MAY 07, 2024 7:16 AM PDT

Alzheimer's by Age 65 Nearly Guaranteed for Carriers of Two Copies of APOE4

WRITTEN BY: Carmen Leitch

Humans carry a gene called APOE, which encodes for a protein called apolipoprotein E. There are variations in the sequence of this gene that create genetic variants of APOE, and one of those variants: APOE4, has long been known to increase a carrier's risk of Alzheimer's disease. Now, scientists have found evidence that as many as 95 percent of people who carry two copies of APOE4 will get Alzheimer's disease by the time they turn age 65. The findings have been reported in Nature Medicine.

Image credit: Pixabay

We each inherit two copies of genes (that are not on the X and Y sex chromosomes), including APOE4, from our parents. When the two copies are identical, they are said to be homozygous. In this study, the researchers determined that almost all individuals who were homozygous for APOE4 also showed signs of Alzheimer's and increased levels of biomarkers of the disease by age 55 compared to people who carry an APOE variant known as APOE3.

The cerebrospinal fluid of 95 percent of APOE4 homozygotes had signs of amyloid, a hallmark of Alzheimer's, by age 65. There were signs of amyloid in PET scans of 75 percent of APOE4 homozygotes by age 65 as well.

People who are homozygous for APOE4 were also found to develop Alzheimer's disease earlier in life compared to those with other versions of APOE. The study has suggested, therefore, that APOE4 homozygosity could represent a unique, genetic form of Alzheimer's disease.

"These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene. This gene has been known for over 30 years and it was known to be associated with a higher risk of developing Alzheimer's disease. But now we know that virtually all individuals with this duplicated gene develop Alzheimer's biology. This is important because they represent between two and three percent of the population," said co-corresponding study author Dr. Juan Fortea, Director of the Memory Unit of the Neurology Service at the Sant Pau Research Institute.

There are other changes in different genes that have been linked to the early onset of Alzheimer's disease, including changes in the genes APP, PSEN1, and PSEN2. In some carriers of variants of these genes, Alzheimer's may start to arise as soon as age 40. There are also different genetic variants that have been associated with different forms of Alzheimer's, such as sporadic or late-onset cases.

This study relied on data from about 3,300 people who donated brain samples, including 273 individuals who were homozygous for APOE4 in one cohort, and another 519 APOE4 homozygotes in a different study cohort. Biomedical data from thousands of others, including controls, were also studied.

These findings could help scientists develop better treatment approaches for APOE4 carriers, and bolster preventative efforts.

Sources: Institut de Recerca Sant Pau (Sant Pau Research Institute), Nature Medicine

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Bachelor's (BA/BS/Other)
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