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Alzheimer Disease: Common and Complex Alzheimer’s disease (AD) is a genetically complex, multifactorial disease that leads to neurodegenerative dementia. There is no cure for AD yet, and due to a high prevalence and continuously increasing incidence it poses a major threat to personal health as well as to the health care system. Patients display a progressive decline of cognitive capabilities, with characteristic early loss of episodic memory, eventually resulting in complete dependency and death. The disease is preceded by a long prodromal phase 1, 2. Neuropathological changes in the AD brain include progressive hippocampal and cortical atrophy, visible upon neuroimaging and macroscopic examination. Characteristic microscopic features are intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein and extracellular depositions of Amyloid-β (Aβ)1–42 peptide, accompanied by neuronal and synapse loss and reactive gliosis [3]. Initial evidence of a genetic etiology of AD was presented by the observation of families with multiple generations affected by a rare early onset form of AD (EOAD, <65years). Molecular genetic investigation of these pedigrees resulted in the identification of the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes as disease genes in AD. Pathogenic mutations in these genes converge to a general mechanism of increased Aβ1-42 accumulation or increased Aβ1–42/Aβ1–40 ratio. Hundreds of dominantly inherited pathogenic mutations have since been described for these genes, mostly in EOAD patients, although only explaining up to 10% of EOAD (reviewed in [4]). Most patients have late-onset AD (LOAD). While a pathogenic mutation in APP, PSEN1 or PSEN2 is infrequently identified in LOAD patients, LOAD is typically considered multifactorial, with a strong polygenic component and an estimated heritability of up to 80%. The most well-known genetic risk factor for AD is the (see Glossary), explaining approximately 25% of the heritability of liability [5]. Over the past decade, complex genetic research on AD has been successful in identifying additional genetic risk factors for AD, both low-penetrant common risk factors (e.g., [6]) and rare Sennoside C with intermediate to high penetrance (e.g., 7, 8, 9). While the amyloid cascade hypothesis has long dominated the efforts towards development of diagnostics and therapeutics for AD, gene discovery studies and pathway-based analysis of genome-wide studies shed light on a range of additional biological processes contributing to AD, proposing new targets for therapy development. Translational impact of these findings is still limited however, owing to – amongst others – pleiotropy of risk genes, limited understanding which genetic variants in identified risk genes or loci actually affect AD risk and how, and the physiological complexity of tissues which is insufficiently represented in genetic analysis. While the field of AD genetics is still in active pursuit of additional genetic risk loci through genome-wide association studies (GWAS) and next generation sequencing studies on increasingly large AD cohorts, a trend is emerging of simultaneous interrogation of transcriptomics data to study the effect of newly identified genetic risk factors at the level of the transcriptome (e.g., [10]). In parallel, refinement of transcriptomics through second and third generation sequencing methodology, single-cell sequencing and bioinformatics analysis allows investigating functional mechanisms involved in AD in previously unattainable detail. Here, we review the state-of-the-art of genetic discovery and transcriptome investigations in multifactorial AD, with emphasis on the insights emerging at their interface.
Genetic Risk Loci and Pathways in Polygenic AD
Rare Genetic Risk Factors The investigation of rare variants in susceptibility of AD has gained significant momentum after the identification through combined whole genome (WGS) and whole exome sequencing (WES) of a rare non-synonymous mutation, p.R47H, in TREM2 that increases risk of AD 7, 31, which has since been widely replicated. Numerous independent studies further reported an enrichment of rare coding variants among AD patients in SORL1 and ABCA7, which were already known to be implicated in AD risk through common risk factors. In SORL1, both heterozygous missense and premature termination codon (PTC) mutations were found, most notably in patients with EOAD and/or familial disease [32]. For ABCA7, strongest evidence of association was found for heterozygous PTC mutations, with widely varying onset age among carriers but an increased proportion of positive family history 8, 33. Large-scale sequencing efforts, such as the Alzheimer Disease Sequencing Project (ADSP) which includes ∼11000 participants, are providing further evidence of rare risk variants in genes initially identified in GWAS [34]. These studies are likely to provide insight into novel risk genes for AD in the near future. An exome-wide association analysis on rare and low-frequency variants using exome chip genotyping proposed rare variants in two additional genes, that is, ABI3 and PLGC2, the latter being protective for AD [9].