Recent guidelines are set to assist medical professionals in recognizing a prevalent memory-loss condition that is frequently misdiagnosed as Alzheimer’s disease in older individuals. This month, diagnostic criteria for limbic-predominant age-related TDP-43 encephalopathy (LATE) were published in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, authored by an international team led by researchers from Penn Medicine. These guidelines represent a significant initial move toward enhancing clinical trials and treatment options for this lesser-known yet common form of memory impairment.
“Establishing clear diagnostic guidelines for different diseases not only provides essential information to patients and their families regarding their prognosis but also aids in determining appropriate treatment options,” stated David Wolk, MD, co-director of the Penn Memory Center and the lead author of the study. “With therapies aimed at reducing amyloid levels associated with Alzheimer’s disease becoming available, it is crucial to ascertain whether a patient possesses these proteins in their brain and would benefit from such treatments. Conversely, if they do not, it becomes essential to diagnose their actual condition, which could be LATE.”
A common yet underrecognized condition
LATE is a newly identified form of dementia that primarily affects individuals over the age of 80, leading to memory loss. Due to this predominant symptom, LATE is often mistakenly identified as Alzheimer’s disease (AD). However, these two conditions stem from different causes; while AD is linked to the accumulation of beta-amyloid and tau proteins in the brain, LATE is characterized by the buildup of TDP-43 protein. This protein was first discovered at Penn Medicine by researchers, including Breakthrough Prize recipient Virginia Lee.
Autopsy studies have demonstrated that LATE is notably common among those aged 80 and older, with TDP-43 accumulation found in 40 percent of individuals in this age bracket. Furthermore, among patients diagnosed with AD, 55 percent exhibited signs of LATE as well. Unlike those with only AD, individuals with solely LATE experience different cognitive issues, primarily affecting memory, whereas AD impacts a broader range of cognitive functions such as executive functioning, planning, language, and visuospatial skills. Typically, those with LATE experience a slower decline in symptoms compared to AD, but the presence of both LATE and AD may lead to a more rapid progression of symptoms. Research indicates that patients suffering from only LATE often have a more stable condition and longer lifespans compared to those with only AD or with both conditions combined.
Currently, there is no available test for detecting TDP-43, and its identification can only be validated through brain autopsy post-mortem. The recent report outlines criteria for diagnosing LATE alone or in conjunction with AD using cognitive assessments, MRI scans to check for hippocampal atrophy, and evaluations for beta-amyloid and tau within cerebrospinal fluid and through PET imaging of the brain.
These diagnostic criteria also assist in distinguishing LATE from other dementia types such as frontotemporal lobar degeneration (FTLD)—which also involves TDP-43 buildup—and dementia with Lewy bodies, which is characterized by misfolded protein accumulation in the brain. In FTLD, individuals typically encounter deficits in executive function and language instead of memory loss, which is detectable through cognitive evaluations. Moreover, they generally do not show atrophy in the hippocampus or medial temporal lobe. Those with dementia featuring Lewy bodies also face impaired motor abilities, along with various cognitive deficits.
“Accurate diagnosis of LATE in its various forms lays groundwork for significant ongoing research,” Wolk explained. “With this diagnosis, we can initiate clinical trials for drugs targeting TDP-43. Moreover, we can assess the effectiveness of current treatments on patients with both LATE and AD, in addition to potentially developing and testing new therapies aimed at both disorders. This sets a foundational step in that direction.”
This study received funding from the National Institutes of Health (P30AG072979, R01 AG064233, P01 AG066597, R01AG034374, R01AG080667, K23AG062750, P30 AG066509).
