Bringing light to dark corners elucidates the cellular mechanisms of Alzheimer's disease

Illness often starts with small things: memory loss, not remembering to turn off the stove, or forgetting what
you ate for lunch.
After the disease progresses, it begins to forget some familiar tasks
.
Slowly, the language began to disappear, and there was no name, no face
recognized.

Statistically, you may be familiar with the situation, perhaps you have experienced it yourself, or you may have come from a familiar friend or family member
.
It's a very unique pain, and the feeling of "I can't do anything" always comes back and forth, making the situation worse
.
However, for the more than 30 million Alzheimer's patients(1) and their families, this is the reality: they watch the invisible monster of disease take one thing away until nothing else
.

But science tells us that it is not intangible, but tangible
.
It has concrete forms, and that's the root cause that allows us to fight back: Alzheimer's disease can be complex or devastating, but it's not insoluble
.
So here we highlight one of the many research groups that are bringing light
to the dark corners of the disease.

Elucidate vascular risk factors for Alzheimer's disease

The brain uses more energy than any other organ, and delivering this energy requires a broad vasculature
.
Although dysfunction of the neurovasculature can impair brain function and even cause dementia, frustratingly, we still know very little
about how this system contributes to Alzheimer's disease (AD).

This lack of information prompted Dr.
Wyss-Coray's lab at Stanford University to study how individual cell types in the neurovasculature mediate AD risk (2
).
The researchers combined an internally developed vascular isolation protocol with Chromium single-cell nuclear gene expression analysis to perform single-cell nuclear RNA sequencing (snRNA-seq)
on the vasculature of 9 AD patients and 8 controls.
With this new method, they collected and characterized the number of vascular nuclei (143,793) more than 200 times higher than previous experiments
.

These results showed a significant reduction in endothelial cells, smooth muscle cells, and fibroblast-like cells in AD, consistent with extensive vascular
deletions.
They identified 463 differentially expressed genes from multiple cell types, multiple of which were identified by GWAS studies as AD risk sites
.
Taken together, these vascular AD features are consistent with disruption of blood flow and provide a potential mechanism
for decreased cerebral blood flow perfusion in AD patients.

Nearly 60% of AD risk genes are expressed in (periperipheral) vascular cells, while multiple risk genes are enriched
in vascular cells.
Surprisingly, however, arterial cells, capillaries, smooth muscle cells, and pericytes are also rich in a large number of immune-related AD risk genes
.
Many immune-related genes, including the risk factor APOE, are expressed in the human vasculature and microglia, but expression in mice is limited to microglia
.
Since mice typically do not develop AD (and genetic intervention is required to mimic AD phenotypes), this prompted the research team to hypothesize that the microglia-vascular axis is a potential mechanism
that causes (or enhances AD risk).

Illuminate the road ahead

It's been 116 years since Alois Alzheimer first described Alzheimer's disease — but PCR was only 37 years old, next-generation sequencing was 22 years, and single-cell sequencing was less than 10 years
.
For those of us who have loved ones with Alzheimer's disease, treatment progress is still very slow
.
However, with insights from research groups such as Dr.
Wyss-Coray, the pace of progress is accelerating
.

Alzheimer's disease is heterogeneous and complex, but far from incomprehensible
.
And, with the help of research tools and techniques that would have been unimaginable 30 years ago, we are moving towards a brighter future
at an unprecedented pace.

Finally, we would like to thank Dr.
Wyss-Coray's team, as well as the larger Alzheimer's disease and related dementia research community
.
Your research illuminates the way for an in-depth understanding and ultimately treatment of Alzheimer's disease and shows that by working together, we will eventually move beyond the mountains
.

References:

1.
Dementia.
Who.
int.

2.
Yang AC, et al.
A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk.
Nature 603: 885–892 (2022).
doi: 10.
1038/s41586-021-04369-3