Individualized pharmacotherapy and Alzheimer’s disease: now and future

Since even target-engaging drugs have been tested without significant outcome, treatments for Alzheimer’s disease (AD) remain stubbornly elusive. A comprehensive risk profile of a patient with AD indicates vast variation in risk markers that may serve to guide treatment. Datasets including several genetic variants such as well-recognized APOE ε4 alleles which define an individual’s likelihood of developing AD by about a decade compared with the general population are becoming increasingly developed. Personalized pharmacogenetic trials that help in diagnosis and treatment choice are now becoming available for clinical practice. Also, amyloid beta (Aβ) peptide biomarkers in the cerebrospinal fluid of AD patients as well as phosphorylated tau measurements, PET scan of Aβ or tau deposition and volumetric MRI are now available. Meanwhile, the application of Plasma markers including serum cytokines and phospholipids are gaining validity and credibility as diagnostic and predictive methods. A new biomarker is misfolded tau that assumes case-specific stable conformations in vivo and may be amenable to treatment with antibodies that are personalized for the patient’s tau strain. Patient-specific neurons derived from induced pluripotent stem cells offer accessibility to numerous personalized data points such as cellular properties, electrophysiological measurements and transcriptomes. While Individual genetic variation maybe assessed as quantitative trait loci (genomic loci that regulate expression levels of mRNA), it is still extensive and poorly understood. Also, variation of personal lifestyle traits like poor nutrition or being sedentary can add up to the current failure of AD clinical trials. Considering these complications, the expected waiting time for an approved AD medication is estimated to be 260 years of independently and sequentially conducted trials. One way to accelerate this is to consider N-of-1 trials in future, in which a patient is fully assessed for genetic variants and endophenotypes and, based on this profile, a thoughtful treatment approach is defined.

Keywords:

Alzheimer’s disease , Biomarkers , Genetic variants , Tau , Amyloid β , N-of-1 trials