Despite decades of rigorous research, scientists are still struggling to crack the mystery of Alzheimer’s disease. Promising preclinical research has consistently led to frustrating clinical trial failures and some have started to question whether we are even targeting the correct pathological mechanisms.
One possible explanation for why we can’t crack the Alzheimer’s code is that we are mistakenly considering the disease as a single homogeneous entity. Currently, Alzheimer's disease (AD) is only really separated into two types, either early-onset Alzheimer's or late-onset Alzheimer's, depending on what stage of a person's life they begin displaying symptoms.
A robust 2018 study investigated the cognitive and genomic characteristics of several thousand patients diagnosed with late-onset Alzheimer’s and concluded Alzheimer’s should be considered six distinctly different conditions instead of one single disease.
This new study arose from a similar foundation, trying to understand why the disease manifests with such a variety of clinical symptoms from patient to patient. One-third of patients displaying clinical characteristics of Alzheimer’s, for example, show no toxic accumulation of amyloid proteins in their brain. And the opposite is also seen, with postmortem brain tissue biopsies revealing comprehensive pathological signs of Alzheimer’s despite no indication of cognitive decline during the person’s life.
"Such differences strongly suggest there are subtypes of AD with different biological and molecular factors driving disease progression," says lead author of the new study, Bin Zhang.
The new research set out to understand the specific molecular characteristics of different Alzheimer’s cases. Using RNA sequencing the researchers analyzed over 1,500 brain tissue samples, spanning five different brain regions.
Three major molecular subtypes of Alzheimer’s were identified based on factors including synaptic signaling, immune activity, mitochondria organization, myelination, and specific gene activity. Only one-third of the cases studied displayed “typical” Alzheimer’s hallmarks, such as decreased synaptic signaling and increased immune response. This subtype was dubbed “class C.”
Importantly, the study suggests the other two identified subtypes (class A and B) showed unique and distinct characteristics. In some instances the subtypes displayed opposite gene regulation, leading the researchers to hypothesize their findings as potentially helping explain previous clinical trial failures.
“This may partially explain how many existing clinical trials that showed promising efficacy in one particular mouse model later do not align with human trial results, assuming that study participants had consisted of a heterogeneous group of participants across many AD subtypes,” the researchers write in the study.
The challenge moving forward will be to find ways to detect these disease subtypes easily in living patients. The comprehensive brain tissue analysis in the study cannot translate into a diagnostic tool, so more work is needed to find biomarkers that correspond with these three subtypes.
"These findings lay down a foundation for determining more effective biomarkers for early prediction of AD, studying causal mechanisms of AD, developing next-generation therapeutics for AD and designing more effective and targeted clinical trials, ultimately leading to precision medicine for AD,” explains Zhang. “The remaining challenges for future research include replication of the findings in larger cohorts, validation of subtype-specific targets and mechanisms, identification of peripheral biomarkers, and clinical features associated with these molecular subtypes."