Genetic diagnosis and prognosis of Alzheimer’s disease: challenges and opportunities

Abstract

Alzheimer’s disease (AD), the most common form of dementia in western societies, is a pathologically and clinically heterogeneous disease with a strong genetic component. The recent advances in high-throughput genome technologies allowing for the rapid analysis of millions of polymorphisms in thousands of subjects has significantly advanced our understanding of the genomic underpinnings of AD susceptibility. During the last 5 years, genome-wide association and whole-exome- and whole-genome sequencing studies have mapped more than 20 disease-associated loci, providing insights into the molecular pathways involved in AD pathogenesis and hinting at potential novel therapeutic targets. This review article summarizes the challenges and opportunities of when using genomic information for the diagnosis and prognosis of AD.

Keywords:

• Alzheimer’s disease
• diagnosis
• genomics
• prognosis
• therapy

Acknowledgements

C Reitz was supported by a Paul B. Beeson Career Development Award (K23AG034550).

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Late-onset Alzheimer’s disease (AD) is the most frequent form of dementia affecting 24 million persons worldwide.

• The etiology of AD is largely unclear, and there is no effective therapy for prevention or treatment.

• AD is a pathologically and clinically heterogeneous disease with a strong genetic component to which both common and rare genetic variants contribute.

• Mapping of the genes and pathways dysregulated in AD will allow to improve genomic profiling for AD diagnosis and prognosis and to develop more targeted and more effective therapeutic measures.

• During the last 5 years, genome-wide association studies have mapped more than 20 common disease-associated variants.

• Targeted sequencing and whole-exome and whole-genome sequencing studies have in addition identified rare disease-associated variants in SORL1, PLD3 and TREM2.

• The identified genetic variants hint to specific pathways involved in AD etiology including inflammation and immune response, lipid metabolism, endocytosis/synaptic function, amyloid processing, tau pathology and synaptic function.

• The ongoing large-scale whole-genome and whole-exome sequencing studies are expected to identify numerous additional susceptibility loci within the near future.