The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review

Abstract

Alzheimer's disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1, and PSEN2 genes cause early onset Alzheimer's disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer's disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions.

Keywords: Alzheimer’s disease; genetics; genome sequencing; genomics; precision medicine; risk factors; risk variants.

Figure 1

Effect sizes of AD associated variants for the respective minor alleles. The red dotted line indicates OR = 1 [log(OR) = 0]. Minor alleles with log(OR) above the line are risk alleles and below the line are protective. Abbreviations: APOEe4(hom), homozygosity for the APOE4 allele; APOEe4(het), heterozygosity for the APOE4 allele; ABCA7-LoFs, aggregated effects of loss-of-function variants in ABCA7; OR, odds ratio; AD, Alzheimer’s disease.

Figure 2

GeneMania network for physical interaction (PI) and pathway. An example of GeneMANIA network when only the PI and pathway links are used. Alzheimer’s disease genes from input list are presented as large black circles, and other genes deemed to be associated with the cluster are small black circles. Genes not linked to the main cluster are discarded.

Figure 3

Precision medicine approach for dementia. This is a graphical outline of how genetic and genomic information could be combined and integrated with electronic health records (EHRs) to improve the accuracy of dementia diagnosis and facilitate drug discovery. Middle-aged and older people (e.g., age > 50) are enrolled in an ongoing protocol that includes medical and family history, diagnostic assessment, and access to EHR. For those who have signs of cognitive impairment, genetic testing using either mutation-panels, genotyping arrays, whole exome sequencing or whole genome sequencing depending on the clinical question is performed alongside biomarkers. If a dementia diagnosis is confirmed through genetics and biomarkers, the patients are referred to specialized behavioral and pharmacological intervention and have the option to participate in drug trials. For the majority of subjects who do not have definitive biological findings, a likelihood risk score may be estimated based on the genetic and biomarker profiles. These risk scores may provide support for clinical diagnosis and identify subjects at risk for dementia. The presymptomatic at risk subject may be enrolled in longitudinal studies on prevention and those who never develop dementia despite having high risk may be studied to identify protective factors.