alzheimers genes

Healthy lifestyle associated with lower dementia risk regardless of genes

  • A very large study found that an unhealthy lifestyle and high genetic risk were independently associated with higher dementia risk, and a healthy lifestyle reduced the risk for those at high genetic risk.

Data from 196,383 older adults (60+; mean age 64) in the UK Biobank found that a healthy lifestyle was associated with lower dementia risk regardless of genes.

Both an unhealthy lifestyle and high genetic risk were associated with higher dementia risk.

Lifestyle factors included smoking, physical activity, diet, and alcohol consumption. Bearing in mind that lifestyle factors were self-reported, 68.1% followed a healthy lifestyle, 23.6% were intermediate, and 8.2% followed an unhealthy lifestyle. Regarding genes, 20% were at high risk, 60% were intermediate, and 20% were at low risk.

Of those at high genetic risk, 1.23% developed dementia in the 8-year period (remember that these are people who are still relatively — the average age at study end would still only be 72), compared with 0.63% of those at low genetic risk. Of those at high genetic risk plus an unhealthy lifestyle, 1.78% developed dementia compared to 0.56% of those at low risk with a healthy lifestyle. Among those who had a high genetic risk but a healthy lifestyle, 1.13% developed dementia in the period.

I trust that these people will continue to be followed — it will be very interesting to see the statistics in another 10 years.

There were 1,769 new cases of dementia during the 8-year study period.

https://www.eurekalert.org/pub_releases/2019-07/jn-ihl071219.php

https://www.theguardian.com/society/2019/jul/14/healthy-lifestyle-may-cut-risk-of-dementia-regardless-of-genes

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Navigation difficulties early sign of Alzheimer's

  • A mobile phone game designed to test spatial navigation skills (Sea Hero Quest) has found that performance can distinguish APOE4 carriers from non-carriers.
  • Preliminary findings from a long-term study indicate that middle-aged adults with close relatives with Alzheimer's did worse on a test that measured their ability to visualise their position, and tended to have a smaller hippocampus.
  • A small study found that increasing difficulties with building cognitive maps of new surroundings was linked to Alzheimer's biomarkers. Difficulties in learning a new route appeared later, among those with early Alzheimer's.

Mobile game detects Alzheimer's risk

A specially designed mobile phone game called Sea Hero Quest has found that gaming data can distinguish between those people who are genetically at risk of developing Alzheimer's disease ond those who are not. The game is designed to test spatial navigation skills — one of the first cognitive areas affected in Alzheimer's.

A standard memory and thinking test could not distinguish between the risk and non-risk groups.

Gaming data was taken from 27,108 UK players aged 50-75. This benchmark data was then compared with 60 people who had been genetically tested, of whom about half carried the APOE4 gene. The gene tested individuals were matched for age, gender, education and nationality with the benchmark cohort.

Previous findings from Sea Hero Quest data have shown that people in different countries and populations navigate differently, but this study shows that APOE4 carriers took less efficient (i.e., longer) routes to checkpoint goals. The difference in performance between carriers and non-carriers was particularly pronounced where the space to navigate was large and open.

https://www.eurekalert.org/pub_releases/2019-04/uoea-tmg042419.php

Getting lost may be the first sign of Alzheimer’s

Preliminary findings from a long-term UK study indicate that middle-aged adults (41-59) with close relatives with Alzheimer's did worse on a test that measured their ability to visualise their position. They also tended to have a small hippocampus.

The Four Mountains test involves showing people a picture of a mountain and asking them to identify it in a selection of four other landscapes.

https://www.theguardian.com/society/2017/may/06/getting-lost-may-be-first-sign-of-alzheimers

Building mental maps precedes route navigation problems

A study involving 71 older adults found that increasing difficulties with building cognitive maps of new surroundings was associated with the development of Alzheimer's biomarkers. Difficulties in learning a new route were not evident at this stage, but appeared later, among those with early Alzheimer's.

The computer task involved navigating a virtual maze consisting of a series of interconnected hallways with four wallpaper patterns and 20 landmarks. Participants were tested on two navigation skills: how well they could learn and follow a pre-set route, and how well they could form and use a cognitive map of the environment. Participants were given 20 minutes to either learn a specified route, or to study and explore the maze with a navigation joystick. They were then tested on their ability to recreate the route or find their way to specific landmarks in the environment.

Humans generally find their way using two distinct forms of spatial representation and navigation: egocentric navigation, in which people rely on past knowledge to follow well-worn routes, moving from one landmark to another, and allocentric navigation, in which people become familiar with their big picture surroundings and create a mental map of existing landmarks, allowing them to plot best available routes and find shortcuts to new destinations. Allocentric navigation relies on the hippocampus, while egocentric navigation is more closely associated with a brain region called the caudate.

Those with cerebrospinal markers for Alzheimer’s but no symptoms, had significant difficulties only when they had to form a cognitive map (that is, with hippocampal allocentric navigation processes). However, additional training did enable them to eventually learn the cognitive map.

The researchers suggest that preclinical Alzheimer’s disease is characterized by hippocampal atrophy and associated cognitive mapping difficulties, and then, (if) the disease progresses, cognitive mapping deficits worsen, the caudate becomes involved, leading to route learning deficits.

Participants included 42 who were cognitively healthy and had no cerebrospinal fluid markers for Alzheimer’s, 13 cognitively normal individuals who had the biomarkers, and 16 with early Alzheimer’s.

http://www.futurity.org/alzheimers-maps-nativation-1143342-2/

Reference: 

[4415] Coughlan, G., Coutrot A., Khondoker M., Minihane A-M., Spiers H., & Hornberger M.
(2019).  Toward personalized cognitive diagnostics of at-genetic-risk Alzheimer’s disease.
Proceedings of the National Academy of Sciences. 116(19), 9285 - 9292.

[4446] Ritchie, K., Carrière I., Su L., O'Brien J. T., Lovestone S., Wells K., et al.
(2017).  The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's disease: The PREVENT study.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(10), 1089 - 1097.

[4445] Allison, S. L., Fagan A. M., Morris J. C., & Head D.
(2016).  Spatial Navigation in Preclinical Alzheimer’s Disease.
Journal of Alzheimer's Disease. 52(1), 77 - 90.

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Why APOE4 gene increases Alzheimer's risk

  • Synapses in Alzheimer's brains found to be clogged with clusterin and amyloid-beta proteins, and APOE4 carriers had more protein clumps than those without the gene variant.
  • APOE4 decreases activity in hippocampus that is critical for memory consolidation.
  • Study of Amazonian hunter-gatherers show APOE4 gene can provide benefits when exposure to parasites is high.

Alzheimer's gene linked to damage to brain connections

A study has found that synapses in people who had died with Alzheimer's contained clumps of clusterin and clumps of amyloid beta. These protein clumps may be damaging the links between neurons.

Those with the APOE4 gene had more clusterin and amyloid beta clumps than people with Alzheimer's without the risk gene. Those without dementia symptoms had less of the damaging proteins in their synapses.

https://www.eurekalert.org/pub_releases/2019-06/uoe-dsl062719.php

Alzheimer's gene impairs memory consolidation by disrupting brainwaves

A mouse study has found that the apoE4 protein decreases two types of brain activity in the hippocampus that are important for memory formation: sharp wave ripples (ripples) and coincident slow gamma activity. During the ripples, prior experiences are replayed numerous times to help preserve the memory of them, and the slow gamma activity that occurs during the ripples helps to ensure that the replay of those memories is accurate.

Mice with apoE4 had fewer ripples than mice with the normal apoE3 protein, and they had less slow gamma activity during the ripples. It appears that apoE4 expression disrupts slow gamma activity during ripples, and this in turn impairs memory consolidation.

The finding points to restoring slow gamma activity in the hippocampus as a therapeutic target.

http://www.eurekalert.org/pub_releases/2016-05/gi-glt050516.php

APOE4 gene benefits those with high parasite exposure

In response to those wondering why we have this gene variant if it's so damaging, a study looked at how the ApoE gene might function differently in the more infectious environment of our hunter-gatherer ancestors. It found that Amazonian forager-horticulturalists who carried ApoE4 and had a high parasitic burden displayed steadier or even improved cognitive function compared to non-carriers with a similar level of parasitic exposure.

For Tsimane ApoE4 carriers without high parasite burdens, the rates of cognitive decline were more similar to those seen in industrialized societies.

ApoE4 has previously been shown to eliminate some infections like giardia and hepatitis. Other studies have shown potential benefits of ApoE4 in early childhood development

https://www.eurekalert.org/pub_releases/2016-12/asu-adc122916.php

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Researchers classify Alzheimer's patients in 6 subgroups

  • More evidence that Alzheimer's disease is not a single disease with a single cause and single pathway comes from a large study classifying patients into 6 groups, only two of which showed strong genetic association.
  • Another study using post-mortem brain tissue found that different genes were associated with different types of brain damage.

A study involving 4,050 people with late-onset Alzheimer's disease (mean age 80) has classified them into six groups based on their cognitive functioning at the time of diagnosis. A genetic study found two of the groups showed strong genetic associations.

The participants received cognitive scores in four domains: memory, executive functioning, language, and visuospatial functioning. The largest group (39%) had scores in all four domains that were fairly close to each other. The next largest group (27%) had memory scores substantially lower than their other scores. Smaller groups had language scores substantially lower than their other scores (13%), visuospatial functioning scores substantially lower than their other scores (12%), and executive functioning scores substantially lower than their other scores (3%). There were 6% who had two domains that were substantially lower than their other scores.

One group showed a very strong genetic association with 33 single nucleotide polymorphisms (SNPs) — this effect was stronger than the strongest effects found by an earlier and much larger international consortium study where Alzheimer's disease was treated as a single condition.

The memory group had a particularly strong relationship with the APOE e4 allele.

The participants were mostly white (92%) and 61% were female.

https://www.eurekalert.org/pub_releases/2018-12/uowh-rca120418.php

The finding is supported by another study using brain tissue from deceased patients with rare and common forms of Alzheimer’s, and from those who didn’t have the disease. The study showed that different genes are associated with different types of brain damage.

Those with the genes implicated in early-onset Alzheimer's (APP, PSEN1, and PSEN2) showed lower numbers of neurons and higher numbers of astrocytes than people who had Alzheimer’s but didn’t carry those mutations.

A similar pattern was found in patients with APOE4. However, carriers of TREM2 showed less neuronal loss and more damage to glial cells.

https://www.futurity.org/alzheimers-disease-genes-brain-cell-damage-1786192/

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Genes linked to Alzheimer's

  • Very large study finds 5 new genes linked to increased Alzheimer's risk.
  • A rare gene variant that protects APOE4 gene carriers from getting Alzheimer's has been identified.
  • Two large surveys found that verbal recall score was significantly affected by TOMM40 genotype. TOMM40 is adjacent to APOE on their chromosome.
  • A study found that TOMM40's effect on Alzheimer's depends on parental history.
  • Data from three very large studies has produced a tool for assessing an individual's genetic risk for developing Alzheimer's, based on 31 genetic markers.
  • A small study found that, of the top 9 genes that affect Alzheimer's risk, excluding the APOE gene, only 2 affect brain atrophy.
  • A new gene variant that is associated with greater amyloid plaque than APOE4 has been identified.

Five new risk genes for Alzheimer's disease

Genetic data from more than 94,000 individuals has revealed five new risk genes for Alzheimer's disease, and confirmed 20 known others. The new genes are: IQCK, ACE, ADAM10, ADAMTS1 and WWOX.

The findings support developing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are "genetic hubs" that are an important part of the disease process.

The study also suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer's and with late onset Alzheimer's. In addition, for the first time, the study implicated a genetic link to tau binding proteins.

The findings follow on from a 2013 report.

https://www.eurekalert.org/pub_releases/2019-02/nioa-dsu022719.php

Gene variant found that protects against Alzheimer's

A large study involving families that had a large number of resilient individuals (those who carried the APOE4 gene but remained healthy into advanced age) has found that the resilient subjects shared a variant in the RAB10 gene while those who got the disease did not share that genetic variant.

https://www.eurekalert.org/pub_releases/2017-11/byu-rig112917.php

Gene linked to Alzheimer's gene affects age-related cognitive decline

TOMM40 and APOE genes are adjacent to each other on chromosome 19, and have sometimes been used as proxies for one another in genetic studies. TOMM40 has largely been thought of as a “sidekick” to ApoE4. But new research suggests it may have a stronger role.

Data from two large surveys — the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing — found that verbal recall score was significantly affected by TOMM40 genotype.

The researchers examined 1.2 million gene variations across the human genome. TOMM40 was the only one with a strong link to declines in immediate recall and level of delayed recall. APOE4 also was linked but not as strongly.

To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10. The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer's or some other form of dementia.

Those who had received a likely diagnosis of dementia or a dementia-like condition were excluded from the study.

https://www.eurekalert.org/pub_releases/2017-09/uosc-it091417.php

Family history of Alzheimer's may alter gene that increases risk

There have been conflicting findings about whether the gene, TOMM40 (Translocase of Outer Mitochondrial Membrane-40kD) increases the risk for Alzheimer's. A new study, however, has found that its impact on memory and dementia risk depends on two other factors: parental history of Alzheimer's, and the length of a specific section of the gene.

In the study, late middle-aged people with a family history (parent with Alzheimer’s) and longer version of the gene had twice as much memory loss up to 10 years later as someone with a family history and a short version of the gene. A similar but stronger finding was seen in a group of older adults.

https://www.eurekalert.org/pub_releases/2017-05/isu-fho051917.php

Multiple genetic markers combine to estimate Alzheimer's risk

Genotype data from three very large studies has enabled researchers to construct a test that can be used to calculate any individual’s yearly risk for onset of Alzheimer's. The polygenic hazard score (PHS) is based on 31 genetic markers.

Those with the highest PHS (top 10%) were more than three times more likely to develop Alzheimer's than those with the lowest PHS, and to do so more than 10 years earlier.

In people with the high-risk version of ApoE, those ranked in the top 10% of risk on the new test got Alzheimer’s at an average age of 84 years, compared with 95 years for those ranked in the lowest 10%.

The study also demonstrates that, aside from ApoE, there are thousands of background genetic variations that each have a tiny influence on Alzheimer’s risk, but whose cumulative influence is substantial.

But note that this doesn’t tell us that it’s all about genes! Lifestyle factors are still very important in determining whether you actually get Alzheimer's.

https://www.eurekalert.org/pub_releases/2017-03/p-mgm031317.php

https://www.theguardian.com/society/2017/mar/22/new-alzheimers-test-can-predict-age-when-disease-will-appear

Two Alzheimer's risk genes linked to brain atrophy

A study involving 50 older adults (50+) with no cognitive difficulties and 90 who had been diagnosed with MCI has examined the top nine genetic variants associated with Alzheimer's risk, excluding the APOe4 gene, to find which of them was associated with atrophy in the cortex and hippocampus.

Only ABCA7 and MA4A6A were associated with brain atrophy.

http://www.eurekalert.org/pub_releases/2015-12/iu-tar122315.php

New gene linked to amyloid beta plaque buildup

A study involving nearly 500 individuals has found that a variant of the IL1RAP gene was associated with higher rates of amyloid plaque buildup in the brains of Alzheimer's patients and older adults at risk for the disease, and its effect on amyloid buildup was stronger than that of APOE4.

IL1RAP codes for the key immune signaling factor Interleukin-1 Receptor Accessory Protein, which plays a central role in the activity of microglia, the immune system cells that clear up waste products such as plaques and tangles.

Additionally, the IL1RAP variant was associated with:

  • a lower level of microglial activity
  • greater atrophy of the temporal cortex
  • faster cognitive decline
  • greater likelihood of progression from MCI to Alzheimer's.

http://www.eurekalert.org/pub_releases/2015-10/iu-rin100515.php

Reference: 

[4419] Kunkle, B. W., & et al
(Submitted).  Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing | Nature Genetics.

[3586] Lambert, J-C., Ibrahim-Verbaas C. A., Harold D., Naj A. C., Sims R., Bellenguez C., et al.
(2013).  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
Nature Genetics. 45(12), 1452 - 1458.

[4420] Ridge, P. G., Karch C. M., Hsu S., Arano I., Teerlink C. C., Ebbert M. T. W., et al.
(2017).  Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience.
Genome Medicine. 9(1), 100.

[4422] Arpawong, T. E., Pendleton N., Mekli K., McArdle J. J., Gatz M., Armoskus C., et al.
(2017).  Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort.
PLOS ONE. 12(8), e0182448.

[4423] Willette, A. A., Webb J. L., Lutz M. W., Bendlin B. B., Wennberg A. M. V., Oh J. M., et al.
(2017).  AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(7), P54 - P55.

[4424] Desikan, R. S., Fan C. Chieh, Wang Y., Schork A. J., Cabral H. J., L. Cupples A., et al.
(2017).  Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.
PLOS Medicine. 14(3), e1002258.

[4412] Ramirez, L. M., Goukasian N., Porat S., Hwang K. S., Eastman J. A., Hurtz S., et al.
(2016).  Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy.
Neurobiology of Aging. 39, 82 - 89.

[4425] Ramanan, V. K., Risacher S. L., Nho K., Kim S., Shen L., McDonald B. C., et al.
(2015).  GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP.
Brain. 138(10), 3076 - 3088.

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Gender differences in Alzheimer's disease may be linked to tau spread

  • Brain scans suggest that tau proteins may spread more rapidly through women’s brains, increasing Alzheimer's risk and speeding its progression.

Accumulating evidence suggests that tau spreads through brain tissue like an infection, traveling from neuron to neuron and turning other proteins into abnormal tangles, subsequently killing brain cells.

A new study using brain scans of healthy individuals and patients with MCI has found that the architecture of tau networks is different in men and women, with women having a larger number of regions that connect various communities in the brain. This difference may allow tau to spread more easily between regions, boosting the speed at which it accumulates and putting women at greater risk for developing Alzheimer's disease.

https://www.eurekalert.org/pub_releases/2019-07/vumc-rap071619.php

https://www.theguardian.com/society/2019/jul/16/research-why-alzheimers-more-likely-women-than-men-tau-protein

Gender & APOE status affects tau accumulation

A study involving 131 cognitively healthy older adults (mean age 77) and 97 with MCI, found that women with MCI who were ApoE ε4 carriers were more susceptible than men to tau accumulation in the brain. However, no gender differences were found among the cognitively healthy adults.

https://www.eurekalert.org/pub_releases/2019-06/sonm-ads062419.php

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The findings of the first study were presented at the Alzheimer's Association International Conference July 14-18, 2019, in Los Angeles.

The second study was presented by Manish Paranjpe at the 2019 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), Abstract 253: "Sex Modulates the ApoE ε4 Effect on Tau 18F-AV-1451 PET Imaging in Individuals with Normal Aging and Mild Cognitive Impairment," Manish Paranjpe, Min Liu, Ishan Paranjpe, Rongfu Wang, Tammie Benzinger and Yun Zhou.

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Alzheimer's gene linked to worse cognition

  • Review found APOE4 carriers scored lower on IQ tests during childhood and adolescence.
  • A large internet-based study found that adults with a first-degree relative with Alzheimer's performed worse on a paired-learning task.

Alzheimer's gene affects IQ from childhood

Analysis of some old longitudinal studies has found that those carrying the APOE4 gene scored lower on IQ tests during childhood and adolescence. The effect was much stronger in girls than in boys, and affected reasoning most strongly.

IQ scores were lower by 1.91 points for each APOE4 allele carried. But boys scored only an average of 0.33 points lower, while girls scored almost 3 points lower for each APOE4 allele.

Almost all the participants (92%) were white.

https://www.eurekalert.org/pub_releases/2019-07/uoc--agm071819.php

Impaired learning linked to family history of Alzheimer's

A large internet-based study found that adults with a first-degree relative with Alzheimer's disease performed worse on a paired-learning task than adult without such a family history, and this impairment appears to be exacerbated by having diabetes or the APOE4 gene.

The online word-pair memory test (called MindCrowd) involved learning 12-word pairs and then completing the missing half of the pair when presented with one of the words. 59,571 individuals participated. Those with a family history of Alzheimer's were able to match about two and one-half fewer word pairs than individuals without a family history.

The family history effect was particularly pronounced among men, as well as those with lower educational attainment, diabetes, and carriers of APOE4.

The effect of family history was shown across every age group, up until age 65.

A subset of 742 participants who had a close relative with Alzheimer's were tested for the APOE gene.

https://www.eurekalert.org/pub_releases/2019-07/e-ill071019.php

Reference: 

Reynolds, C.A. et al. 2019. APOE effects on cogntion from childhood to adolescence. Neurobiology of Aging, Available online 18 April 2019.

[4418] Talboom, J. S., Håberg A., De Both M. D., Naymik M. A., Schrauwen I., Lewis C. R., et al.
(2019).  Family history of Alzheimer’s disease alters cognition and is modified by medical and genetic factors.
(Irish, M., & Franco E., Ed.).eLife. 8, e46179.

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Genes help explain why Alzheimer’s drugs have been so unsuccessful

  • A gene present in 75% of the human population may be a key reason why a class of drugs for Alzheimer’s disease seem promising in animal studies but fail in human studies.
  • Cell study finds APOE4 protein is slightly misshapen, causing it to break down into disease-causing fragments. But APOE4 doesn't affect amyloid-beta in mice.

Data from a ten-year study involving 345 Alzheimer's patients has found that cholinesterase inhibitors work better with those who don't have the gene CHRFAM7A. The gene is a fusion between a gene that codes for an Alpha 7 receptor for acetylcholine, and a kinase, a type of enzyme. It is not present in the animals genetically engineered to provide Alzheimer's models, but is present in 75% of humans.

Three of the four available Alzheimer’s drugs work by stimulating all receptors that respond to acetylcholine. More specific drugs for Alpha 7 have been in development for over 10 years but have yet to be successful.

The Alpha 7 receptor is one of the receptors binding amyloid beta.

More research is needed to confirm these preliminary findings.

https://www.eurekalert.org/pub_releases/2019-07/uab-sfc071719.php

https://www.futurity.org/alzheimers-disease-drugs-chrfam7a-2108902/

Scientists fix APOE4 gene in human brain cells

Research using human brain cells has found that the APOE4 protein is slightly misshapen and can’t function properly. It breaks down into disease-causing fragments, resulting in a number of problems, including the accumulation of the protein tau and of amyloid peptides.

The presence of APOE4 does not change the production of amyloid beta in mouse neurons, so this is a crucial species difference which shows why our animal models are of limited value.

Further research confirmed that it was specifically the presence of APOE4, and not the absence of the more common allele, APOE3, that promotes Alzheimer’s.

The human APOE4 neurons were treated with compounds developed to change the structure of the apoE4 protein so it resembles the APOE3 protein. This treatment eliminated the signs of Alzheimer's disease, restored normal function to the cells, and improved cell survival.

https://www.eurekalert.org/pub_releases/2018-04/gi-sfg040818.php

Reference: 

The first study was presented at the annual Alzheimer's Association International Conference (AAIC) in Los Angeles, July 2019.

[4416] Wang, C., Najm R., Xu Q., Jeong D-eun., Walker D., Balestra M. E., et al.
(2018).  Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector.
Nature Medicine. 24(5), 647 - 657.

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Cholesterol genes link risk of heart disease & Alzheimer’s

  • A very large genetic study provides evidence that cardiovascular disease risk and Alzheimer's risk are related because of one shared element: genes involved in cholesterol and lipid metabolism.

The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, is known to be involved in cholesterol and lipid metabolism. Now the largest ever genetic study of Alzheimer’s disease, using DNA from more than 1.5 million people, has identified 90 points across the genome that were associated with an increased risk of both cardiovascular disease and Alzheimer’s disease.

The study focused on specific risk factors for heart disease (e.g., high BMI, type 2 diabetes, high cholesterol) to see if any were genetically related to Alzheimer’s risk. It was found that only those genes involved in lipid metabolism also related to Alzheimer's risk.

Six of the 90 regions had very strong effects on Alzheimer’s and heightened blood lipid levels, including several points within the CELF1/MTCH2/SPI1 region on chromosome 11 that was previously linked to the immune system.

The same genetic risk factors were also more common in people with a family history of Alzheimer’s, even though they had not themselves developed dementia or MCI.

The findings suggest that cardiovascular and Alzheimer's risk co-occur because of a shared genetic basis.

They also suggest a therapeutic target — namely, pathways involved in lipid metabolism.

https://www.futurity.org/alzheimers-disease-heart-disease-cholesterol-1913312-2/

https://www.eurekalert.org/pub_releases/2018-11/wuso-cda111118.php

Reference: 

Broce I, Karch C, Desikan R, et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathologica, published online Nov. 9, 2018.

 

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Lower tau levels may obscure early Alzheimer’s in black patients

  • Two large studies show an association between the Alzheimer's protein tau and the Alzheimer's gene APOE4, but the association varies across race and gender.

Data from 1,215 older adults, of whom 173 (14%) were African-American, has found that, although brain scans showed no significant differences between black and white participants, cerebrospinal fluid (CSF) showed significantly lower levels of the brain protein tau in African-Americans.

While both groups showed the same (expected) pattern of higher tau levels being associated with greater chance of cognitive impairment, the absolute amounts of tau protein were consistently lower in African-Americans.

However, when APOE status was taken into account, it was found that those who held the low-risk variants of the “Alzheimer’s gene” had similar levels of tau, regardless of race. It was only African-Americans with the APOE4 gene variant that showed lower levels of tau.

This suggests that the APOE4 risk factor has different effects in African-Americans compared to non-Hispanic white Americans, and points to the need for more investigation into how Alzheimer’s develops in various populations.

Interestingly, another study, using data from 1798 patients (of whom 1690 were white), found that there was a strong gender difference in the association between APOE status and tau levels in the CSF.

Previous research has shown that the link between APOE4 and Alzheimer's is stronger in women than men. This study points to a connection with tau levels, as there was no gender difference in the association between APOE and amyloid-beta levels, amyloid plaques, or tau tangles.

https://www.futurity.org/alzheimers-disease-black-patients-1951502/

Reference: 

Morris JC, Schindler SE, McCue LM, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. Published online January 07, 2019. doi:10.1001/jamaneurol.2018.4249

Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol. 2018;75(8):989–998. doi:10.1001/jamaneurol.2018.0821

 

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