Alzheimer's & other dementias
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.
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.
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
 Jackson, R. J., Rose J., Tulloch J., Henstridge C., Smith C., & Spires-Jones T. L.
(2019). Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers.
Brain Communications. 1(1),
 Gillespie, A. K., Jones E. A., Lin Y-H., Karlsson M. P., Kay K., Yoon S. Yeon, et al.
(2016). Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples.
Neuron. 90(4), 740 - 751.
 Trumble, B. C., Stieglitz J., Blackwell A. D., Allayee H., Beheim B., Finch C. E., et al.
(2016). Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden.
The FASEB Journal. 31(4), 1508 - 1515.
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.
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.
 Mukherjee, S., Mez J., Trittschuh E. H., Saykin A. J., Gibbons L. E., Fardo D. W., et al.
(2018). Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups.
Molecular Psychiatry. 1 - 10.
 Li, Z., Del-Aguila J. L., Dube U., Budde J., Martinez R., Black K., et al.
(2018). Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure.
Genome Medicine. 10(1), 43.
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.
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.
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.
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.
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.
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.
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:
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
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.
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.
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.
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.
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.
Reynolds, C.A. et al. 2019. APOE effects on cogntion from childhood to adolescence. Neurobiology of Aging, Available online 18 April 2019.
 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.
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.
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.
The first study was presented at the annual Alzheimer's Association International Conference (AAIC) in Los Angeles, July 2019.
 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.
Poor sleep has been associated with the development of Alzheimer's disease, and this has been thought to be in part because the protein amyloid beta increases with sleep deprivation. A new study explains more.
Experiments with mice show that sleep deprivation also rapidly increases levels of the other key Alzheimer’s disease protein, tau tangles.
The work built on findings that tau is high in older people who sleep poorly, and that, when people are kept awake all night, their tau levels rise by about 50%.
When mice had tau proteins seeded in the hippocampus of their brains, those who were kept awake for long periods each day (mice are nocturnal), showed significantly greater spread of tau tangles than those mice allowed to sleep normally. Moreover, the new tangles appeared in the same areas of the brain affected in people with Alzheimer’s.
Disrupted sleep also increased release of synuclein protein, a hallmark of Parkinson’s disease. People with Parkinson’s—like those with Alzheimer’s—often have sleep problems.
All of this supports the idea that sleep directly protects against the development of Alzheimer's.
 Holth, J. K., Fritschi S. K., Wang C., Pedersen N. P., Cirrito J. R., Mahan T. E., et al.
(2019). The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans.
Science. 363(6429), 880 - 884.
A small study has found that a 12-week exercise program significantly improved cognition in both older adults with MCI and those who were cognitively healthy, but that effect on blood flow in the brain was different in these two groups.
While the exercise increased cerebral blood flow in the frontal cortex of those in the healthy group, those with MCI experienced decreases in cerebral blood flow. It has been speculated that the brain responds to early difficulties by increasing cerebral blood flow. This suggests that exercise may have the potential to reduce this compensatory blood flow and improve cognitive efficiency in those who are in the very early stages of Alzheimer's Disease.
The exercise training program consisted of four 30-minute sessions of moderate-intensity treadmill walking per week.
Both working memory and verbal fluency were tested (using the Rey Auditory Verbal Learning Test, and the Controlled Oral Word Association Test).
Changes in cerebral blood flow were measured in specific brain regions that are known to be involved in the pathogenesis of Alzheimer's disease, including the insula, the anterior cingulate cortex, and the inferior frontal gyrus.
Among those with MCI, decreased blood flow in the left insula and anterior cingulate cortex was strongly associated with improved verbal fluency.
Alfini, A. J. et al. 2019. Resting Cerebral Blood Flow After Exercise Training in Mild Cognitive Impairment. Journal of Alzheimer's Disease, 67 (2), 671-684.
A Japanese study looking at 128 patients' fecal samples, found that fecal concentrations of ammonia, indole, skatole and phenol were higher in dementia patients compared to those without dementia, while levels of beneficial Bacteroides were lower in dementia patients.
The findings were presented at the American Stroke Association's annual conference.
A clinical trial involving 9361 older adults (50+) with hypertension but without diabetes or history of stroke has found that intensive control of blood pressure significantly reduced the risk of developing mild cognitive impairment.
While there was also a 15% reduction in dementia, this result did not reach statistical significance. This may have been due to the small number of new cases of dementia in the study groups.
Participants were randomly assigned to a systolic blood pressure goal of either less than 120 mm HG (intensive treatment) or less than 140 mm HG (standard treatment). They were then classified after five years as having no cognitive impairment, MCI or probable dementia.
The trial was stopped early due to its success in reducing cardiovascular disease. As a result, participants were on intensive blood pressure lowering treatment for a shorter period than originally planned. This impacted the number of cases of dementia occurring.
Hypertension affects more than half of Americans over age 50 and more than 75% of those older than 65.
The SPRINT MIND Investigators for the SPRINT Research Group. (2019). Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA, 321(6), 553–561.
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