Genetic Risk Factors for Alzheimer’s Disease

Alzheimer’s disease is a progressive form of dementia that severely impacts the cognitive abilities and daily functioning of affected individuals. Genetic factors play a crucial role in determining the risk of developing the disease, with certain genetic variations potentially increasing susceptibility. Understanding these genetic factors not only helps us recognize our own risk but also opens up opportunities for research and the development of more effective preventive measures.

The following information is based on the research titled “The Genetics of Alzheimer Disease” conducted by author Rudolph E. Tanzi, published in 2012.
Family history is the second strongest risk factor for Alzheimer’s disease (AD), following advanced age. Twin and family studies estimate that genetic factors account for at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in the APP, PSEN1, and PSEN2 genes virtually guarantee early-onset familial AD (before age 60), which accounts for about 5% of total AD cases. On the other hand, common gene variants such as the ε4 and ε2 alleles of the APOE gene can influence susceptibility in about 50% of late-onset AD cases. These four genes are responsible for 30%–50% of the heritability of AD. Recent genome-wide association studies have identified an additional 11 candidate genes for AD. This paper summarizes the past, present, and future efforts to elucidate the complex and heterogeneous genetic underpinnings of AD.

After advanced age, family history is the second greatest risk factor for Alzheimer’s disease (AD). The well-characterized mutations in the APP, PSEN1, PSEN2, and APOE genes account for only 30%–50% of the heritability of AD.

1. Genetics of Early-Onset Familial Alzheimer’s Disease (EO-FAD)

After advanced age, family history is the second greatest risk factor for Alzheimer’s disease (AD). Alzheimer’s disease is considered a hereditary condition with two forms: familial early-onset cases, which are typically characterized by Mendelian inheritance (EO-FAD), and late-onset cases (≥60 years) that lack a consistent inheritance pattern (LOAD). Twin and family studies estimate that genetic factors contribute to at least 80% of Alzheimer’s cases.

Early-onset familial Alzheimer’s disease (EO-FAD) is often caused by rare mutations that are fully penetrant across three different genes:

• The APP gene (Amyloid Precursor Protein) located on chromosome 21
• The PSEN1 gene (Presenilin 1) located on chromosome 14
• The PSEN2 gene (Presenilin 2) located on chromosome 1

To date, 24 mutations have been identified in the APP gene, 185 mutations in PSEN1, and 13 mutations in PSEN2. Most of these mutations are inherited in an autosomal dominant manner with high penetrance, leading to EO-FAD.

Most mutations causing EO-FAD result in a common molecular phenotype: an increased ratio of Aβ42 to Aβ40. The relative increase in Aβ42 promotes the aggregation of this peptide into oligomers and ultimately into amyloid fibrils.

Studies on the molecular mechanisms of EO-FAD-causing mutations have facilitated the development of γ-secretase modulators aimed at reversing the Aβ42

β40 ratio, which are promising compounds for the treatment and prevention of Alzheimer’s disease.

In summary, Alzheimer’s disease has a clear genetic component, especially in the early-onset form. The main genes associated with Alzheimer’s have been identified as APP, PSEN1, and PSEN2. Family history is an important risk factor for Alzheimer’s disease. Research into the genetics of the disease has deepened our understanding of its pathogenesis and aided in the development of new promising treatment methods.

2. Genetics of Late-Onset Alzheimer’s Disease

In recent years, the most popular strategy for identifying new candidate genes for Alzheimer’s disease has been genome-wide association studies (GWAS). In GWAS, up to one million genetic markers can be tested for their association with disease risk and phenotypic characteristics such as age of onset, biomarkers, imaging results, and neurological features. More than a dozen GWAS studies have been reported for Alzheimer’s disease.

The first genome-wide significant finding was the GAB2 gene, reported by Reiman and colleagues in 2007. GAB2 is believed to influence tau phosphorylation and regulate Aβ production.

In 2008, we reported three new candidate genes for Alzheimer’s disease, including ATXN1, CD33, and an unidentified gene region on chromosome 14. ATXN1 affects Aβ levels by modulating the β-secretase enzyme. CD33 is associated with the regulation of the innate immune system.

In 2009, two large-scale GWAS identified three additional new genes: CLU, CR1, and PICALM. CLU encodes apolipoprotein J, which plays a role in lipid metabolism and Aβ clearance. CR1 is involved in inflammation and the removal of immune complexes. PICALM is related to synaptic transport and endocytosis.

Subsequent GWAS have identified several other candidate genes, such as BIN1, ABCA7, MS4A6A/MS4A4E, EPHA1, CD2AP, and CD33. In total, 11 new genes have been discovered through GWAS.

In summary, GWAS studies have opened up many new avenues for understanding the complex genetic mechanisms of late-onset Alzheimer’s disease. This indicates that Alzheimer’s disease has a clear genetic component, with many genes associated with the condition already identified. However, these genetic variants are risk factors rather than direct causes of the disease, unlike mutations causing early-onset Alzheimer’s disease.

The question of whether “Alzheimer’s disease is hereditary” can be answered affirmatively, but the degree of heritability depends on various factors. While early-onset Alzheimer’s disease has a high heritability due to gene mutations, late-onset Alzheimer’s disease has a more complex genetic mechanism, involving multiple genes and environmental factors. Genetic factors associated with late-onset Alzheimer’s disease, such as APOE and newly discovered genes from GWAS, act as genetic risk factors that increase susceptibility to the disease but do not necessarily cause it.

3. Summary

Our understanding of the causes and pathogenesis of Alzheimer’s disease (AD) can be divided into two eras: before and after the identification of the genes associated with AD. Three decades of genetic research on AD have revolutionized our understanding of the disease’s causes and accelerated the discovery and development of new therapies aimed at treating and preventing AD (Tanzi and Bertram, 2005). The modern era of AD research, guided by genetics, began in the 1980s and 1990s with gene linkage studies and positional cloning efforts that led to the identification of three genes associated with early-onset familial AD (EO-FAD): APP, PSEN1, and PSEN2. The APOE gene, associated with late-onset AD, was discovered using a similar strategy but was ultimately validated through genetic association studies. Genetic association studies remain the most common method for identifying new genes related to late-onset AD (LOAD), often conducted in the form of large-scale genome-wide association studies (GWAS) aimed at scanning the entire human genome for new disease loci. Recently, our family-based GWAS and other case-control studies (reviewed in Bertram et al., 2009, 2010) have led to the elucidation of new susceptibility variants, all of which have only a small effect on disease risk. Moreover, up to 50% of the heritability of AD remains unexplained by known genes and candidate loci identified from GWAS.

Our initial understanding of the causes of AD began with the identification of rare causal mutations in the three EO-FAD genes. More recently, we discovered two rare pathogenic mutations in the ADAM10 gene that impair ADAM10 enzyme activity and lead to AD by age 70 with high penetrance (Kim et al., 2009). Based on approximately 200 EO-FAD gene mutations and two LOAD mutations in the ADAM10 gene, it is important to search for additional rare sequence variants in other genes that may predispose individuals to AD. Ultimately, insights into the causes and pathogenesis of AD obtained from genetic studies will continue to enhance our understanding of the pathological mechanisms leading to AD. Furthermore, these findings will aid in the development of new treatment strategies aimed at preventing, halting, and even reversing AD.

In summary, genetic factors play a decisive role in the formation of the risk of Alzheimer’s disease, with important genes and genetic variants such as APP, PSEN1, PSEN2, and APOE. Understanding these factors not only raises awareness of the disease but also opens up opportunities for developing effective preventive and treatment measures. Continued research into genetic factors will be key in the fight against Alzheimer’s, aiming for a future where patients can be better protected from this disease.