The latest advances in Alzheimer's research

We’ve come a long way in the diagnosis of Alzheimer's disease since the German physician Alois Alzheimer first described the eponymous condition as “a peculiar disease” in 1906.

A pioneer in correlating symptoms with microscopic findings, Dr. Alzheimer observed shrinkage and abnormal deposits involving nerve cells during a brain autopsy of a patient with substantial memory loss and other dementia symptoms.

Since then, important inroads have been made into the diagnosis and treatment of this devastating condition. Nevertheless, Alzheimer's and other forms of dementia exact a high human and financial cost—with more than 6 million Americans living with Alzheimer's in 2021, according to the Alzheimer’s Association.

Here’s a closer look at advances in our understanding of Alzheimer's pathology and treatment.

AβO hypothesis

The amyloid-β oligomer (AβO) hypothesis was first proposed in 1998, and since then, thousands of articles have been published on these CNS neurotoxins. AβOs stymie nerve impulses over the long term and lead to selective nerve death, as well as trigger chief aspects of Alzheimer's pathology including inflammation, synapse loss, oxidative damage, and tau pathogenesis.

Findings from behavioral and neuropathological studies, as well as cell studies, support the hypothesis that increased AβO levels in the brain result in disease. Studies involving the protective effect of AβO-selective antibodies support the direct role of these neurotoxins In Alzheimer's disease.

According to the authors of a widely cited review published in the Journal of Alzheimer’s Disease, “[I]f the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease-modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.”

Therapeutic approaches to combat AβOs include blocking receptors, impairing signaling pathways, clearing AβOs, and blocking tau or other downstream effectors.

APOE4

Apolipoprotein E4 (APOE4) is a gene that is strongly linked to a higher risk of Alzheimer's, with nearly a quarter of the population harboring it. Moreover, 2% to 3% of the population carry two copies of the gene (ie, homozygous APOE 4/4). 

Genome-wide association studies implicate lipid metabolism in Alzheimer's disease and other late-onset forms of dementia; APOE codes for a lipid-carrier protein, which is important in the synthesis of lipoprotein particles. 

Intriguingly, the APOE4 genotype is also tied to increased risk for heart disease and metabolic syndrome, as well as decreased mortality. With regard to Alzheimer's disease, it functions in a dose-dependent fashion and fosters earlier onset of this dementia when present.  

APOE4 is a focus of research efforts with implications in the treatment of Alzheimer's disease. In a preclinical study published this year in Science Translational Medicine, investigators found that changing the culture medium of cell lines by adding choline—a soluble phospholipid precursor—reconstituted the cellular lipidome to its baseline (homeostatic) status in APOE4 expressing astrocytes and in yeast expressing human APOE4.

“Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype,” wrote the authors. “Importantly, our study suggests that manipulating lipid metabolism could be a therapeutic approach to help to alleviate the consequences of carrying the APOE4 allele.”

In an NIH featured-research article published this year, the study’s corresponding author reified the results of the study. “What we would really like to see is whether in the human population, in those APOE4 carriers, if they take choline supplements to a sufficient amount, whether that would delay or give them some protection against developing dementia or Alzheimer’s disease.”

ALZ-801

Although beta-amyloid (Aβ) is widely recognized as playing a key role in the pathology of Alzheimer's disease, few anti-amyloid agents have demonstrated promise in clinical trials. To date, the anti-oligomer agent ALZ-801 has advanced furthest.

ALZ-801 is an optimized oral prodrug of tramiprosate, and selectively inhibits the formation of Aβ42 oligomers. More specifically, tramiprosate is conjugated to valine, thus stabilizing blood plasma levels and increasing brain penetration, as well minimizing GI adverse effects.

In a review published in Alzheimer’s Research and Therapy, authors noted that the agent boosted cognitive test scores in homozygous APOE4/4 subjects exhibiting mild Alzheimer's disease. It also maintained hippocampal volume per MRI, thus suggesting a disease-modifying effect of ALZ-801/tramiprosate treatment.