In order to understand how genetic mutations cause familial Alzheimer’s disease (FAD), it’s helpful to understand a bit about the science of genetics. In this article, we’ll answer the following questions:
Where exactly are genetic mutations found?
What are chromosomes?
What are genes?
What is DNA?
How do genetic mutations cause FAD?
Where exactly are genetic mutations found?
Most people know that our bodies are made up of cells. But some people are surprised when they learn that every cell, even skin cells, carry ALL our genetic information, including any mutations we have. That means scientists can culture skin cells from FAD patients and turn them into brain cells to study the disease.
What are chromosomes?
If the human genome is a comprehensive instruction manual for the body, then chromosomes are the chapters. Chromosomes serve as storage centers for our genetic information, and they’re found inside every cell of a person’s body.
A pair of chromosomes. Chromosomes are long, threadlike strands that are tightly coiled. Each chromosome contains many individual genes.
A cell and its nucleus. The central region of each cell is called its nucleus, and that’s where chromosomes are found.
Chromosomes large enough to be seen under a microscope. In humans, there are 23 pairs of chromosomes. Half come from a person’s mother and the other half come from their father.
What are genes?
Genes are segments of DNA that contain the instructions for something specific within the body.
A zoomed-in view of the DNA within a chromosome’s coiled structure. A chromosome contains hundreds to thousands of genes, with the exact number varying depending on the specific chromosome.
Humans have around 20,000 genes inside each of the cells in their bodies.
Genes determine physical characteristics that can influence everything from how a person looks to diseases they’re at risk of developing.
In some cases, many genes act together to produce a certain trait. One study discovered that over 12,000 single changes in a person’s DNA are associated with height.¹
What is DNA?
DNA, short for Deoxyribonucleic Acid, is the smallest fundamental building block of life, serving as text or “letters” of the instruction manual for the human body.
Almost every cell in a person’s body contains the same DNA, packaged as chromosomes.
Just as letters in the alphabet appear in a certain order to form words and sentences, the order of these chemical bases determines the information for building and maintaining a living organism, including everything from eye color to blood type.
The text or “letters” of DNA. The actual genetic instructions consist of four types of chemical bases known as adenine (A), thymine (T), cytosine (C), and guanine (G).
These chemical bases pair up with each other, A with T and C with G to form base pairs.
The spiral or double helix structure of DNA occurs as the base pairs attach to a sugar phosphate backbone.
This structure of DNA allows the DNA to replicate or make exact copies of itself, which is critical when making a new cell.
How do genetic mutations cause familial Alzheimer’s disease (FAD)?
Familial Alzheimer's disease (FAD) is an inherited form of Alzheimer's, linked to mutations in certain genes on our chromosomes. Three genes, in particular, are associated with FAD:
amyloid precursor protein (APP), located on chromosome 21
presenilin 1 (PSEN1), located on chromosome 14
presenilin 2 (PSEN2), located on chromosome 1
Across these genes, there are over 300 individual mutations that lead to the development of FAD.
A “genetic mutation” exists when a person has a different chemical base in a particular spot within their DNA. For example, they may have an A (adenine) instruction where most other people have a T (thymine) instruction.
A mutated gene. When one of the chemical bases is something different than it would otherwise be, that’s called a variant (or mutation). Sometimes these changes cause “normal” things like different eye colors. Sometimes they cause abnormal things, like disease.
For people with FAD genetics, a change is found in the particular part of their DNA that causes differences in the brain. These genes are involved in the production and processing of amyloid-β (pronounced amyloid-beta). The mutations ultimately cause the formation of amyloid-β plaques in the brain, a characteristic feature of Alzheimer's disease.
Similarly, researchers have identified 90 changes in the DNA letters of genes that influence the risk of developing late-onset Alzheimer’s disease. Some of these changes have been mapped and identified in specific genes, such as APOE and TREM2, while others remain unknown.²
Sources
Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, et al. A saturated map of common genetic variants associated with human height. Nature. 2022 Oct;610(7933):704–12. doi:10.1038/s41586-022-05275-y. Link
de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, et al. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores. Nat Commun. 2021 Jun 7;12(1):3417. doi:10.1038/s41467-021-22491-8. Link