Down syndrome

Down Syndrome risk of Alzheimer’s connected to white matter integrity

Brain scans of 10 persons with Down syndrome but no dementia, 10 persons with Down syndrome and dementia, and 10 healthy controls, have revealed a linear correlation between cognitive ability and compromised

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Genes, brain size, brain atrophy, and Alzheimer’s risk

May, 2012

A round-up of genetic news.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

More genes involved in Alzheimer’s

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

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

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

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

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

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

Another gene identified in early-onset Alzheimer's

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

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

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

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

 

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

New genetic cause of Alzheimer's disease

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

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

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

Evidence that Alzheimer's protein switches on genes

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

[2866] Cao, X., & Südhof T. C.
(2001).  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60.
Science. 293(5527), 115 - 120.

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

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

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

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

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

Reference: 

[2858] Consortium, E N I G M-A(ENIGMA)., & Cohorts Heart Aging Research Genomic Epidemiology(charge)
(2012).  Common variants at 12q14 and 12q24 are associated with hippocampal volume.
Nature Genetics. 44(5), 545 - 551.

[2909] Taal, R. H., Pourcain B S., Thiering E., Das S., Mook-Kanamori D. O., Warrington N. M., et al.
(2012).  Common variants at 12q15 and 12q24 are associated with infant head circumference.
Nature Genetics. 44(5), 532 - 538.

[2859] Cohorts Heart Aging Research Genomic Epidemiology,(charge), & Consortium E G G(EGG).
(2012).  Common variants at 6q22 and 17q21 are associated with intracranial volume.
Nature Genetics. 44(5), 539 - 544.

[2907] Stein, J. L., Medland S. E., Vasquez A A., Hibar D. P., Senstad R. E., Winkler A. M., et al.
(2012).  Identification of common variants associated with human hippocampal and intracranial volumes.
Nature Genetics. 44(5), 552 - 561.

[2925] Bell, R. D., Winkler E. A., Singh I., Sagare A. P., Deane R., Wu Z., et al.
(2012).  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.
Nature.

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

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

[2728] Cruchaga, C., Chakraverty S., Mayo K., Vallania F. L. M., Mitra R. D., Faber K., et al.
(2012).  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families.
PLoS ONE. 7(2), e31039 - e31039.

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

[2897] Pottier, C., Hannequin D., Coutant S., Rovelet-Lecrux A., Wallon D., Rousseau S., et al.
(2012).  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.
Molecular Psychiatry.

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

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Learning difficulties

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

New screening tool helps identify children at risk

An exam, called the NICU (neonatal intensive care unit) Network Neurobehavioral Scale (NNNS), has been created to identify newborns who may have problems with school readiness and behavior at age four. This opens up the possibility of early intervention to prevent these problems. The screening exam has been tested on 1248 babies, mostly black and on public assistance. Five discrete behavioral profiles were reliably identified; the most extreme negative profile was found in 5.8% of the infants. Infants with poor performance were more likely to have behavior problems at age three, school readiness problems at age four, and low IQ at 4 ½ — 40% had clinically significant problems externalizing (impulsivity and acting out), internalizing (anxiety, depression, withdrawn personalities), and with school readiness (delays in motor, concepts and language skills), and 35% had low IQ.

[596] Liu, J., Bann C., Lester B., Tronick E., Das A., Lagasse L., et al.
(2010).  Neonatal neurobehavior predicts medical and behavioral outcome.
Pediatrics. 125(1), e90-98 - e90-98.

http://www.eurekalert.org/pub_releases/2009-12/bu-nst120709.php

Cognitive dysfunction reversed in mouse model of Down syndrome

Down syndrome is characterized by specific learning impairments (for example, difficulties in using spatial and contextual information to form new memories, but less difficulty at remembering information linked to sensory cues) that point to the hippocampus as a problem area. Investigation has revealed that the problem lies in degeneration of the locus coeruleus, which sends norepinephrine to neurons in the hippocampus. Now a study using genetically engineered mice has found that norepinephrine precursor drugs improved performance in the mice within a few hours. However, the effect did wear off quite quickly too. Other research has looked at acetylcholine, which also acts at the hippocampus. The present findings suggest the best medication regimen will be one that improves both norepinephrine and acetylcholine signals. Locus coeruleus degeneration is also seen in dementia; Alzheimer’s develops among those with Down syndrome at a significantly higher rate than in the general population.

Salehi, A. et al. 2009. Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome. Science Translational Medicine, 1 (7), 7-17.

http://www.eurekalert.org/pub_releases/2009-11/sumc-nds111309.php
http://www.eurekalert.org/pub_releases/2009-11/uoc--cdr111609.php http://www.the-scientist.com/blog/display/56154/

Testing one time is not enough

A study demonstrating the perils of one-time testing gave 16 common cognitive and neuropsychological tests to groups of people ages 18-39, 50-59 and 60-97 years. The variation between scores on the same test given three times during a two-week period was as big as the variation between the scores of people in different age groups. “It's as if on the same test, someone acted like a 20-year-old on a Monday, a 45-year-old on Friday, and a 32-year-old the following Wednesday”. The study makes clear the dangers of diagnosing learning disability, progressive brain disease or impairment from head injury on the basis of testing on a single occasion. The researcher suggests we should view cognitive abilities as a distribution of many potential levels of performance instead of as one stable short-term level; that people have a range of typical performances, a one-person bell curve. It may also be that within-person variability could be a useful diagnostic marker in itself — for example, extreme fluctuations might be an early warning of mental decline.

[921] Salthouse, T. A.
(2007).  Implications of within-person variability in cognitive and neuropsychological functioning for the interpretation of change.
Neuropsychology. 21(4), 401 - 411.

http://www.physorg.com/news102689828.html
http://www.eurekalert.org/pub_releases/2007-07/apa-csv062507.php

Common cholesterol-lowering drug reverses learning disabilities in mice

Following their discovery that neurofibromatosis 1 (NF1) — the leading genetic cause of learning disabilities — is linked to dysfunction in a protein called Ras, researchers have successfully used a commonly prescribed cholesterol-lowering statin drug (lovastatin) to reverse the learning deficits in mice. Clinical trials with humans are being planned.

[1348] Li, W., Cui Y., Kushner S., Brown R., Jentsch J., Frankland P., et al.
(2005).  The HMG-CoA Reductase Inhibitor Lovastatin Reverses the Learning and Attention Deficits in a Mouse Model of Neurofibromatosis Type 1.
Current Biology. 15(21), 1961 - 1967.

http://www.eurekalert.org/pub_releases/2005-11/uoc--rf110405.php
http://www.newscientist.com/channel/health/dn8276

More light on a common developmental disorder

Chromosome 22q11.2 deletion syndrome is the most common genetic deletion syndrome, and causes symptoms such as heart defects, cleft palate, abnormal immune responses and cognitive impairments. Two related studies have recently cast more light on these cognitive impairments. Previously it was known that numerical abilities were impaired more than verbal skills. The new study found children with the chromosome deletion performed more poorly on experiments designed to test visual attention orienting, enumerating, and judging numerical magnitudes. All three tasks relate to how the children mentally represent objects and the spatial relationships among them, supporting previous arguments that such visual-spatial skills are a fundamental foundation to the later learning of counting and mathematics. The second study found that such children had changes in the shape, size and position of the corpus callosum, the main bridge between the two hemispheres.

[1139] Simon, T. J., Bearden C. E., Mc-Ginn D MD., & Zackai E.
(2005).  Visuospatial and Numerical Cognitive Deficits in Children with Chromosome 22Q11.2 Deletion Syndrome.
Cortex. 41(2), 145 - 155.

[812] Simon, T. J., Ding L., Bish J. P., McDonald-McGinn D. M., Zackai E. H., & Gee J.
(2005).  Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study.
NeuroImage. 25(1), 169 - 180.

http://www.eurekalert.org/pub_releases/2005-03/chop-lbt030205.php

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Link among Alzheimer's disease, Down syndrome, atherosclerosis and diabetes

January, 2010

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

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

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Circadian clock may be critical for remembering what you learn

October, 2008

We know circadian rhythm affects learning and memory in that we find it easier to learn at certain times of day than others, but now a study involving Siberian hamsters has revealed that having a functioning circadian system is in itself critical to being able to remember. The finding has implications for disorders such as Down syndrome and Alzheimer's disease. The critical factor appears to be the amount of the neurotransmitter GABA, which acts to inhibit brain activity. The circadian clock controls the daily cycle of sleep and wakefulness by inhibiting different parts of the brain by releasing GABA. It seems that if it’s not working right, if the hippocampus is overly inhibited by too much GABA, then the circuits responsible for memory storage don't function properly. The effect could be fixed by giving a GABA antagonist, which blocks GABA from binding to synapses. Recent mouse studies have also demonstrated that mice with symptoms of Down syndrome and Alzheimer's also show improved learning and memory when given the same GABA antagonist. The findings may also have implications for general age-related cognitive decline, because age brings about a degradation in the circadian system. It’s also worth noting that the hamsters' circadian systems were put out of commission by manipulating the hamsters' exposure to light, in a technique that was compared to "sending them west three time zones." The effect was independent of sleep duration.

Reference: 

[688] Ruby, N. F., Hwang C. E., Wessells C., Fernandez F., Zhang P., Sapolsky R., et al.
(2008).  Hippocampal-dependent learning requires a functional circadian system.
Proceedings of the National Academy of Sciences. 105(40), 15593 - 15598.

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