Alzheimer’s disease is a devastating disease that profoundly affects patients, families, and caregivers. What do we know about Alzheimer’s disease? We know that Alzheimer’s disease is complex, both in diagnosis and treatment. The only way to definitively diagnose the disease is by brain autopsy after the patient has passed away, although clinical signs and in some cases laboratory tests or radiology are used to determine whether Alzheimer’s is the most likely explanation for a patient’s cognitive decline. There is currently no cure, and no medications have been shown to be effective in reversing or significantly slowing the progression of the disease, but in recent years there has been an abundance of research revealing modifiable risk factors that appear to be valuable targets for risk reduction. A current major focus in Alzheimer’s disease research is early detection and early evaluation of risk, so that preventive measures may be taken for those at highest risk.
The earlier patients can be identified as being at risk, the earlier they can make changes that have been shown to lower the risk of developing Alzheimer’s disease. The hallmark sign of Alzheimer’s disease is the build-up of amyloid plaques in the brain, which starts decades before symptoms appear. Special imaging techniques are now available to evaluate plaques in the brains of living patients, but these are expensive, they are not widely available for all patients, and they are almost never used before symptoms are present, so they are not currently a practical method for early risk assessment. Special laboratory studies are also being evaluated to potentially help with early detection of amyloid levels, but these are not commonly used in clinical practice and are not yet widely available. One low cost, non-invasive method for early risk assessment, which can be easily employed in clinical practice, is genetic testing.
Alzheimer’s disease is highly heritable, meaning that a significant component of an individual’s risk for the disease is due to genetic factors. Most estimates suggest that approximately 50% of any individual’s risk is genetically determined, while the other 50% is due to other variables including the presence or absence of other medical conditions (e.g. diabetes, hypertension, thyroid abnormalities, etc.) as well as diet and lifestyle choices. What genes contribute to the heritability in Alzheimer’s disease? One gene—APOE (apolipoprotein E)–is the most significant and accounts for about 25% of Alzheimer’s heritability, while the remainder is due to the combined effect of a large number of other genes that each have lesser but important contributions. APOE testing has been widely available for a while and it is valuable but, but it does not provide a complete picture of a patient’s genetic risk on its own.
Genome-Wide Association Studies (GWAS) over the last 10-12 years have identified at least 30 other genes that contribute significantly to Alzheimer’s heritability. None of the genes identified so far have the same effect size as APOE, but the combination of the other genes’ effects is substantial. The differences are large enough that analyzing an extended genetic panel can produce results for overall genetic risk that is substantially different from what would have been predicted with APOE testing alone, and thus much more accurate as a predictive tool on an individual basis compared to APOE testing alone. This will be useful both for patients and for medical professionals looking to help patients understand their risk.
Polygenic risk scores take into account the contribution of multiple genes to calculate disease risk. To calculate a polygenic risk score, the presence or absence of variation in each gene in question must be understood. Within our genomes (all of our genes together), strands of DNA are composed of long sequences of “nucleotides.” No two genomes are the same, such that the specific nucleotides found at particular positions within a gene may vary among individuals. These are called variants, or “single nucleotide polymorphisms” (SNPs – pronounced “snips”). Different SNPs contribute differently to disease risk. A polygenic score creates is a composite genetic score that takes the various effects of all of these variants into account. This can show a wide variation in risk between individuals and is much more precise as a risk assessment tool compared to APOE testing alone.
Genetics do not change throughout life and they are not modifiable, so a polygenic assessment of Alzheimer’s genes is a useful risk assessment tool regardless of when it is used and the same result will be produced no matter when in the patient’s life the analysis is performed. The polygenic risk score is a low-cost, non-invasive method to alert high genetic risk individuals about their risk for developing Alzheimer’s disease at any time in their lives – including in mid-life (30s, 40s, and 50s) when the pathologic amyloid plaques are first starting to accumulate and when risk reduction techniques are most likely to be effective. Polygenic risk scores, along with other clinical assessments, will be a powerful method for determining which individuals are at the highest risk and thus which ones may benefit the most from a serious assessment of other non-genetic risk factors. Non-genetic risk factors are modifiable, and addressing these factors is our best current method for reducing an individual’s risk. In the future, other methods of risk reduction, including drugs that prevent amyloid plaque accumulation, may also be available. Understanding a patient’s risk level using polygenic risk assessment will be equally important for determining which patients are most likely to benefit from these types of interventions.
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