Ironically, the first person to be diagnosed with what is now Alzheimer’s disease was missing its major risk factor. When she first began showing symptoms of dementia in 1901, Auguste Deter was not particularly old. Despite Deter’s case, aging is the largest risk factor for developing Alzheimer’s, by a large margin. But “geroscience has not been translated into drugs for Alzheimer’s disease,” Howard Fillit, Alzheimer’s Drug Discovery Foundation co-founder and chief scientific officer, told BioWorld. “We’re just starting to see that cross-fertilization now.”

After decades of trying and dozens of failed trials, amyloid targeting has paid off with the first disease-modifying agents reaching the market. But success does not mean slam dunk. Aduhelm (aducanumab, Biogen Inc.) was dogged by controversy throughout its brief tenure, and Biogen pulled the plug on it in early 2024. Leqembi (lecanemab, Biogen Inc.) has received full approval. In this second installment of a three-part series on Alzheimer’s, BioWorld looks at the nuanced view of amyloid’s role in the disease.

Ironically, the first person to be diagnosed with what is now Alzheimer’s disease was missing its major risk factor. When she first began showing symptoms of dementia in 1901, Auguste Deter was not particularly old. Despite Deter’s case, aging is the largest risk factor for developing Alzheimer’s, by a large margin. But “geroscience has not been translated into drugs for Alzheimer’s disease,” Howard Fillit, Alzheimer’s Drug Discovery Foundation co-founder and chief scientific officer, told BioWorld. “We’re just starting to see that cross-fertilization now.” This first article of a three-part BioWorld series on Alzheimer’s disease looks at how a group of researchers, as well as some startups, are trying to approach Alzheimer’s via an aging lens.

Precision psychiatry got some love at two quite different meetings this week, the European Congress of Neuropsychopharmacology’s New Frontiers meeting and BioEurope Spring. The New Frontiers Meeting, an annual two-day meeting dedicated to cutting-edge issues in brain disease research, focused on big-picture and scientific – at times almost philosophical – questions of how to get to a classification scheme for brain disorders that aligns with the underlying biology.

To Steve Hyman, the manual that clinicians currently use to diagnose mental disorders is an active obstacle to getting a scientific understanding of those disorders. Hyman, who is director of the Stanley Center for Psychiatric Research at the Broad Institute, MIT and Harvard, and a former director of the National Institute of Mental Health (NIMH), listed multiple weaknesses of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM), whose diagnoses, he said, are “arbitrary, rigid, life-stage and context-insensitive,” as well as blind to the fact that mental disorders exist along a continuum.

In cell and animal models of amyotrophic lateral sclerosis (ALS), the expression of toxic dipeptides in neurons led to changes in the extracellular matrix (ECM) as a protective response. The authors wrote that their findings, which appeared in Nature Neuroscience on Feb. 29, 2024, could suggest new strategies for how to approach ALS.

Separate teams of investigators have reported new insights into how the brain disposes of metabolic waste via the glia-based lymphatic system, or glymph system. In two papers published in Nature on Feb. 28, 2024, scientists from Washington University in St. Louis described how in sleeping animals, the synchronized activity of neurons drove ionic gradients that facilitated the movement of fluid through brain tissue. And researchers from the Massachusetts Institute of Technology showed that, in a mouse model of Alzheimer’s disease (AD), the glymphatic system mediated clearance of amyloid-β after sensory stimulation at a 40-Hertz rhythm.

Autoantibodies call to mind disease – autoimmune disease, to be exact. But the physiological roles of autoantibodies are, at the very least, more complex than this view accounts for. “The autoantibody reactome is extraordinary,” Aaron Ring told BioWorld. “Nearly everyone has autoantibodies, whether they know it or not.”

Investigators at the National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) have used a gene-constrained analysis to identify nine new Alzheimer’s disease (AD) risk genes that are possibly linked to the higher prevalence of AD in people with African ancestry. One of those genes, GNB5, regulates the stability of certain G protein-signaling proteins, which are activated by G protein-coupled receptors (GPCRs). The authors showed that mice with only one copy of Gnb5 developed more amyloid plaques and tau tangles than those with two copies.

Humans love to think of our species as unique. But on a genetic level, such uniqueness is surprisingly hard to find. And while that may be a blow to the ego, it also means that an evolutionary lens is one way to search for insights into human diseases. Animals are “adapted to use the same genes that you and I have, but in very different ways,” Ashley Zehnder told BioWorld. Zehnder is co-founder and CEO of Fauna Bio Inc., which uses comparative genomics to identify gene networks that underlie disease resistance in different animal species.