More on Alzheimer's genes

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.

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.

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.

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.

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.


[3923] Zhou H, Hu S, Matveev R, Yu Q, Li J, Khaitovich P, Jin L, Lachmann M, Stoneking M, Fu Q, et al. A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years. bioRxiv [Internet]. 2015 . Available from:

[3918] Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, Chasman DI, McEvoy LK, Holland D, Chen C-H, et al. Polygenic Overlap Between C-Reactive Protein, Plasma Lipids and Alzheimer's Disease. Circulation [Internet]. 2015 . Available from:

[3922] Xia D, Watanabe H, Wu B, Lee SHun, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ. Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease. Neuron [Internet]. 2015 ;85(5):967 - 981. Available from:

[3916] Ashbrook DG, Williams RW, Lu L, Stein JL, Hibar DP, Nichols TE, Medland SE, Thompson PM, Hager R. Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. BMC Genomics [Internet]. 2014 ;15(1). Available from:

[3920] Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine [Internet]. 2014 ;6(243):243ra86 - 243ra86. Available from:

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