Genetic Biomarkers in Alzheimer’s Disease

Like Huntington’s disease, cystic fibrosis, sickle cell anemia, and Down syndrome, early-onset Alzheimer’s disease (EOAD) is an inherited genetic disorder. Variations in three genes—amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2)—have been identified as causal factors in EOAD. A growing body of literature also reports evidence of heritability in nonfamilial or late-onset Alzheimer’s disease (LOAD), which accounts for >95% of all AD cases; however, APOE is the only gene variant found to be consistently associated with LOAD. Together with three familial genes (APP, PSEN1, PSEN2), APOE accounts 30–50% of heritability of AD. All four genes were identified by genetic linkage analysis and positional cloning. A few low-penetrance gene variants in AD have been identified, including APOE4, SOLR1, TOMM40, BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP. Of these, APOE4 is the most strongly associated with LOAD, but the link varies with ethnicity, age, and sex. APOE4 variation is therefore not suitable for use as a LOAD biomarker, but it has been considered as a disease risk factor. Almost all reports of newly discovered LOAD genetic biomarker candidates are either nonreproducible or are limited to certain ethnic groups. The genetic component of LOAD thus remains largely unknown and is an active area of AD research. Other nongenetic risk factors, such as age and previous head trauma, have been implicated in LOAD and have been shown to cause changes in miRNA expression and posttranslational modifications that affect molecular signaling. These nongenetic factors may be involved in epigenetic mechanisms that underlie LOAD. In this chapter, we outline methodological approaches to identifying genetic LOAD biomarkers and provide a summary of AD genetic biomarker research.