What are the genetics of Alzheimer's?

Alzheimer's disease genetics involve both non-deterministic and deterministic genes. The non-deterministic gene most commonly associated with Alzheimer’s is the ApoE gene, which has three isoforms: E2, E3, and E4. The E4 isoform has historically provided protection against infections and is associated with an increased risk of Alzheimer’s. However, having the gene does not guarantee the development of the disease. Most people have the E3 variant, which is the most common, and combinations of these isoforms determine different levels of risk—E3/3 being the most common, E3/4 having increased risk, and E4/4 being very rare and carrying the highest risk.

On the other hand, there are rare deterministic genes like PSEN1, PSEN2, and APP, which collectively account for about 1% of all Alzheimer's cases. If an individual has one of these deterministic genes, they will develop Alzheimer's, usually at an early age, often in their 50s.

Moreover, the presence of amyloid plaques in the brain, typically associated with Alzheimer's, is currently under question, as there have been cases where people with no cognitive impairment had brains full of these plaques upon autopsy, suggesting the role of amyloid in Alzheimer's disease might be complex and not fully understood. The controversy lies in the emphasis on amyloid-beta and the understanding of the disease's pathology, as the presence of amyloid and neurofibrillary tangles have been seen in individuals without any cognitive decline.

These points are elaborated by Peter Attia in a discussion with Andrew Huberman on the Huberman Lab 1 2 3.