In medicine, often the simplest diagnosis is the right one. One of the notable exceptions to that rule, however, is when it comes to conditions that affect our brains as we age.
Earlier this month, a research team led by scientists at the University of Kentucky gave a name to yet another condition that causes dementia. They call it LATE, or limbic-predominant age-related TDP-43 encephalopathy. LATE can often be confused for Alzheimer’s disease. It also causes memory loss, but its symptoms tend to progress slower than Alzheimer’s, and it only shows up in adults over 80 years old. The pathology that causes LATE is completely different than what causes other forms of dementia, though. Rather than buildups of misshapen amyloid plaques and clumps of tau (proteins that appear normally in brains), as is characteristic with Alzheimer’s disease, LATE results in misshapen proteins called TDP-43 in three regions of the brain: the amygdala, hippocampus, and middle frontal gyrus. It’s still not clear what causes TDP-43 to clump up outside of cells’ nuclei, where it’s normally found in healthy people.
According to the team’s research, described in the journal Brain last month, estimates from autopsy studies suggest that LATE may occur in as many as 25% of adults over age 80. And it may be detracting from attempts to develop treatments for other conditions, like Alzheimer’s disease: Although it appears the progression of LATE is relatively slow, when patients have both LATE and Alzheimer’s disease, they deteriorate much faster. “It’s additive,” explained Peter Nelson, a neuropathologist at the University of Kentucky and lead author of the paper.
By reaching a consensus on what LATE actually is, scientists can start working on identifying biomarkers for the disease, and eventually potential treatments. Perhaps more importantly, it means they can better discern which patients may be suited for clinical trials for other types of dementia. It’s likely that part of the reason so many Alzheimer’s clinical trials have failed is because some participants also had LATE.
LATE is yet another unique type of deterioration that causes dementia. Dementia is any condition that impairs a person’s cognitive functions—memory, behavior, decision-making—to the point that it interferes with everyday life. Over the years, scientists have learned that there are several different causes of dementia, most of which are the result of an abnormal buildup of deformed proteins. Although symptom-wise dementia may look similar among patients, there could be totally different root causes.
|Dementia type||Typical age of onset||Notable symptoms||Pathology|
|Alzheimer’s disease||65 +||Memory loss, followed by more general cognitive decline, like difficulty concentrating or remembering directions.||Buildups of plaque made of amyloid beta and tangles of tau.|
|LATE (limbic-predominant age-related TDP-43 encephalopathy)||80 +||Memory loss, but with a slower progression. Often makes memory symptoms of AD worse.||Clumps of protein called TDP-43.|
|PART (primary age-related tauopathy)||80 +||Memory loss, slower deterioration than LATE.||Tangles of tau similar to those in Alzheimer’s disease, but no amyloid plaques.|
|Vascular dementia||50 +||Varies; inability to form new memories, disorientation, difficulty reasoning and impaired judgment. Sometimes vision loss or trouble speaking.||Tiny blockages of blood to brain cells and microstrokes throughout the brain.|
|Lewy Body dementia||varies||Difficulty with motor control as well as memory loss and general cognitive decline. Parkinson’s is a form of Lewy Body dementia.||Misshapen alpha-synuclein proteins.|
|ARTAG (aging-related tau astrogliopathy)||80 +||More data needed.||Misshapen tau on and around brain cells called astroglial cells.|
|Fronto temporal dementia||45 to 65||Behavior problems, such as impulse control.||Degradation of the front of the brain (multiple causes).|
To complicate the problem further, people often suffer from multiple conditions that lead to dementia. In 2018, researchers from Rush University in Illinois published work suggesting that out of a cohort of over 1,000 participants who had died of dementia, as many as 78% had two different kinds. Fifty-eight percent of participants had three kinds of dementia, and about a third had four or more. Although Alzheimer’s disease occurred in about two thirds of participants, only 9% of them had only the amyloid plaques and tau tangles associated with the condition.
As long as treatments for dementia can’t target specific causes, they’ll likely continue to fail.
“The aged brain,” says Nelson, “is the most complicated thing in the world.”