Where Alzheimer’s disease begins – The local activity of risk genes determines the most affected areas of the brain

Where in the brain Alzheimer’s disease causes brain cells to die first is not the same for everyone affected. For many, the degradation begins in the center of memory, for others visual and speech impairments appear first. The research team could now clarify why. Thus, the locally different activity of risk gene variants such as APOE-4 in the brain plays a critical role in determining where harmful clumps of amyloid and tau proteins first form.

Even before the first symptoms of Alzheimer’s dementia are recognizable, misfolded proteins amyloid beta and tau accumulate in the brains of those affected. They are thought to trigger brain cell loss and progressive mental impairment. Usually, the brain areas important for memory in the temporal lobe and adjacent brain areas are damaged first, so Alzheimer’s disease usually first manifests as forgetfulness and problems with orientation.

But that’s not always the case: “There are some atypical cases of Alzheimer’s disease where patients develop speech or vision problems first, rather than memory problems,” explains lead author Brian Gordon of Washington University in Saint Louis. “When you look at her brain, you see damage in the speech and vision centers, but hardly in the memory centers.” Four subtypes of Alzheimer’s disease can now be distinguished, depending on the symptoms and the pattern of spread of the harmful tau fibrils.

Target risk genes

But why? In search of the factor that determines these differences in the course and affected areas of the brain, Gordon, his colleague Aylin Dincer and their team took a closer look at the most important genetic risk factor for Alzheimer’s disease: apolipoprotein-4 (APOE-4). This variant of the gene, which is actually responsible for regulating blood lipid levels, promotes the deposition of amyloid plaques and can increase the risk of Alzheimer’s disease up to twelvefold.

However, it was previously unclear what role this gene plays in the accumulation of harmful tau fibrils in the brains of those affected – and whether it may also affect the spatial pattern of Alzheimer’s disease in the brain. To find out, Dincer and her colleagues examined the symptoms, distribution of amyloid and tau, and gene activity of APOE-4 and other Alzheimer’s disease risk genes in the brains of 350 test subjects in their mid-70s over four years.

Gene activity influences the pattern of damage

The result: APOE-4 and other Alzheimer’s risk genes are not equally active everywhere in the brain. Their activity is found where Alzheimer’s dementia first manifests itself. “There was a close match between the sites of high APOE gene expression and where you saw tau fibrils and cellular damage,” reports Gordon. These were often the frontal lobe, the temporal lobe, the hippocampus and the amygdala—the very areas responsible for the typical symptoms of dementia in most Alzheimer’s patients.

However, there were also patients with aberrant patterns of tau deposition and gene activity. “There appear to be fundamental differences in which areas are susceptible to the damage that is typical of Alzheimer’s disease, and these differences are likely determined by an individual’s genetic makeup,” says Gordon. What combinations of gene variants are involved in detail and why have not yet been clarified.

Unanswered questions remain

“Herogeny tells us that there’s still something we don’t understand about how and why Alzheimer’s develops,” says Gordon. “When we see someone with visual impairment as the first early sign, the question becomes which specific gene signature triggers this locally specific pattern of brain damage.” He and his team therefore want to continue researching why and how patterns of risk gene activity in patients with Alzheimer’s disease.

In addition to more precise data on individual differences in gene expression, the question of what role the dosage of APOE-4 and other gene variants plays is a starting point for further studies: depending on heredity, a person may carry one or two copies of this gene variant. This also affects the associated risk. The researchers also want to take a closer look at astrocytes, the brain cells in which APOE is most active. It is possible that their individually different distribution also plays a role in the spatial distribution of Alzheimer’s foci in the brain. (Science Translational Medicine, 2022; doi: 10.1126/scitranslmed.abl7646)

Quelle: Washington University School of Medicine

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