Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets

Abstract

To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer’s disease (AD). However, the definition of AD has been confounded with dementia in many studies. Thus, overinterpretation of genetic findings with regard to mechanisms and drug targets may explain, in part, controversies in the field. Here, we analyze the different forms of genetic risk of AD and how these can be used to model disease. We stress the importance of studying gene variants in the right cell types and in the right pathological context. The lack of mechanistic understanding of genetic variation has become the major bottleneck in the search for new drug targets for AD.

Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores is most accurate when using all genetic information.

“…In the threshold model, liability for a genetic disorder is (normally) distributed across the population and polygenic risk scores are a measure of disease liability 39 . The relative contributions of alleles of various effect sizes and frequencies are not fully resolved; while common alleles of small risk, captured by genome-wide association study arrays, capture between a third and a half of the genetic variance in liability, APOE alone substantially increases risk for the disorder 40 . A major problem with AD and using PRS to categorise people at risk, is the age of the study participants.…”

“…In conclusion, identifying individuals at high and low polygenic risk is very important for further work to understand how genetic risk translates into mechanisms of disease 40 . It might also become very relevant for drug development efforts targeting precise mechanisms of disease, as the PRS scores could be used to select small samples of patients in which proof of concept for the treatment can be obtained before testing the drug in larger cohorts.…”

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

“…Soluble Aβ dimers and oligomers are able to hyperactivate and damage glutamateric neurons and synapses [ 27 , 31 ]. In addition, all major gene modifications, which have been identified so far in association with an increased AD risk, are related to Aβ generation, aggregation and clearance, and microglia responses [ 4 ]. Furthermore, the anti-Aβ antibodies aducanumab [ 32 ] and donanemab [ 33 ] have shown potential to delay cognitive decline by reducing brain Aβ load, when treatment of patients with antibody takes place very early in the disease.…”

“…In Alzheimer’s disease (AD), neurodegenerative but also contributing vascular and hemostatic changes in the brain lead to the loss of memory and cognitive skills, robbing humans ultimately of their essential personality. To date, there is no medicine in clinical use or recognizable in the research pipeline that can effectively combat AD, a disease, which affects more than 1 million people in Germany and 40 million worldwide [ 1 , 2 , 3 , 4 , 5 , 6 ]. Of these individuals, less than 10% develop symptoms well before the age of 65 due to their hereditary predisposition, known as early-onset AD [ 4 ].…”

“…To these standard AD therapeutics belong cholinesterase inhibitors, such as donepezil, galantamine, rivastigmin, and glutamate antagonists like memantine [ 5 ]. Therefore, an urgent task of pharmaceutical research is to search for novel, more effective drugs to possibly cure or considerably mitigate AD [ 3 , 4 ]. Another strategy is to look for new therapeutic approaches, which are based on already known active ingredients with other approval for use [ 6 ].…”