Genetics of Alzheimer disease

APOE4 is a major susceptibility gene for Alzheimer’s disease, and leads to accelerated break down in blood brain barrier in the hippocampus and medial temporal lobe (Montagne et al, 2020).

• The Alzheimer’s Association cautions against routine genetic testing for APOE4 for AD unless they have had genetic counseling because:

- The risk is only relative and not deterministic (people with one copy have about three times the risk of developing AD)

- There is no treatment for AD

- Additional issues may arise, such as anxiety about getting dementia, discrimination, or issues obtaining disability or long-term care insurance

Most early onset AD have sporadic, nonfamilial form (or have unidentified polygenic mutations). Only 11% have association with one of 3 known autosomal dominant mutations (PSEN1, PSEN2, APP) (Mendez 2019).

1) PSEN1 (presenilin 1) mutation

a. APOE3 Christchurch (R1365) mutation appears protective in PSEN1 carriers – a case report demonstrated despite high brain amyloid levels, the patient had limited tau and symptoms (Arboleda-Velasquez et al, 2019)

2) PSEN2

3) APP

References

Alzheimer’s Association Medical and Scientific Advisory Council. Genetic Testing. https://www.alz.org/media/documents/genetic-testing-statement.pdf (2017).

Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019). https://pubmed.ncbi.nlm.nih.gov/31686034/

Mendez, M. F. Early-onset Alzheimer Disease and Its Variants: Contin. Lifelong Learn. Neurol. 25, 34–51 (2019). https://pubmed.ncbi.nlm.nih.gov/30707186/

Montagne, A. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76 (2020). https://pubmed.ncbi.nlm.nih.gov/32376954/