Genetics and Dementia

Most cases of Alzheimer’s disease arise with no known cause. There are, however, genetic variants that increase the likelihood of developing cognitive impairment earlier in life.  These variants include rare genetic mutations in the amyloid precursor proteins, presenilin 1 or presenilin 2.


A more common genetic predisposition comes from the apolipoprotein epsilon 4 genotype known as APOE4. APOE4 is a well-established genetic variant. It is known to double the risk of early cognitive decline if one receives a copy of the APOE4 allele from each parent.[1] The presence of the APOE4 genotype alone is not enough to diagnose Alzheimer’s disease before clinical symptoms of dementia appear because there are too many false positives[2] 


The onset of Alzheimer’s disease begins with abnormal processing of amyloid proteins, resulting in a build-up of amyloid-beta protein in the brain. The genetic variant APOE4 affects how well the body is able to clear amyloid proteins from the brain. This, in turn, accelerates the deposits of amyloid-beta and Tau proteins in the brain.  The combination of amyloid-beta and Tau proteins has a neurotoxic effect. It seems to lead to brain cellular dysfunction, atrophy of the brain, and subsequent clinical symptoms of dementia. 


There are many biomarkers for Alzheimer’s disease that can help measure the severity and progression of Alzheimer’s disease. For example, PET scans can be used to detect the presence of beta-amyloid proteins in the brain. Cerebrospinal fluid can be tested for the presence of phosphorylated tau. Neuropsychology tests can detect abnormal auditory verbal learning.[3]  The biomarkers may help “stage” Alzheimer’s disease from the preclinical stage to later stages of dementia.


Because no cure for genetic variants for Alzheimer’s dementia currently exists, the diligent control of other modifiable risk factors is the best way to delay the onset of Alzheimer’s disease and minimize neurologic impairment from it.


[1] Albert M, Soldan A, Gottsman R,, Cognitive changes preceding clinical symptom onset of mild cognitive impairment and relationship to APOE genotype. Curr Alzheimer Res, 2014; 11(8):773-784.

[2] Mayeux R, Saunders AM, Shea S,, Utility of the Apolipoprotein E genotype in the diagnosis of Alzheimer’s disease, N Engl J Med 1998; 338:506-511.

[3] Gross AL, Mungas DM, Leoutsakos JMS,, Alzheimer’s disease severity, objectively determined and measured, Alzheimer’s & Dementia: Diagnosis, assessment & disease monitoring 4 (2016) 159-168.