“Clear guidelines to diagnose different diseases not only help inform patients and their families of their prognosis but also help to guide decisions about which treatments to pursue,” said David Wolk, MD, co-director of the Penn Memory Center and first author of the research. “As therapies that clear the amyloid associated with Alzheimer’s disease become available to patients, we need to be able to determine whether a patient actually has these proteins in their brain and will benefit from the treatment. And if they don’t, we need to identify what disease they do have, which can be LATE.”

A prevalent, but not widely known condition

LATE is a newly characterized type of dementia that causes memory loss in individuals generally over 80 years of age. Because the main symptom of LATE is memory loss, it is often incorrectly diagnosed as AD. However, LATE has a different underlying cause than AD; while AD is characterized by buildup of proteins called beta-amyloid and tau on the brain, LATE is caused by a buildup of a different protein, called TDP-43, which was discovered at Penn Medicine by Breakthrough Prize-winning researchers Virginia Lee and colleagues.

Autopsy analysis has revealed that LATE is quite common among adults over 80 years old; TDP-43 buildup associated with LATE was present in 40 percent of adults in that age group. Autopsy of individuals with AD revealed that 55 percent also had LATE. As compared to people with only AD, those with only LATE have different cognitive symptoms. LATE predominantly affects memory, while individuals with AD experience impairment of more wide-ranging roles of cognition, like executive functioning, planning, language and visuospatial function. Individuals with LATE tend to also have a slower progression of symptoms than AD, but when individuals have both LATE and AD, symptoms tend to progress faster. Research suggests that patients with just LATE have a more stable course and live longer than patients with just AD, or patients with both LATE and AD.

Unlike beta-amyloid and tau, there is no test for TDP-43, and its presence on the brain can only be confirmed by brain autopsy after death. In the new report, researchers detail criteria for diagnosing LATE by itself or when it co-occurs with AD, using cognitive evaluations, MRI scans looking for atrophy in the hippocampus, and testing for the presence of beta-amyloid and tau in cerebrospinal fluid and in PET scans of the brain.

These diagnostic criteria also help differentiate LATE from other types of dementia, like frontotemporal lobar degeneration (FTLD), which also involves TDP-43 buildup, or dementia with Lewy bodies, where proteins mis-fold and accumulate on the brain. In FTLD, individuals experience loss of executive function and language rather than memory loss, which can be noted by cognitive evaluation. Additionally, these individuals will not exhibit atrophy of the hippocampus or medial temporal lobe. In dementia with Lewy bodies, individuals experience impaired motor function, in addition to other cognitive impairments.

“Being able to accurately diagnose LATE in both forms sets the stage to engage in further, important research,” Wolk said. “Not only can we use this diagnosis to develop clinical trials for TDP-43 drugs, but we can also investigate the efficacy of existing therapies on individuals with both LATE and AD, and potentially develop and test new therapies that target both diseases. These criteria offer a first step in this direction.”

This research was supported by the National Institutes of Health (P30AG072979, R01 AG064233, P01 AG066597, R01AG034374, R01AG080667, K23AG062750, P30 AG066509).