Genetics of Alzheimer's Disease: What We Know

Beta Amyloid Deposits (Brown/Red) in Brain Tissue of AD Patient

The understanding of the genetics of Alzheimer’s disease continues to progress.  Berkis and colleagues at the University of Washington School of Medicine recently published an excellent summary of the state-of-the-art in this area.  Of note, one of the authors of this manuscript is Dr. Debby Tsuang.  Dr. Tsuang was a former student of mine when I was on the faculty at the University of Iowa College of Medicine.  It is always rewarding to find research published by former students.  Great work Debby!

 The summary begins with what we know about Alzheimer’s Disease (AD).  The strongest risk is age with the rate of dementia increasing from about .3% for those between 65 and 69 to an estimated 25% to 45% of individuals over 85 years of age.  Typical duration of illness is 8 to 10 years resulting in significant costs to individuals, families and society.

Definitive diagnosis of AD requires brain autopsy and histopathological confirmation of amyloid plaques and neurofibrillary tangles in the brain neocortex.  Diagnoses made before of AD by experts then to be correct 80 to 90% of the time.  The plaques found in AD are made primarily by a beta amyloid.  One form of beta amyloid (A Beta 42) appears much more prone to produce the brain placques found in the brain with AD. Beta amyloid is produced when a precursor (amyloid precursor protein) is cleaved by a secretase enzyme.  The genes and proteins that control beta amyloid production have some of the strongest links to AD. 

AD appears in at least two patterns in the general population—clustering in families with an autosomal dominant genetic pattern and occurring sporadically.  Here are the genes that at this point appear important in the autosomal dominant pattern of AD:

• Amyloid Precursor Protein: Amyloid precursor protein (APP) gene is located on chromosome 21, the chromosome linked to Down syndrome (trisomy 21).  Down syndrome is associated with development of amyloid deposit and pathological features similar to AD.  Humans with APP mutations can have AD beginning in 40 to 50 year age range.  APP mutations are felt to account for 15% of early onset AD cases.  These mutations appear to increase AD risk by raising the levels of the A beta 42 form of beta amyloid.
• Presenilin 1—The presenilin 1 (PSEN1) gene is found on chromosome 14.  Presenilin 1 appears to modulate secretase cleavage of amyloid precursor protein (APP).   Mutations of PSEN1 appear to be the most important cause of early age onset AD.  Some cases of AD with gene mutations of PSEN1 have an age of onset of AD as ealy as 30 years of age.
• Presenilin 2—The presenilin 2 (PSEN2) gene is found on chromosome 1.  Like PSEN1, PSEN2 also is involved in the cleavage of APP to produce beta amyloid.  It also appears to produce more of the plaque forming variant of beta amyloid (A Beta 42).  Compared to PSEN1, defects of PENS2 typically produce a later age of onset in families with the mutation. 

Apolipoprotein E Protein Model

One gene (APOE) has been identified as responsible for some of the risk of sporadic AD:

• Apolipoprotein E (APOE):  The APOE gene appears to account for both some cases of late-onset familial AD as well as late-onset sporadic AD.  The epsilon 4 variant of the APOE gene is linked to higher risk of AD as well as poorer outcome after traumatic brain injury and stroke.  Located on chromosome 19, APOE appears primarily involved regulating the distribution of cholesterol and trigylcerides throughout the body including the brain.  The mechanism for how APOE influences AD is not clear.  Some have proposed the mechanism relates to increased amyloid aggregation or influencing the tau protein involved in neurofibrillary tangle formation.

What are the practical implications of what we now know about the genetics of AD?   Genetic testing is available for genotyping the APOE gene.  Presence of the APOE epsilon 4 gene increase risk for late onset AD.  However, many individuals with the APOE epsilon 4 gene do not develop late onset AD.  Individuals without the APOE epsilon 4 gene are not risk free for late onset AD.   The authors suggest knowing your family history may be a better predictor of your own risk of late onset AD than knowing your APOE gene status.

For families with multiple family members with early onset AD (before age 60 to 65) this issue is a little more complex.  With early onset AD, 20% to 70% of cases can be linked to a PSEN1 gene mutation with 10-15 % linked to an APP gene mutation.  For asymptomatic younger family members with early onset AD, genotyping may identify a personal increased risk for AD.  Additionally, such knowledge might inform risk of passing on an early onset AD risk to one’s children.   Decisions about genotyping in high risk families are complicated by lack of effective treatment approaches.   Due to the complexity and individuality of genetic testing in AD, it is best to work with a trained genetic counselor in making a personal decision.  In the United States, information about locating a genetic counselor can be found at the web site of the National Society of Genetic Counselors.

Image of beta amyloid deposits in brain of Alzheimer's Disease from Wikipedia Commons authored by Nephron


Image of APOE from Wikipedia Commons via public domain at Protein Data Bank uploaded by JohnSDSUGrad.


Bekris LM, Yu CE, Bird TD, & Tsuang DW (2010). Genetics of Alzheimer disease. Journal of geriatric psychiatry and neurology, 23 (4), 213-27 PMID: 21045163