Genetics of Alzheimer’s disease

Alzheimer’s disease (AD) is a complex neurodegenerative disease that affects millions of adults and families around the globe. Unfortunately, patients with AD may suffer for many years with progressive dementia due to a lack of effective treatment options. With an aging population in many countries, AD is estimated to affect 78 million people worldwide by 2030.

For decades, scientists have sought and studied the genes and proteins involved in AD. This infographic highlights the relative prevalence of genetic variants across the general population and ties them to the risk level of developing AD. The most well-studied mutant alleles, while disease-causing, are actually less prevalent. Highly penetrant mutations in the genes APP, PSEN1, and PSEN2 are known to lead to early-onset AD (<age 60), which accounts for 5–10% of all cases. These mutant alleles can be hereditary or deterministic genes that cause familial AD in 35–65% of early-onset AD cases. The remaining cases of early-onset AD are considered sporadic. The discovery of these genes has shed light on the cellular mechanisms that lead to AD, highlighting how the alternative processing of a key target, amyloid-ß, may impact plaque formation in the brain.

The more common form, known as late-onset Alzheimer’s disease (LOAD) (>age 60), is genetically heterogeneous and polygenic in nature. Late-onset AD can develop due to inherited risk factors, or it may appear as sporadic AD. The most significant risk factor for late-onset AD discovered to date is a mutant allele of APOE that was identified in 1993. Apolipoprotein E (APOE) is crucial for mediating cholesterol metabolism and is required to transport cholesterol from astrocytes to neurons.

The road to discovering additional risk factors for AD has been long, but recent work using large genome-wide association studies (GWAS) has led to the identification of ~95 additional risk loci. As of February 2021, 42 of these loci are novel, highlighting the need to classify and better understand these genes, any resulting proteins, and how they affect AD risk.

Genetic studies like these offer an excellent way to begin searching for genes that may potentially be involved in AD. GWAS and other genetic studies are correlative; while they identify loci near a gene of interest, further research is needed to determine whether a particular gene is involved in AD. Functional investigations into promising target proteins using various techniques are required to examine the cellular mechanisms that impact neurodegeneration. Performing antibody-based assays provides a means to detect, visualize, and examine the relationship between known Alzheimer’s-related proteins and novel therapeutic targets. Once putative target proteins have been identified and characterized, they may serve as much-needed, early-stage biomarkers for AD.

Selected Reviews:

• Guerreiro R, Brás J, Hardy J. SnapShot: Genetics of Alzheimer's Disease. Cell. 2013;155(4):968-968.e1.
• Bellenguez, C., Küçükali, F., Jansen, I.E. et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 54, 412–436 (2022).
• https://www.alzforum.org/news/research-news/massive-gwas-meta-analysis-digs-trove-alzheimers-genes. Published 2021. Accessed September 15, 2022.
• Schwartzentruber J, Cooper S, Liu J. Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.. Nat Genet. 2021;53(3):392-402.
• Bertram L, Tanzi R. Genomic Mechanisms in Alzheimer's Disease. Brain Pathology. 2020.
• AlzGene. Alzgene.org. http://www.alzgene.org/TopResults.asp. Published 2011. Accessed September 15, 2022.
• Kunkle, B.W., Grenier-Boley, B., Sims, R. et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity, and lipid processing. Nat Genet. 51, 414–430 (2019).
• Kamboh M. Genomics and Functional Genomics of Alzheimer's Disease. Neurotherapeutics. 2021;19(1):152-172.
• Chen H, Petty L, Sha J et al. Genetically regulated expression in late-onset Alzheimer's disease implicates risk genes within known and novel loci. Transl Psychiatry. 2021;11(1).

created January 2023