Finding the Center: Alzheimer’s disease may originate from an unlikely brain region
A cloudy afternoon on a serene university campus. Alice, a linguistics professor in her fifties, is jogging. The sky is crisp and white. The green hedgerows are neatly trimmed. Scattered across the path, busy people are going on about their day: a young student in a brown tweed jacket is handing out fliers; an older man with feather-grey hair walks leisurely ahead. Suddenly, Alice stops jogging, and for a moment she seems to have vanished and left her body behind. Everything falls silent. The campus she has known for many years has suddenly become surreal, its familiar buildings frighteningly unrecognizable. She does not remember where she is or how she got there. Perhaps she is unsure even of who she is. A deep sense of fear and uncertainty overwhelms her. This sequence, which occurs only a few minutes into the 2014 award-winning drama “Still Alice,” is a clue to the question at the heart of the film: How does it feel when a person’s life is irreversibly altered by Alzheimer’s disease?
The concept of dementia has existed for thousands of years. The Roman philosopher Cicero [2nd century B.C.] described it as a characteristic “not of all old men, but only those who are weak in will,” while the Old Testament was thoughtful in counseling its readers to “be kind to your father, even if his mind fail him” (Ecclesiasticus 3:12). Yet, it was only in the last century that the essential clinical symptoms and neurodegenerative changes associated with dementia were first discovered. In 1907, the German psychiatrist and pathologist Alois Alzheimer described for the first time a startling new pathology in the brain of a deceased woman who had suffered from an acute form of dementia. Examining a section of her brain under a microscope, Alzheimer observed the presence of distinctive protein structures described as ‘plaques’ and ‘neurofibrillary tangles’ that were to become hallmarks of the disease that now bears his name.
We now know that Alzheimer’s disease is the leading cause of dementia, contributing to 60-70% of all cases globally. Yet, despite decades of research into characterizing its origin and spread, so much of the disease has remained unknown. For one, though recent breakthroughs in molecular genetics have identified mechanisms by which Alzheimer’s pathology can spread from one brain region to another, the initial stages of the disease pathology, and the direction of its spread across different brain regions, remains ill-defined. The prevailing staging model, used to guide neuroimaging research in humans and rodents, suggests that the accumulation of ‘amyloid’ and ‘phosphorylated tau’ (p-tau) – toxic proteins that constitute the pathological hallmarks of the disease – first appears within a distinct region known as the entorhinal cortex, which plays an important role in mediating learning and memory. However, this model has been challenged by reports of the earlier appearance of Alzheimer’s pathology in a different brain region, the basal forebrain, in which a small group of neurons (called area Ch4) send signals to the entorhinal cortex and are highly sensitive to degeneration in the early stages of Alzheimer’s disease. Still, a third theory points to the possibility that Alzheimer’s pathology in the two regions – entorhinal cortex and basal forebrain – occurs in parallel, with degeneration in both regions taking place simultaneously.
A series of recent publications in Nature Communications and Brain, co-authored by Dr. Taylor Schmitz, PhD from Western University, sought to assess these competing theories of Alzheimer’s degeneration by asking the question: does Alzheimer’s disease pathology spread in a predictive or parallel manner? The importance of this question lies in its potential implications. If degeneration spreads in a parallel manner, this would indicate the presence of two distinct brain regions from which Alzheimer’s pathology first emerges, simultaneously spreading from these regions to the rest of the brain; whereas, if spread occurs in a predictive manner, this could mean that Alzheimer’s pathology initially occurs in a single brain region, and from there begins to spread to other regions, eventually overwhelming the entire brain.
(a) Area Ch4 of the human basal forebrain; neurons from this area have been shown to be highly sensitive to degeneration in the early stages of Alzheimer’s disease. (b) The entorhinal cortex, a region involved in mediating learning and memory. Images obtained from the article Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology published in Nature Communications.
To address this question, the researchers made use of magnetic resonance imaging (MRI) – a technique that uses a magnetic field and radio waves to produce detailed pictures of the brain – to compare the ‘density’ of brain cells in basal forebrain and entorhinal cortex regions of a group of older adults ranging from cognitively normal individuals to those with clinical symptoms of Alzheimer’s disease. Next, a predictive modelling strategy was used to test whether degeneration in one brain region was able to predict later degeneration in the other region.
The studies found a significant decrease in brain cell ‘density’ in both the basal forebrain and entorhinal cortex as the disease progressed, indicating that Alzheimer’s degeneration indeed occurs in both brain regions. However, using the predictive modelling system, they revealed that degeneration in the basal forebrain was able to predict eventual degeneration in the entorhinal cortex, whereas the reverse was not the case – entorhinal cortex degeneration, while leading to eventual memory impairment, could not predict subsequent degeneration in the basal forebrain.
Additionally, in cognitively normal individuals in pre-clinical stages of the disease (i.e., before the onset of clinical symptoms), the researchers showed that a marked increase in ‘amyloid’ and ‘p-tau’ protein accumulation coincided with degeneration in the basal forebrain, but not in the entorhinal cortex, further demonstrating a basal forebrain to entorhinal cortex sequence of spread. Taken together, these results run counter to the prevailing explanation that Alzheimer’s degeneration spreads from the entorhinal cortex to the basal forebrain, or that degeneration in both regions occurs in parallel.
These findings could present critical implications for Alzheimer’s disease treatment. For one, possible Alzheimer’s treatments looking to target specific neurons at early stages of the disease may be more effective if they target neuron populations in the basal forebrain, which may represent some of the earliest cells affected by Alzheimer’s pathology. Such site-directed interventions may be useful for modifying progression of the disease before the onset of cognitive decline.
In addition, the discovery that degeneration of specific brain cells in the basal forebrain could occur in cognitively normal individuals before the onset of clinical symptoms may allow for earlier diagnosis of the disease. While currently available medications do not prevent, stop, or reverse Alzheimer’s disease, they can help lessen the symptoms, such as memory loss and confusion, for a limited time. As an early Alzheimer’s diagnosis has the potential to provide millions of patients with a better chance of benefiting from treatment, this could mean that for individuals like Alice, treatment could occur long before the symptoms that overwhelm her mind during her afternoon jog begin to emerge. Early diagnosis may also prompt important lifestyle changes to be adopted, which could help preserve cognition in these patients.
In one scene, Alice, having been diagnosed and made her condition public, delivers a speech at an Alzheimer’s conference to a roomful of listeners. When she fumbles and drops her papers on the floor, the room is aghast with empathy. In this moment of tension and despair, it is as though all fate is settled; the slide from the intelligent linguistics professor to the crushed and fragile shadow of her former self is complete. And yet, when Alice kneels to collect her papers from the floor and continues her speech, we feel resilience persevere in the face of defeat. It is as though a tremulous hope pokes through to provide us with a small but indispensable comfort.