We know that traumatic brain injury increases the risk of later developing neurodegenerative disorders such as Alzheimer's disease, but we haven't known why. New mouse studies suggest a reason.

In the research, mice who had a toxic form of tau protein (taken from mice who had suffered TBI) injected into their hippocampus, showed impaired memory and cognition. Moreover, levels of the aggregated tau protein not only increased in the hippocampus, but also in the cerebellum (which is quite some distance away from the hippocampus). This is consistent with other research showing that tau tangles spread from the initial injection site, using mice modeling Alzheimer's disease.

The study followed on from previous research showing that this form of tau protein increases after a traumatic brain injury and may contribute to development of chronic traumatic encephalopathy (a condition experienced by many professional athletes and military personnel).

The findings support the hypothesis that many of the symptoms of TBI may be down to an increase in these tau tangles, and that this may also be responsible for the increased risk for neurodegenerative disease. As an obvious corollary, it also suggests that the tau tangles are an important therapeutic target.

http://www.eurekalert.org/pub_releases/2016-01/uotm-tbi011216.php

A ten-year study involving 2,092 older adults (average age 76) has found that people tended to lose awareness of memory problems two to three years before the onset of dementia.

Being unaware of your own memory problems is common in dementia, but previous research has focused on those already diagnosed with dementia. In this study, participants had no cognitive impairment at the beginning of the study.

Overall, subjective memory ratings taken annually were modestly correlated with performance (only modestly — people tend not to be that great at accurately assessing their own memory!), and this awareness was stable with age. However, in the subset of those who developed dementia (239 participants; 11%), this awareness started to deteriorate an average of 2.6 years before dementia was diagnosed (after which it dropped rapidly).

In a subset of those who died and had their brains examined (385 participants), a decline in memory awareness was associated with three pathologies:

• tau tangles
• gross cerebral infarcts
• transactive response DNA-binding protein 43 pathology (TDP-43 is a protein involved in transcription, the first step in producing proteins from genes; mutations in the gene that produces TDP-43 have been linked to frontotemporal dementia and amyotrophic lateral sclerosis (ALS)).

There was no decline in memory awareness in those who didn't show any of these pathologies.

Those who were older at the beginning of the study were more likely to retain memory awareness longer, perhaps because they were more alert to memory problems.

http://www.theguardian.com/society/2015/aug/27/dementia-sufferers-start-losing-memory-up-to-three-years-before-condition-develops-us-study

A long-running study comparing African-Americans and Nigerians has found the incidence of dementia has fallen significantly over two decades among the African-Americans, but remained the same for the Nigerians (for whom it was lower anyway).

The study enrolled two cohorts, one in 1992 and one in 2001, who were evaluated every 2–3 years until 2009. The 1992 cohort included 1440 older African-Americans (70+) and 1774 Nigerian Yoruba; the 2001 cohort included 1835 African-Americans and 1895 Yoruba. None of the participants had dementia at study beginning.

The overall standardized annual incidence rate was 3.6% for the 1992 African-American cohort, and 1.4% for the 2001 cohort. For the Yoruba, it was 1.7% and 1.4%, respectively.

It's suggested that one reason for the improvement among African-Americans may be medications for cardiovascular conditions. Although both groups had similar rates of high blood pressure, this was recognized and treated in the American group but not in the Nigerian.

As you can see, African-Americans in the earlier cohort were more than twice as likely as Africans to develop dementia. Their decrease has brought them into line with the African rate.

Although the rate of new cases of dementia decreased, the African-Americans enrolling in 2001 had significantly higher rates of diabetes, hypertension and stroke, but also higher treatment rates, than the African-Americans who enrolled in 1992.

The finding offers hope that treatment can offset the expected increase in dementia resulting from the rise in lifestyle diseases.

http://www.eurekalert.org/pub_releases/2015-08/iu-sn080415.php

Alzheimer's the evolutionary cost of better brains?

A recent genetics paper reports on evidence that changes in six genes involved in human brain development occurred around 50,000 to 200,000 years ago. These mutations may have helped increase the connectivity of our neurons, making us smarter. But these same genes are also implicated in Alzheimer's. Researchers speculate that the disorder is thus connected to our increased intelligence — the price we pay for having better brains. This is not inconsistent with a previous suggestion that the myelin ("white matter") sheathing our brain wiring was the key evolutionary change in making us unique, and that this myelin sheathing may also be the cause of our unique vulnerability to neurological disorders.

The study examined the genomes of 90 people with African, Asian, or European ancestry.

http://www.scientificamerican.com/article/alzheimer-s-origins-tied-to-rise-of-human-intelligence/

http://biorxiv.org/content/early/2015/05/26/018929

Genetics overlap found between Alzheimer's disease and cardiovascular risk factors

Data from genome-wide association studies of more than 200,000 individuals has revealed a genetic overlap between Alzheimer's disease and two significant cardiovascular disease risk factors: high levels of inflammatory C-reactive protein (CRP) and plasma lipids. The two identified genes (HS3ST1 and ECHDC3, on chromosomes 4 and 10) were not previously associated with Alzheimer's risk. However, the association of high plasma lipid levels and inflammation with Alzheimer's risk is supported by previous research.

The findings support the idea that inflammation and high blood lipids play a role in dementia risk, and may offer therapeutic targets.

http://www.eurekalert.org/pub_releases/2015-04/uoc--gof041615.php

How genetic changes lead to familial Alzheimer's disease

Variants in the presenilin-1 gene are the most common cause of inherited, early-onset Alzheimer's. Because presenilin is a component of gamma secretase, which cuts up amyloid precursor protein into Abeta40 and Abeta42 (the protein found in plaques), it's been thought that these presenilin-1 variants increase the activity of gamma secretase. However, attempts to stop Alzheimer's by using drugs to block gamma-secretase have so far been fruitless (indeed, counter-productive). Now a new mouse study has explained why: it appears that the presenilin-1 variants may in fact decrease, rather than increase, the activity of gamma-secretase. This suggests that the presenilin-1 variants are acting on other causes of Alzheimer's, and also suggests the possibility that restoring gamma-secretase, rather than blocking it, may be a more effective therapeutic strategy.

Mice genetically engineered for Alzheimer's are usually given dispositions for excessive amyloid plaques. However, it's becoming clear that Alzheimer's is more complex than a single cause. This may explain the signal failure of mouse models to provide treatments that work on humans. This research provides a different mouse model, which may help in the development of treatments.

http://www.eurekalert.org/pub_releases/2015-03/nion-srh031115.php

Mining big data yields new Alzheimer's gene

Analysis of brain scans from the ENIGMA Consortium and genetic information from The Mouse Brain Library has revealed a new gene for Alzheimer's risk. The gene MGST3 regulates the size of the hippocampus.

The finding confirms the importance of hippocampal volume for maintaining memory and cognition, and supports the idea that “cognitive reserve” helps prevent age-related cognitive decline and dementia.

http://www.eurekalert.org/pub_releases/2014-10/uom-mbd100914.php

Gene involved in waste removal increases risk of Alzheimer's & other neurodegenerative disorders

Previous research has pointed to the gene TREM2 as a genetic risk factor for Alzheimer's disease. A recent study explains why variants in this gene might be associated with neurodegenerative disorders such as Alzheimer's, Parkinson's, ALS, and frontotemporal dementia.

It appears that the gene is involved in the microglia — the “cleaners” of the brain. Variants in the gene affect the recognition of waste products left behind by dead cells, reducing the amount of debris that the microglia can cope with.

The finding may point to a way of slowing the progression of these neurodegenerative diseases even when the disease is well established.

http://www.eurekalert.org/pub_releases/2014-07/lm-ndg070314.php

http://www.eurekalert.org/pub_releases/2014-07/uadb-lbp070314.php

A large meta-analysis has concluded that having diabetes increases the chance that a person with mild cognitive impairment will progress to dementia by 65%.

There was no consistent evidence that hypertension or cholesterol levels increased the risk of someone with MCI progressing to dementia. Smoking was similarly not associated with increased risk, although the reason for this probably lies in mortality: smokers tend to die before developing dementia.

There was some evidence that having symptoms of psychiatric conditions, including depression, increased the risk of progressing to dementia.

There was some evidence that following a Mediterranean diet decreased the risk of an individual with amnestic MCI progressing to Alzheimer's, and that higher folate levels decrease the risk of progressing from MCI to dementia. The evidence regarding homocysteine levels was inconsistent.

The evidence indicates that level of education does not affect the risk of someone with MCI progressing to dementia.

Do note that all this is solely about progression from MCI to dementia, not about overall risk of developing dementia. Risk factors are complex. For example, cholesterol levels in mid-life are associated with the later development of dementia, but cholesterol levels later in life are not. This is consistent with cholesterol levels not predicting progression from MCI to dementia. Level of education is a known risk factor for dementia, but it acts by masking the damage in the brain, not preventing it. It is not surprising, therefore, that it doesn't affect progression from MCI to dementia, because higher education helps delay the start, it doesn't slow the rate of decline.

Do note also that a meta-analysis is only as good as the studies it's reviewing! Some factors couldn't be investigated because they haven't been sufficiently studied in this particular population (those with MCI).

The long-running Cache County study has previously found that 46% of those with MCI progressed to dementia within three years; this compared with 3% of those (age-matched) with no cognitive impairment at the beginning of the study.

More recently, data from the long-running, population-based Rotterdam study revealed that those diagnosed with MCI were four times more likely to develop dementia, over seven years. compared with those without MCI. Of those with MCI (10% of the 4,198 study participants), 40% had amnestic MCI — the form of MCI that is more closely associated with Alzheimer's disease.

The 2014 study also found that older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, were all risk factors for MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI. Waist circumference, hypertension, and diabetes were not significantly associated with MCI. This may be related to medical treatment — research has suggested that hypertension and diabetes may be significant risk factors only when untreated or managed poorly.

http://www.theguardian.com/science/occams-corner/2015/feb/24/speeding-up-the-battle-against-slowing-minds

http://www.eurekalert.org/pub_releases/2015-02/ucl-dad022015.php

http://www.eurekalert.org/pub_releases/2014-08/ip-drq080614.php