not yet been tested on Hispanics or Asian-Americans.

The tests were described in a presentation at the 2007 International Conference on Prevention of Dementia, in Washington, DC.

http://www.eurekalert.org/pub_releases/2007-06/uoc--stp060707.php

Personality changes may help detect Lewy bodies dementia

Dementia with Lewy bodies is the second most common neurodegenerative cause of dementia. It shares characteristics with both Alzheimer's and Parkinson's disease, but some medications used to treat Alzheimer's patients are potentially dangerous for people with dementia with Lewy bodies. Early diagnosis is therefore important. A new study has found that people with dementia with Lewy bodies often display passive personality changes some time before cognitive deficits are evident, offering hope that a simple personality test might help diagnosis.

Galvin, J.E., Malcom, H., Johnson, D. & Morris, J.C. 2007. Personality traits distinguishing dementia with Lewy bodies from Alzheimer disease. Neurology, 68, 1895-1901.

http://www.eurekalert.org/pub_releases/2007-05/aaon-pcm052107.php

New dementia screening tool detects early cognitive problems

A new screening tool for dementia — the Saint Louis University Mental Status Examination (SLUMS) — appears to work better in identifying mild cognitive problems in the elderly than the commonly used Mini Mental Status Examination — particularly for the more educated patients. It takes a clinician about seven minutes to administer the SLUMS, which supplements the Mini Mental Status Examination by asking patients to perform tasks such as doing simple math computations, naming animals, recalling facts and drawing the hands on a clock. The SLUMS is available at this link http://medschool.slu.edu/agingsuccessfully/pdfsurveys/slumsexam_05.pdf

Tariq, S.H. et al. 2006. Comparison of the Saint Louis University Mental Status Examination and the Mini-Mental State Examination for Detecting Dementia and Mild Neurocognitive Disorder—A Pilot Study. American Journal of Geriatric Psychiatry, 14, 900-910.

http://www.eurekalert.org/pub_releases/2006-11/slu-nds103006.php

More sensitive tests for predicting Alzheimer's

The first study used data from 119 participants in the Longitudinal Aging Study Amsterdam. The memory test scores of those who two years later developed Alzheimer's were compared with the scores of those who stayed healthy. Three tests were very good at predicting who would later develop Alzheimer's: a Paired-Associate Learning Test, which cued participants to recall five semantically related and five semantically unrelated pairs of words; a Perceptual Identification Task, which measured how fast participants read aloud words briefly presented on a computer screen; a Visual Association Test, which cued participants to recall six line drawings of common objects that had been presented earlier in an illogical interaction with another object or cue. On the word-pair memory test, people destined to develop Alzheimer's disease didn't do any better when words were related than when they weren't, suggesting they’d already lost deep semantic knowledge. On the word-reading test, word repetition didn't help high-risk participants to perform better, a sign that implicit learning was impaired. The popular Mini Mental Status Exam (MMSE), a test mainly sensitive to episodic memory, was not as good a predictor.
In the second study, a dichotic listening task, which measures how well people process information when they hear one thing in the left ear and another in the right ear, was found to also be predictive of Alzheimer’s, confirming that people have problems with selective attention very early in the disease.

Spaan, P.E.J., Raaijmakers, J.G.W. & Jonker, C. 2005. Early Assessment of Dementia: The Contribution of Different Memory Components. Neuropsychology, 19 (5).

Duchek, J.M. & Balota, D.A. 2005. Failure to Control Prepotent Pathways in Early Stage Dementia of the Alzheimer's Type: Evidence from Dichotic Listening. Neuropsychology, 19 (5).

http://www.eurekalert.org/pub_releases/2005-09/apa-pfm092105.php

Early warning signs of Alzheimer's show up years before official diagnosis

A meta-analysis of 47 studies of Alzheimer's disease has revealed that people can show early warning signs across several cognitive domains years before they are officially diagnosed, confirming that Alzheimer's causes general deterioration and tends to follow a stable preclinical stage with a sharp drop in function. People at the preclinical stage showed marked preclinical deficits in global cognitive ability, episodic memory, perceptual speed, and executive functioning; along with somewhat smaller deficits in verbal ability, visuospatial skill, and attention. There was no preclinical impairment in primary memory. There is no clear qualitative difference between the normal 75-year old and a preclinical Alzheimer’s sufferer; instead it seems that the normal elderly person, the preclinical Alzheimer’s person, and the early clinical Alzheimer’s patient represent three instances on a continuum of cognitive capabilities.

Bäckman, L., Jones, S., Berger, A-K. & Laukka, E.J. 2005. Cognitive impairment in preclinical Alzheimer's disease: A meta-analysis. Neuropsychology, 19 (4).

http://www.eurekalert.org/pub_releases/2005-07/apa-ews072505.php

More sensitive test norms better predict who might develop Alzheimer's disease

Early diagnosis of Alzheimer's is becoming more important with new medical and psychological interventions that can slow (but not stop) the course of the disease. Given this, it is suggested that more sensitive testing may be necessary for highly intelligent people, who, on average, show clinical signs of Alzheimer's later than the general population. Once they show such signs, they decline much faster. A study of 42 older people with IQ's of 120 or more, used two different test norms to forecast problems: the standard norm, derived from a large cross-section of the population, or an adjusted high-IQ norm that measured changes against the individual's higher ability level. The raised cutoffs predicted that 11 of the 42 individuals were at risk for future decline – compared with standard cutoffs, which indicated they were normal. True to the former prediction, three and a half years later, nine of those 11 people had declined. Six of those went on to develop mild cognitive impairment (MCI), a transitional illness from normal aging to a dementia (of which one type is Alzheimer's). Five of these individuals have since received a diagnosis of Alzheimer's disease, two years after this study was submitted. It is also suggested that, at the other end of the scale, those with below-average intelligence have the potential for being misdiagnosed as 'demented' when they are not, and the norms should be adjusted downwards accordingly.

Rentz, D.M., Huh, T.J., Faust, R.R., Budson, A.E., Scinto, L.F.M., Sperling, R.A. & Daffner, K.R. 2004. Use of IQ-Adjusted Norms to Predict Progressive Cognitive Decline in Highly Intelligent Older Individuals. Neuropsychology, 18 (1).

http://www.eurekalert.org/pub_releases/2004-01/apa-mst122903.php

New method of distinguishing Alzheimer's from Lewy body dementia

Looking at specific changes in alertness and cognition may provide a reliable method for distinguishing Alzheimer's from dementia with Lewy bodies (DLB) and normal aging. Four characteristics significantly distinguished patients with DLB from persons with Alzheimer’s and normal elderly controls: daytime drowsiness and lethargy despite getting enough sleep the night before; falling asleep two or more hours during the day; staring into space for long periods and episodes of disorganized speech. "For the normal elderly control group, one or two of these behaviors was found in only 11 percent of the group. For the patients with AD, one or two of these behaviors were not uncommon, but over 63% of the patients with DLB had three or four of these behaviors.” DLB accounts for as much as 20 to 35% of the dementia seen in the United States.

Ferman, T.J., Smith, G.E., Boeve, B.F., Ivnik, R.J., Petersen, R.C., Knopman, D., Graff-Radford, N., Parisi, J. & Dickson, D.W. 2004. DLB fluctuations: Specific features that reliably differentiate DLB from AD and normal aging. Neurology, 62,181-187.

http://www.eurekalert.org/pub_releases/2004-01/ama-nmo010804.php

Brief telephone questionnaire screens for early signs of dementia

Researchers have developed a brief telephonic questionnaire that helps distinguish between persons with early signs of dementia and persons with normal cognitive function. The questionnaire provides a way to reach out to persons with dementia whose impairment otherwise may go undetected until substantial cognitive deterioration has occurred. The questionnaire consists of a test of delayed recall and 2 questions that ask whether the person needs help with remembering to take medications or with planning a trip for errands. It is estimated that of 100 people who score positive on this test, 42 will actually have cognitive impairment. In other words, this does not provide a diagnosis of Alzheimer’s, but provides evidence that further evaluation is required. The rate of false positives compares favorably to other types of screening tests. A further study is underway to confirm the validity and reliability of the test.

Fillit, H. et al. 2003. A Brief Telephonic Instrument to Screen for Cognitive Impairment in a Managed Care Population. Journal of Clinical Outcomes Management, , 419-429.

http://www.eurekalert.org/pub_releases/2003-09/twc-btq091603.php

Verbal memory tests predict dementia

The Longitudinal Aging Study Amsterdam tested the memories of a large group of elderly people on two occasions, two years apart. Performance on the memory tests was then compared between those who developed dementia during those two years and those who did not. It was found that those who later were found to have dementia were scarcely better at remembering word pairs clearly linked in meaning (for example, pipe - cigar) than word pairs without such a link (for example nail - butter), on the first test. (those who not have dementia two years later did, as is usual, benefit from such a link in meaning). In addition, those in the early stage of dementia did not benefit from the repeated presentation of words. The results suggest a means by which elderly people in the early stages of dementia can be identified, which is important because the drugs used to inhibit dementia only work in the earliest stages of the disease.

This was revealed in doctoral research by the neuropsychologist Pauline Spaan from the University of Amsterdam.

http://www.eurekalert.org/pub_releases/2003-01/nofs-mtp012403.php

Verbal memory test best indicator of who will have Alzheimer's disease

A meta-analysis of 31 studies involving a total of 1,144 Alzheimer's patients and 6,046 healthy controls, supports the use of the California Verbal Learning Test in predicting future Alzheimer’s type dementia. Long delay recall and percent recall were the best predictors, with executive function type measures also being predictive but less so than both the long and short delay memory tests. Changes in the hippocampus were the best volumetric or neuroimaging measure but in general volumetric measures were less sensitive to preclinical stages of the dementia than were the neuropsychological tests. It should be noted that a decline in various types of memory, especially verbal episodic memory, is also observable in normal elderly; the crucial factor in determining a pre-dementia state lies in the size of the memory deficit.

Zakzanis, K.K. & Boulos, M.I. 2002. A Meta-Analysis of ApoE Genotype and Neuropsychologic and Neuroanatomic Changes in Preclinical Alzheimer's Disease. Presentation at the 110th Annual Convention of the American Psychological Association (APA) on August 25.

http://www.eurekalert.org/pub_releases/2002-08/apa-vmt081302.php

Early diagnosis of Alzheimer's

An analysis of data from 40 participants enrolled in a long-term study at the UCSD Alzheimer’s Disease Research Center (ADRC) found that "paper-and-pencil" cognitive skills tests administered to normal subjects averaging 75 years of age contained early signs of cognitive decline in those subjects who later developed Alzheimer’s disease. All participants were symptom-free when they took the test. The differences were quite subtle - only some performance measures were affected.

Jacobson MW, Delis DC, Bondi MW, Salmon DP. Do neuropsychological tests detect preclinical Alzheimer's disease: Individual-test versus cognitive-discrepancy score analyses. Neuropsychology. 2002;16(2):132–139.

http://www.eurekalert.org/pub_releases/2002-04/uoc--trs040502.php

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Early Markers

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

Measuring brain atrophy in patients with mild cognitive impairment

A study involving 269 patients with mild cognitive impairment provides evidence that a fully automated procedure called Volumetric MRI (that can be done in a clinical setting) can accurately and quickly measure parts of the medial temporal lobe and compare them to expected size. It also found that not only atrophy in the hippocampus but also the amygdala is associated with a greater risk of conversion to Alzheimer’s.

Kovacevic, S. et al. 2009. High-throughput, Fully Automated Volumetry for Prediction of MMSE and CDR Decline in Mild Cognitive Impairment. Alzheimer Disease & Associated Disorders, 23 (2), 139-145.

http://www.eurekalert.org/pub_releases/2009-06/uoc--mba061609.php

Cerebrospinal fluid shows Alzheimer's disease deterioration much earlier

A study involving 60 patients with subjective cognitive impairment, 37 patients with non-amnestic mild cognitive impairment, and 71 with amnestic mild cognitive impairment, has found that 52% of those with SCI, 68% of those with naMCI, and 79% of those with aMCI showed decreased concentrations of Aβ42 and increased concentrations of tau protein in the cerebrospinal fluid. The findings confirm the use of biomarkers in the CSF for very early diagnosis

Visser, P.J. et al. 2009. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment and mild cognitive impairment in the DESCRIPA study: a prospective, case-control study. The Lancet Neurology, 8 (7), 619–627.

http://www.eurekalert.org/pub_releases/2009-06/uog-cfs061809.php

Weight loss in old age may signal dementia

An 8-year study involving over 1,800 older Japanese Americans has found that those with lower body mass index (BMI) scores at the beginning of the study were 79% more likely to develop dementia than those with higher scores. In addition, those who lost weight over the study period at a faster rate were nearly three times more likely to develop dementia than those who lost weight more slowly, and this association was stronger in those who were overweight or obese to start.

Hughes, T.F. et al. 2009. Association between late-life body mass index and dementia: The Kame Project. Neurology, 72, 1741-1746.

http://www.eurekalert.org/pub_releases/2009-05/aaon-wli051209.php

New tool can help predict Alzheimer's risks

A new 15-point scale of risk factors for Alzheimer's has been developed and correctly classified 88% of the 3,375 older adults in the study. 56% of those with scores of 8 or higher developed dementia within six years, compared to 23% with moderate scores and just 4% with low scores. The risk factors include poor cognitive test performance (2–4 points), body mass index below 18.5 (2 points), older age (1–2 points), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point), presence of the ApoE4 gene (1 point), MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point).

Barnes, D.E. et al. 2009. Predicting risk of dementia in older adults. The late-life dementia risk index. Neurology, published May 13, 2009.

http://uk.reuters.com/article/scienceNews/idUKTRE54C77920090513

Eye tracking test detects mild cognitive impairment

A test first developed for use with nonhuman primates is now being used to detect mild cognitive impairment (MCI) in humans. The infrared eye-tracking test involves showing one image and then another after a 2-second delay, and then repeating the test 2 minutes later. Those without cognitive impairment spend most of their time looking at the new image, but it was found that those with MCI spent less time looking at the new picture, presumably because they have less memory of seeing the original image before. Those with Alzheimer's disease look at both images equally. It’s hoped that this test may allow dementia to be spotted much earlier.

Crutcher, M.D. et al. 2009. Eye Tracking During a Visual Paired Comparison Task as a Predictor of Early Dementia. American Journal of Alzheimer's Disease and Other Dementias, Published online February 26 2009.

http://www.eurekalert.org/pub_releases/2009-04/eu-yru041509.php

Shrinking in hippocampus precedes Alzheimer's

An imaging study of 64 Alzheimer's patients, 44 people with mild cognitive impairment, and 34 people with no memory or thinking problems, has found that those with smaller hippocampal volumes and higher rates of shrinkage were two to four times as likely to develop dementia over the study period (average 18 months) as those with larger volumes and a slower rate of atrophy. During that time, 23 of the people with MCI developed Alzheimer's, and three of the healthy participants.

Henneman, W.J.P. et al. 2009. Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures. Neurology, 72, 999-1007.

http://www.eurekalert.org/pub_releases/2009-03/aaon-sih031009.php

Brain atrophy pattern in some MCI patients predicts Alzheimer's

A study of 84 patients with mild Alzheimer's, 175 patients with MCI and 139 healthy controls has revealed a pattern of regional brain atrophy in patients with MCI that indicates a greater likelihood of progression to Alzheimer's. Brain scans results showed widespread cortical atrophy in some patients with MCI, most importantly, atrophy in parts of the medial and lateral temporal lobes and in the frontal lobes — a pattern also present in the patients with mild Alzheimer's disease. Those exhibiting such atrophy declined significantly over a year and were more likely to progress to a probable diagnosis of Alzheimer's. MCI patients without that pattern of atrophy remained stable after a year. It should be noted that such atrophy affects not only memory, but also planning, organization, problem solving and language.

McEvoy, L.K. et al. 2009. Alzheimer Disease: Quantitative Structural Neuroimaging for Detection and Prediction of Clinical and Structural Changes in Mild Cognitive Impairment. Radiology, Published online February 6.

http://www.eurekalert.org/pub_releases/2009-02/rson-msb020309.php

Blood test could give early warning of Alzheimer’s risk

A simple blood test may enable us to predict whether someone will soon develop Alzheimer’s, allowing them to take action that might delay its development. In the study of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed Alzheimer’s over 4.6 years of follow-up. Higher blood levels of amyloid-beta 42 peptide at the onset of the study were associated with a threefold increased risk of Alzheimer’s, with the levels significantly declining at the onset of Alzheimer’s (perhaps because it has started accumulating in the brain).

Schupf, N. et al. 2008. Peripheral Aβ subspecies as risk biomarkers of Alzheimer's disease. PNAS, 105 (37), 14052-14057.

http://www.eurekalert.org/pub_releases/2008-09/cumc-rst090808.php

Women lose weight at least a decade before developing dementia

Another study has come out associating weight loss with later dementia. The study found that women who later developed dementia started losing weight up to 20 years before the disease was diagnosed. On average, those with dementia weighed 12 pounds less than those without the disease the year the disease was diagnosed. The association may be related to a loss in the sense of smell, and increasing apathy. The association was not found with men, probably because older men were less likely to be preparing their own food. The findings do of course conflict with others suggesting that obesity in middle-age may be a risk factor for dementia. More research is needed to clarify the situation.

Knopman, D.S. et al. 2007. Incident dementia in women is preceded by weight loss by at least a decade. Neurology, 69, 739-746.

http://www.eurekalert.org/pub_releases/2007-08/aaon-wlw081407.php

Simple test predicts 6-year risk of dementia

A 14-point index combining medical history, cognitive testing, and physical examination — a simple test that can be given by any physician — has been found to predict a person’s risk for developing dementia within six years with 87% accuracy. As measured by the index, the risk factors for developing dementia are an age of 70 or older, poor scores on two simple cognitive tests, slow physical functioning on everyday tasks such as buttoning a shirt or walking 15 feet, a history of coronary artery bypass surgery, a body mass index of less than 18, and current non-consumption of alcohol. The results do need to be validated in other populations — for example, they have not yet been tested on Hispanics or Asian-Americans.

The tests were described in a presentation at the 2007 International Conference on Prevention of Dementia, in Washington, DC.

http://www.eurekalert.org/pub_releases/2007-06/uoc--stp060707.php

Brain structure changes years before memory loss begins

Another study provides evidence that people who develop dementia or Alzheimer's disease experience brain structure changes years before any signs of memory loss begin. The study involved 136 people over the age of 65 who were considered cognitively normal at the beginning of the five-year study. By the end of the study, 23 people had developed MCI, and nine of the 23 went on to be diagnosed with Alzheimer's disease. Compared to the group that didn't develop memory problems, the 23 who developed MCI or Alzheimer's disease had less gray matter in key memory processing areas (specifically, anteromedial temporal lobes and left angular gyrus) even at the beginning of the study when they were cognitively normal. They also had lower cognitive test scores, though these scores were still within normal range.

Smith, C.D. et al. 2007. Brain structural alterations before mild cognitive impairment. Neurology, 68, 1268-1273.

http://www.eurekalert.org/pub_releases/2007-04/aaon-bsc041007.php

Memory complaints early warning for Alzheimer's

A post-mortem study of 90 older adults from the Rush Memory and Aging Project found that those who had yet to have any clinical symptoms of Alzheimer's disease still showed a strong link between their self-reported memory complaints and brain pathology associated with Alzheimer's disease.

Barnes, L.L., Schneider, J.A., Boyle, P.A., Bienias, J.L. & Bennett, D.A. 2006. Memory complaints are related to Alzheimer disease pathology in older persons. Neurology, 67, 1581-1585.

http://www.eurekalert.org/pub_releases/2006-11/rumc-cam113006.php

New early diagnostic test trialed

A mouse study has used a laser scan of the eyes to accurately diagnose Alzheimer's well before the disease was evident in the brain. The study follows on from earlier research revealing that beta-amyloid protein is evident in the eyes of Alzheimer’s patients. The test, which is a very quick and simple procedure, is now in the first stage of experimental trials in people.

The findings were announced at the annual meeting of the Optical Society of America.

http://www.sciencentral.com/articles/view.htm3?article_id=218392859

Link between increased weight-loss rate and dementia

Confirming earlier indications, a long-term study of the elderly has revealed that their average rate of weight loss doubles (from 0.6 pounds per year to 1.2 pounds per year) in the year before symptoms of Alzheimer's-type dementia first become detectable. The finding may be useful as one of several early biomarkers. The study analyzed data on 449 seniors, of whom 125 were eventually diagnosed with mild dementia. Interestingly, at the beginning of the study, this group weighed about 8lb less on average than the other participants, although the two groups lost weight at the same rate for four to five years, before weight loss increased in the group that would eventually be diagnosed with mild dementia. It is not yet known why there should be this connection between weight loss and dementia.

Johnson, D.K., Wilkins, C.H. & Morris, J.C. 2006. Accelerated weight loss in Alzheimer's disease precedes diagnosis. Archives of Neurology, 63, 1312-1317.

http://www.eurekalert.org/pub_releases/2006-09/wuso-bdf090806.php

Weight Loss Precedes Dementia Diagnosis In Women

A study has come out finding that, in women, declining weight precedes dementia by many years.
The retrospective study analyzed the medical records of 560 patients diagnosed with the onset of dementia between 1990 and 1994. The patients were matched with 560 controls. Among the women, average weight increased slightly over the preceding 30 years for the control group, but drifted downwards over the 30 years for those who developed dementia. The researchers suggest that changes in the brain interfered somehow with maintenance of body weight. The trend was not observed in men.

Findings were presented July 16 at the Alzheimer's Association International Conference on Alzheimer's Disease and Related Disorders in Madrid, Spain.

http://www.sciencedaily.com/releases/2006/07/060716090233.htm

Link between size of hippocampus and progression to Alzheimer's

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

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

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

Alzheimer's disease onset tied to lapses in attention

A new finding may lead to another tool to detect Alzheimer’s early, and also offers support for the idea that breakdowns in attention may be at the heart of many of the memory problems experienced by Alzheimer’s sufferers. The study, involving 94 older adults (average age mid-70s) who were either healthy controls or in the early stages of Alzheimer’s, found those in the early stages of Alzheimer's disease had greater difficulty shifting attention back and forth between competing sources of information in a dichotic listening task. The finding may also explain why early-stage patients start to struggle with everyday tasks that call for processing a lot of information, such as driving. Prior research has found that performance on dichotic listening predicts accident rates in commercial bus drivers.
[note: this study was briefly reported on in September, but only mentioning its use as an early test]

Duchek, J.M. & Balota, D.A. 2005. Failure to Control Prepotent Pathways in Early Stage Dementia of the Alzheimer's Type: Evidence from Dichotic Listening. Neuropsychology, 19 (5).

http://www.eurekalert.org/pub_releases/2005-11/wuis-ado110905.php

A new analysis of a standard brain test may help predict dementia

A new study gives promise of early diagnosis of Alzheimer’s. A computer analysis of an EEG (electroencephalograph) test was almost 95% accurate in predicting those people in their 60s and 70s who would develop dementia over the next 7 to 10 years. There were several distinctive features in the brain waves of those who would later show cognitive impairment. The study now needs to be replicated with a larger sample.

Prichep, L.S., John, E.R., Ferris, S.H., Rausch, L., Fang, Z., Cancro, R., Torossian, C. & Reisberg, B. 2005. Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging. Neurobiology of Aging, In Press, Corrected Proof, Available online 6 October 2005.

http://www.eurekalert.org/pub_releases/2005-10/dumc-ana100505.php

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.

http://www.eurekalert.org/pub_releases/2005-08/acs-brn081905.php

Protein studies may lead to new Alzheimer's test

A new technique has identified more than 400 proteins in human spinal fluid — 40 times more than previously known. On average, one of every five proteins identified was substantially changed in patients with Alzheimer's disease compared to older people without neurological disease. The finding may lead to a new test for diagnosing Alzheimer’s.

Zhang, J., Goodlett, D.R., Quinn, J.F., Peskind, E., Kaye, J.A., Zhou, Y., Pan, C., Yi, E., Eng, J., Wang, Q., Aebersold, R.H. & Montine, T.J. 2005. Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease Journal of Alzheimer's Disease, 7(2), 125-133.

http://www.eurekalert.org/pub_releases/2005-04/uow-psm041905.php

New test is first step in early detection of Alzheimer's disease

A new technique called bio-bar-code amplification (BCA) technology has been found to be able to detect miniscule amounts of ADDL in human cerebrospinal fluid, bringing promise of an early diagnostic test for Alzheimer’s. The researchers hope to develop the technology so that the test could be done using a blood or urine sample instead of cerebrospinal fluid, which is more difficult to obtain.

Georganopoulou, D.G., Chang, L., Nam, J.M., Thaxton, C.S., Mufson, E.J., Klein, W.L. & Mirkin, C.A. 2005. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proceedings of the National Academy of Sciences, 102, 2273-2276.

http://www.eurekalert.org/pub_releases/2005-01/nu-nti012805.php
http://www.eurekalert.org/pub_releases/2005-01/nsf-nds012805.php

Smell test to help early diagnosis

One of the first types of memory affected by Alzheimer’s is olfactory memory – our database of smells. Researchers have now developed a simple scratch-and-sniff test that may enable Alzheimer’s to be detected in its very early stages. On the basis of a five-year study tracking 150 people with mild memory loss and Alzheimer's disease and 63 healthy adults, 10 specific odors proved to be the best predictors for Alzheimer's Disease: strawberry, smoke, soap, menthol, clove, pineapple, natural gas, lilac, lemon and leather. The test takes only 5 to 8 minutes, and seems to have comparable predictive ability as detailed memory and neuropsychological testing.

The findings were presented at the 2004 meeting of the American College of Neuropsychopharmacology.

http://www.eurekalert.org/pub_releases/2004-12/g-sfl121004.php

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.

http://www.eurekalert.org/pub_releases/2004-06/mcog-adi060204.php

Loss of smell linked to key protein in Alzheimer's disease

Loss of smell is one of the first clinical signs of Alzheimer’s and Parkinson’s disease. Now researchers have linked smell loss in genetically altered mice with excessive levels of a key protein associated with these diseases. If smell function declines as the levels of this protein increase in brain regions associated with smelling, the research could validate the use of smell tests for diagnosing Alzheimer's disease.

Macknin, J.B., Higuchi, M., Lee, V.M-Y., Trojanowski, J.Q. & Doty, R.L. 2004. Olfactory dysfunction occurs in transgenic mice overexpressing human t protein. Brain Research, 1000, 174-178.

http://www.eurekalert.org/pub_releases/2004-03/uopm-los030304.php

Diagnosing Alzheimer's disease may soon be possible earlier

Diagnosing Alzheimer's disease is problematic because we have had no definitive tests for the disease (other than after death, by examining the brain). Recent research suggests that two markers in cerebrospinal fluid may indicate the presence of Alzheimers. This is exciting not only because it would make diagnosis easier, but because it might enable us to diagnose it much earlier. However, to be clinically useful, they will need to develop tests that use more readily available fluids (such as urine).

Praticò, D., Clark, C. M., Lee, V. M.-Y., Trojanowski, J. Q., Rokach, J., & FitzGerald, G. A. (2000). Increased 8,12-iso-iPF2α-VI in Alzheimer’s disease: Correlation of a noninvasive index of lipid peroxidation with disease severity. Annals of Neurology, 48(5), 809–812. doi:10.1002/1531-8249(200011)48:5<809::AID-ANA19>3.0.CO;2-9

Gene marker for late-onset Alzheimer's disease nearer discovery

Three independent studies have linked late-onset Alzheimer's disease to a locus on chromosome 10 that affects processing of the amyloid-beta protein, a peptide important in the formation of the characteristic amyloid plaques found in the brains of people with Alzheimer's disease. Researchers are optimistic the precise gene will be found in the next few years.
Before this, a particular form of the apolipoprotein E (APOE) gene on chromosome 19 has been the only widely recognized genetic risk factor in late onset Alzheimer’s disease. There is also some evidence of a risk factor gene on a region of chromosome 12.
So far, three genes have been found that are linked to the rare early-onset Alzheimer's (when symptoms appear before age 60).

Bertram, L., Blacker, D., Mullin, K., Keeney, D., Jones, J., Basu, S., … Tanzi, R. E. (2000). Evidence for Genetic Linkage of Alzheimer’s Disease to Chromosome 10q. Science, 290(5500), 2302–2303. doi:10.1126/science.290.5500.2302

Ertekin-Taner, N., Graff-Radford, N., Younkin, L. H., Eckman, C., Baker, M., Adamson, J., … Younkin, S. G. (2000). Linkage of Plasma Aβ42 to a Quantitative Locus on Chromosome 10 in Late-Onset Alzheimer’s Disease Pedigrees. Science, 290(5500), 2303–2304. doi:10.1126/science.290.5500.2303

Myers, A., Holmans, P., Marshall, H., Kwon, J., Meyer, D., Ramic, D., … Goate, A. M. (2000). Susceptibility Locus for Alzheimer’s Disease on Chromosome 10. Science, 290(5500), 2304–2305. doi:10.1126/science.290.5500.2304

http://www.eurekalert.org/pub_releases/2000-12/MCJ-Loc1-2112100.php

tags problems: 

Alzheimer's Genes

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

Impact of Alzheimer's gene on healthy brains

And another new imaging analysis technique has cast light on the impact of the Alzheimer’s gene ApoE4 in healthy brains. Healthy older adults with the gene were found to have reduced cognitive performance, decreased brain volume in the hippocampus and amygdala, and decreased white matter integrity in the left parahippocampal gyrus.

Honea, Robyn A., Eric Vidoni, Amith Harsha and Jeffrey M. Burns. Impact of APOE on the Healthy Aging Brain: A Voxel-Based MRI and DTI Study. J Alzheimers Dis 18:3, 553-564.

http://www.eurekalert.org/pub_releases/2009-11/ip-nna111709.php

Three new genes associated with Alzheimer's found

Only one gene, ApoE4, has been associated with the non-familial (common) form of Alzheimer’s. Now the largest ever Alzheimer's genome-wide association study involving 16,000 individuals, has found three more. CLU or ApoJ (which produces a protective protein called clusterin or apolipoprotein J), PICALM (important at synapses and involved in transporting molecules within and into nerve cells), and CR1. Both CLU and CR1 have previously been implicated in the clearance of amyloid beta peptide. CLU is encoded on chromosome 8, CR1 on chromosome 1, and PICALM on chromosome 11.

Harold, D. et al. 2009. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics, 41, 1088–1093. Lambert, J-C et al. 2009. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genetics, 41, 1094-1099.

http://www.eurekalert.org/pub_releases/2009-09/art-lea090309.php

Carriers of Alzheimer's gene show different brain activity as young adults

Possession of the ApoE4 gene variant associated with Alzheimer’s risk is found in about a quarter of the population, and has been shown to be associated with differences in the hippocampus in middle-aged and elderly healthy carriers. Now a new study of 36 younger adults (20-35) has revealed that differences in brain activity patterns between carriers and non-carriers are also evident at this stage, not only when performing a memory task, but even when the brain was at rest. Carriers of the gene had more brain activity in the hippocampus during the memory task, and more activity in the default mode network during rest. The findings support a theory that the brain's memory function may gradually wear itself out in those who go on to develop Alzheimer's.

Filippini, N. et al. 2009. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proceedings of the National Academy of Sciences, 106, 7209-7214.

http://www.eurekalert.org/pub_releases/2009-04/icl-yaa040609.php

Having a parent with dementia may affect memory in midlife

A study of 715 participants from the second generation of the Framingham Heart Study (average age 59) has found that, among those with the ApoE ε4 gene, those who had parents with dementia scored significantly worse on tests of verbal memory and visual memory than persons who did not have parents with dementia. The impairment was strongest in those whose parents had Alzheimer’s (rather than other forms of dementia), and in them was equivalent to around 15 years of brain aging. The effect of parental dementia was not found in those who didn’t have the ApoE ε4 gene.

Debette, S. et al. 2009. Parental Dementia and Alzheimer Disease Are Associated with Poorer Memory in Middle-Aged Adults: The Framingham Offspring Study. Presented April 29 at the American Academy of Neurology's 61st Annual Meeting in Seattle, Washington.

http://www.eurekalert.org/pub_releases/2009-02/bu-brf021209.php
http://www.eurekalert.org/pub_releases/2009-02/aaon-hap021009.php

Memory gene linked to late-onset Alzheimer's

Following the finding that carriers of one variant (the T-allele) of the KIBRA gene performed better on memory tests compared to those carrying the C-allele, researchers have now found that carriers of the T-allele have a 25% lower risk of developing Alzheimer's disease. The conclusion is supported by three studies. A study of 702 deceased persons diagnosed with Alzheimer's, and 1,026 living and deceased persons with and without Alzheimer's, found that non-carriers of the KIBRA T-allele had increased risk of late-onset Alzheimer¹s. A study of brain tissue from 47 deceased individuals found that KIBRA, and a subset of other molecules directly interacting with it, were significantly altered in regions of the brain involved in Alzheimer's disease pathology, but not in a region of the brain typically unaffected -- the primary visual cortex. PET scans of 136 individuals aged 47 to 68, with close relatives diagnosed with Alzheimer's, of whom half carried the T-allele, found that non-carriers exhibited, on average, less metabolic activity in key brain regions known to be altered in the earliest stages of the disease. Similar findings have been found when looking at the epsilon 4 allele of apolipoprotein E (the ‘Alzheimer’s gene’). In the current study, the effects of this allele were controlled for.

Corneveaux, J.J. et al. In press. Evidence for an association between KIBRA and late-onset Alzheimer's disease. Neurobiology of Aging

http://www.eurekalert.org/pub_releases/2008-09/ttgr-itt091508.php

Healthy children of Alzheimer patients show early brain changes

A study of 28 neurologically-normal subjects, between ages 45 and 65, of whom 12 carried the ‘Alzheimer’s gene’ APOE-4, has found that although there was no significant difference in educational level or neuropsychological performances, those who didn’t carry the gene had significantly better functional connectivity between the hippocampus and the posterior cingulated cortex.

The findings were presented at the Alzheimer's Association International Conference on Alzheimer's disease in Chicago, July 29.

http://www.eurekalert.org/pub_releases/2008-07/mcow-nsf072308.php

Women more likely to have memory problems in very old age

Dementia risk for both men and women increases from age 65 to 85, but a study of about 900 people age 90 and older has found that women were nearly twice as likely to have dementia in their 90s compared to men. The results also showed that the likelihood of having dementia doubled every five years in women but not in men. Women with a higher education appeared to be as much as 45% less likely to have dementia compared to women with less education.

Corrada, M.M. et al. 2008. Prevalence of dementia after age 90: Results from The 90+ Study. Neurology, 71 (5), 337-343.

http://www.eurekalert.org/pub_releases/2008-07/aaon-amo062408.php

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.

http://www.eurekalert.org/pub_releases/2008-06/wuso-gvl060608.php

Maternal inheritance more importance than paternal for Alzheimer's risk?

In an intriguing preliminary study comparing brain metabolism among cognitively normal people who have a father, a mother, or no relatives with Alzheimer’s disease, researchers have found that only those with an affected mother have reduced brain metabolism in the same brain regions as Alzheimer’s patients.

Mosconi, L. et al. 2007. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. PNAS, 104, 19067-19072.

http://www.eurekalert.org/pub_releases/2007-11/nyum-aml110607.php

Familial link between Parkinson's and dementia

A study of relatives of patients with Parkinson’s disease provides evidence that relatives of patients with Parkinson’s disease (primarily younger age at onset Parkinson’s) have an increased risk of cognitive impairment or dementia.

Rocca, W.A. et al. 2007. Risk of Cognitive Impairment or Dementia in Relatives of Patients With Parkinson Disease. Archives of Neurology, 64(10),1458-1464.

http://www.eurekalert.org/pub_releases/2007-10/jaaj-rop100407.php

High stress and genetic risk factor lead to increased memory decline

A study involving 91 older, healthy subjects (mean age 78.8 years) has found that those low on stress (low levels in cortisol) or without the APOE-ε4 gene performed better on memory measures than those with high stress or those with the APOE-ε4 gene. Those who had the gene and had high stress levels showed the greatest memory impairment.

Peavy, G.M. et al. 2007. The Effects of Prolonged Stress and APOE Genotype on Memory and Cortisol in Older Adults. Biological Psychiatry, 62 (5), 472-478.

http://www.eurekalert.org/pub_releases/2007-08/e-naf082707.php

New Alzheimer's gene

A study comparing more genetic markers in the DNA of people with and without Alzheimer’s disease than ever before has revealed a new gene that may increase a person’s risk for developing Alzheimer’s disease. The gene — GAB2 — appears to modify an individual’s risk when associated with other genes, including APOE4. It’s suggested that the healthy form of the GAB2 gene protects brain cells from developing tangles. If confirmed, this discovery could provide a target for future therapeutic drugs.

Reiman, E.M. et al. 2007. GAB2 Alleles Modify Alzheimer's Risk in APOE e4 Carriers. Neuron, 54, 713-720.

http://www.eurekalert.org/pub_releases/2007-06/ttgr-rti060107.php

Study examines genetic risk factors for Alzheimer's disease

A Welsh study that tested more than 17,000 gene variants in 4,000 volunteers has found evidence for several genes contributing to Alzheimer’s disease, the most interesting one being GALP, thought to affect the development of tangles within brain cells.

The findings will be published in a future issue of Human Molecular Genetics.

http://www.eurekalert.org/pub_releases/2007-03/cu-seg030507.php

Two-fold role of Alzheimer’s genes?

The genes responsible for an inherited form of Alzheimer's disease — two genes known as presenilins — are primarily known for their role as an enzyme that cleaves amyloid precursor protein (APP) to form amyloid ß-peptide, which function has a direct connection to Alzheimer’s, and consequently has been the focus of attention. However, new research indicates that these genes also may control the balance of calcium within cells by acting as a calcium channel, and that the mutated forms of these genes lose this ability. Given the role that calcium signaling plays in cognitive function, it may be that this other role of presenilins is also important in the development of Alzheimer’s. If so, drugs that restore normal calcium levels might be useful for treating Alzheimer's disease.

Tu, H. et al. 2006. Presenilin Forms ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations. Cell, 126, 981–993.

http://www.eurekalert.org/pub_releases/2006-09/cp-ssa090106.php

New genetic cause of Alzheimer's disease

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

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

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

Alzheimer's has higher genetic risk than thought

In a study far larger than any undertaken before, results suggest the highest estimates of the genetic risk of developing Alzheimer’s are in fact correct. The study involved all participants in the Swedish Twin Registry aged 65 or older in 1998 (nearly 12,000 of them) and found 392 pairs with evidence of Alzheimer's in at least one twin. In the model that best fit the data, genetic influence accounted for 79% of Alzheimer's risk, with 95% probability of being within the range 67 to 88%. The other 21% of Alzheimer's risk was due to non- shared environmental causes. Risk from shared environments was statistically negligible. Genetic risk for Alzheimer's was the same for men and women after controlling for age. The study raises doubts about the widely held view that Alzheimer's has two forms: the "familial," with genetic roots, and the "sporadic," with environmental causes. This doesn’t mean, however, that environment is unimportant.

Gatz, M. et al. 2006. Role of Genes and Environments for Explaining Alzheimer Disease. Archives of General Psychiatry, 63, 168-174.

http://www.eurekalert.org/pub_releases/2006-02/uosc-aft020206.php

Key genetic risk for Alzheimer's linked to myelin breakdown

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

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

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

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

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

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

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

Genes influence memory in families with Alzheimer's disease

A study of 1,036 people from 266 families, most of whom had more than one person living with Alzheimer's in the extended family, found that about half of the variation in memory performance among individuals was due to genetics. The influence of genetics was not as strong in the areas of attention, abstract reasoning, language and visual-spatial ability. The genetic influence seemed to have little to do with the gene apolipoprotein E, known to increase the risk of developing Alzheimer's. It should be noted, however, that participants in the study had an average of only six years of education.

Lee, J.H., Flaquer, A., Stern, Y., Tycko, B. & Mayeux, R. 2004. Genetic influences on memory performance in familial Alzheimer disease. Neurology, 62, 414-421.

http://www.eurekalert.org/pub_releases/2004-02/aaon-gim020304.php

Genes identified for age of onset of Alzheimer's

Genes responsible for controlling the age of onset of Alzheimer's or Parkinson's diseases in those individuals genetically predisposed to developing these diseases have been identified. It appears that chromosome 10, already thought to contain a risk gene for Alzheimer's disease, could also contain an age at onset gene that affects both Alzheimer's and Parkinson's diseases.

Li, Y. et al. 2002. Age at Onset in Two Common Neurodegenerative Diseases Is Genetically Controlled. American Journal of Human Genetics, 70, 985-993.

http://www.eurekalert.org/pub_releases/2002-02/dumc-dri022502.php

Evidence that Alzheimer's protein switches on genes

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

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

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

New genetic risk factor for susceptibility to Alzheimer's disease

In a decade-long research study following more than 300 first-degree relatives of 189 Alzheimer's patients, researchers at the University of Pittsburgh have identified a small area of chromosome 10 that, when combined with the previously identified APOE E4 gene, significantly increase a person's risk of developing the disease. This combination of genes produced a 16-fold increase in the risk of AD among first-degree relatives. By comparison, this effect is greater than the increased risk of lung cancer caused by smoking. These new results are supported by independent studies of AD patients and controls from Pittsburgh, Boston, and Bonn, Germany.

The study was reported in Molecular Psychiatry, 6 (4), pages 413-419.

http://www.eurekalert.org/pub_releases/2001-06/MP-Ngrf-1706101.php

Gene marker for late-onset Alzheimer's disease nearer discovery

Three independent studies have linked late-onset Alzheimer's disease to a locus on chromosome 10 that affects processing of the amyloid-beta protein, a peptide important in the formation of the characteristic amyloid plaques found in the brains of people with Alzheimer's disease. Researchers are optimistic the precise gene will be found in the next few years.
Before this, a particular form of the apolipoprotein E (APOE) gene on chromosome 19 has been the only widely recognized genetic risk factor in late onset Alzheimer’s disease. There is also some evidence of a risk factor gene on a region of chromosome 12.
So far, three genes have been found that are linked to the rare early-onset Alzheimer's (when symptoms appear before age 60).

The findings are reported in the Dec. 22 issue of Science.

http://www.eurekalert.org/pub_releases/2000-12/MCJ-Loc1-2112100.php

tags problems: 

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.

http://www.eurekalert.org/pub_releases/2009-06/uof-pat061509.php

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.

http://www.eurekalert.org/pub_releases/2007-05/aaon-bip052107.php

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.

http://www.eurekalert.org/pub_releases/2005-06/uosc-adl061605.php

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.

http://www.eurekalert.org/pub_releases/2004-06/mcog-adi060204.php

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.

http://www.eurekalert.org/pub_releases/2004-03/sri-anh031504.php

tags problems: 

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.

http://www.eurekalert.org/pub_releases/2006-01/nion-sla011206.php

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.

http://www.eurekalert.org/pub_releases/2005-06/ani-asa062005.php

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 http://www.jneurosci.org/content/21/8/2661

http://www.eurekalert.org/pub_releases/2001-04/CWRU-Rlfc-1604101.php

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 .

http://www.eurekalert.org/pub_releases/2001-03/RPSL-Oobc-1803101.php

tags problems: 

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.

http://www.eurekalert.org/pub_releases/2009-03/vfi-pta031909.php

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.

http://www.eurekalert.org/pub_releases/2008-03/ip-paf031208.php

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.

http://www.eurekalert.org/pub_releases/2005-11/uopm-ctt111105.php

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.

http://www.eurekalert.org/pub_releases/2005-10/gi-szi101705.php

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.

http://www.eurekalert.org/pub_releases/2005-07/vfii-adn072705.php

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.

http://www.eurekalert.org/pub_releases/2005-05/dbnl-faa051305.php

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 A&#946; Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice. Neuron, 45(5), 675-688.

http://www.eurekalert.org/pub_releases/2005-03/uoc--uri030105.php

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

http://www.eurekalert.org/pub_releases/2005-02/vfii-pta013105.php

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.

http://www.eurekalert.org/pub_releases/2001-07/aaft-sgc070201.php

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 http://www.jneurosci.org/content/21/12/4183

http://www.eurekalert.org/pub_releases/2001-06/UoPM-Psfr-1406101.php

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 http://www.jneurosci.org/content/21/1/RC120

http://www.eurekalert.org/pub_releases/2001-01/NIoE-Ehis-0101101.php

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

http://www.eurekalert.org/pub_releases/2000-12/UoCS-Rrir-0412100.php

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.

http://www.eurekalert.org/pub_releases/2000-11/JHMI-Hsse-0511100.php

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.

http://www.eurekalert.org/pub_releases/2000-11/UoR-Simt-0511100.php

ADDLs

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.

http://www.eurekalert.org/pub_releases/2005-08/acs-brn081905.php

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.

http://www.eurekalert.org/pub_releases/2004-12/nu-fsh120104.php

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.

http://www.eurekalert.org/pub_releases/2003-08/nu-tpc081803.php

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 http://www.pnas.org/content/106/14/5901.abstract?sid=14f68dbd-bdda-42c1-8fd5-32ef39913522

http://www.eurekalert.org/pub_releases/2009-03/uoia-moa031709.php
http://www.eurekalert.org/pub_releases/2009-03/mbl-tbt032609.php

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.

http://www.eurekalert.org/pub_releases/2004-06/foas-api060304.php

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.

http://www.eurekalert.org/pub_releases/2004-01/nu-gtp010504.php

tags problems: 

Vaccines

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

Immunization with AB42 does not prevent dementia despite clearing associated brain plaques

Disappointingly, analysis of 80 Alzheimer's patients who had been involved in trialing immunisation against amyloid-β in September 2000, has found that, despite a lower level of amyloid-β plaques, there was no improved survival or increased time to severe dementia in those who were immunised.

Holmes, C. et al. 2008. Long-term effects of AB42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. The Lancet, 372 (9634), 216-223.

http://www.eurekalert.org/pub_releases/2008-07/l-iwa071608.php

Vaccine prevents Alzheimer's

A vaccine has successfully prevented the development of amyloid plaques and tau tangles in the brains of genetically engineered mice. The vaccinated mice also demonstrated normal learning skills and functioning memory. There were no major side-effects. Human trials are still a few years off.

Frazer, M.E. et al. 2008. Reduced Pathology and Improved Behavioral Performance in Alzheimer's Disease Mice Vaccinated With HSV Amplicons Expressing Amyloid-β and Interleukin-4. Molecular Therapy, 16, 845-853.

http://www.eurekalert.org/pub_releases/2008-05/uorm-vti051908.php

Alzheimer's vaccine clears plaque but doesn't improve memory

A two-year canine study has revealed that although a promising vaccine being tested for Alzheimer's disease clears beta-amyloid plaques from the brain, it doesn’t seem to help restore lost learning and memory abilities. Autopsies showed that although plaques had been cleared from multiple brain regions, damaged neurons remained. The findings suggest that simply treating beta-amyloid plaques may have only limited clinical benefit if started after there is significant plaque growth, and a combination of vaccination with other therapies aimed at repairing damaged neurons may be best.

Head, E. et al. 2008. A Two-Year Study with Fibrillar β-Amyloid (Aβ) Immunization in Aged Canines: Effects on Cognitive Function and Brain Aβ. Journal of Neuroscience, 28, 3555-3566.

http://www.eurekalert.org/pub_releases/2008-04/uoc--avc040408.php

Transdermal vaccine effective in treating Alzheimer's disease in mice

Previous research on an Alzheimer's vaccine proven safe and effective in an animal model was suspended when the initial clinical trial caused brain inflammation and death in a small percentage of patients. A new mouse study has now had success with a transdermal method of delivery (a skin patch), that doesn’t appear to trigger the toxic reaction of past immunization strategies. Further research is needed to assess whether the transdermal vaccine can curb memory loss as well as reduce Ab plaque.

Nikolic, W.V. et al. 2007. Transcutaneous -amyloid deposits without T cell infiltration and microhemorrhage. Proceedings of the National Academy of Sciences, 104 (7), 2507-2512.

http://www.eurekalert.org/pub_releases/2007-01/uosf-tve011807.php

Hopeful results from interrupted Alzheimer's vaccine study

Phase 2 of a human clinical trial vaccinating patients with beta-amyloid was halted in 2002 when some participants developed brain inflammation. Participants continued to be monitored, however, and results show that participants whose immune systems mounted a response against beta amyloid performed significantly better on a series of memory tests than those who received a placebo injection (but not on 5 tests often used to diagnose dementia). There were also signs of reduced levels of tau protein (a protein considered a sign of cell death) in those who had an immune response. As a result, new trials are underway, this time using humanized antibodies rather than beta amyloid itself. The antibodies should help trigger the immune system to attack beta amyloid, but will be cleared by the body soon after injection.

Gilman, S., Koller, M., Black, R.S., Jenkins, L., Griffith, S.G., Fox, N.C., Eisner, L., Kirby, L., Boada Rovira, M., Forette, F. & Orgogozo, J-M. for the AN1792(QS-21)-201 Study Team. 2005. Clinical effects of Aß immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64, 1553-1562.

Fox, N.C., Black, R.S., Gilman, S., Rossor, M.N., Griffith, S.G., Jenkins, L. & Koller, M. for the AN1792(QS-21)-201 Study Team. Effects of Aß immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology, 64, 1563-1572.

http://www.eurekalert.org/pub_releases/2005-05/uomh-hrf050505.php

Progress on Alzheimer's vaccine

Efforts to create a vaccine for Alzheimer’s have been hindered by potential side effects — some human participants in an earlier trial developed severe inflammation in the brain. A mouse study has now substantially increased the safety of the vaccine by including a tetanus toxin to alter the immune response. Future studies are planned using the herpes virus.

Bowers, W.J., Mastrangelo, M.A., Stanley, H.A., Casey, A.E., Milo, L.J.Jr. & Federoff, H.J. 2004. HSV amplicon-mediated Ab vaccination in Tg2576 mice: differential antigen-specific immune responses. Neurobiology of Aging, available online 25 June 2004.

http://www.eurekalert.org/pub_releases/2004-06/uorm-hta062904.php

Mice immunized against Alzheimer's

Using a new vaccine, NYU School of Medicine researchers have prevented the development of Alzheimer's disease in mice genetically engineered with the human gene for the disease. The researchers are optimistic that this new vaccine is safer than one already being tested in early human clinical trials. The new vaccine, modeled on a fragment of a protein called amyloid, which is most frequently implicated in causing Alzheimer's, reduced the amount of amyloid plaque in the brains of mice by 89 percent. At the same time, the vaccine reduced the amount of soluble amyloid beta in the brain by 57 percent. Early clinical trials of the new vaccine could begin within one year.

Sigurdsson, E. M., Scholtzova, H., Mehta, P. D., Frangione, B., & Wisniewski, T. (2001). Immunization with a Nontoxic/Nonfibrillar Amyloid-β Homologous Peptide Reduces Alzheimer’s Disease-Associated Pathology in Transgenic Mice. The American Journal of Pathology, 159(2), 439–447. doi:10.1016/S0002-9440(10)61715-4

http://www.eurekalert.org/pub_releases/2001-08/nyum-nrs080101.php

A vaccine for Alzheimer's

A vaccine may help prevent and treat the disabling memory loss and cognitive impairment of Alzheimer's disease. Alzheimer's occurs when amyloid-beta peptides accumulate in the brain, forming plaque. While previous studies have shown that vaccinating mutated mice with this amyloid-beta peptide could remove the plaque deposits, there was never any evidence of improvement in brain function, until now. The researchers also believe this study provides the final element of proof that Alzheimer's is initiated by amyloid-beta peptides. The researchers believe clinical trials could begin on human subjects within the year.

Johnson, J. D., McDuff, S. G. R., Rugg, M. D., & Norman, K. A. (2009). Recollection, Familiarity, and Cortical Reinstatement: A Multivoxel Pattern Analysis. Neuron, 63(5), 697–708. doi:10.1016/j.neuron.2009.08.011

http://www.eurekalert.org/pub_releases/2000-12/UoT-UoTr-1912100.php

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