By Deborah Borfitz 

July 5, 2022 | A combined analysis of autopsy cohorts in 13 studies across three continents highlights growing appreciation of the heterogeneity of dementia and the critical need for clinical trials to tease out the underlying molecular mechanisms. The “inconvenient truth” is that the brain is the most complicated organ in the body and entitled to more than one aging-related disease, according to Pete Nelson, M.D., Ph.D., neuropathologist and R.C. Durr Foundation Chair in Alzheimer's Disease at the University of Kentucky.  

“Grappling with that complexity is a prerequisite to finding therapies that work,” he says. “If you try to treat everything as though it’s disease X, when it is also Y, Z, and PDQ, it is going to be really challenging to treat anything successfully.” 

Of growing interest is LATE—short for limbic-predominant age-related TDP-43 encephalopathy—named only three years ago by consensus of a multidisciplinary international group to describe a condition mimicking Alzheimer’s disease but for its lack of the usual neuropathological hallmarks (accumulation of amyloid-β and tau protein) and onset only after age 80, Nelson says. Alzheimer’ disease, in contrast, tends to strike between 65 and 85 years of age and “level off or even decline in advanced old age.” 

As recently reported in Acta Neuropathologica (DOI: 10.1007/s00401-022-02444-1), LATE is far more prevalent than previously thought and, to complicate matters further, co-occurs as often as not in individuals with late-stage Alzheimer’s disease. Overall, among the 6,200 examined brains of study participants averaging 88.1 years at death, the prevalence of brain changes from LATE was nearly 40%.  

What works for one type of dementia probably would not work for the other, says Nelson. That “almost zero” therapies of any kind exist currently is no coincidence. Progress on dementia lags decades behind cancer, which in the 1990s shifted from one-size-fits-all therapies to pathway-specific treatments targeting the underlying molecular mechanisms that were more effective and less toxic for patients.  

‘Imperfect Correlation’ 

The study was an impressively sized collaboration between 10 Alzheimer’s Disease Research Centers funded by the National Institute on Aging. Cohorts used for the study came from these centers, plus others from United Kingdom, Brazil, Austria, and Finland. 

For the past several decades, labs the world over had all been seeing the same “imperfect correlation” between Alzheimer’s disease pathology and Alzheimer’s symptoms and scratching their heads, Nelson says. By 2019, a critical mass of evidence had emerged to classify the new form of dementia and give it a name. Determining the prevalence of LATE became possible because researchers were now all looking at the dementia using the same language, definitions, thresholds, and criteria.   

Clinical trials in dementia represent the “critical waypoint between going from where we are now to a future where there are therapies,” says Nelson. “This will probably involve peeling off subsets of people that can be targeted by certain mechanism-specific therapies and, to do that, we need to know what the mechanisms are and figure out what the heterogeneity is all about.” 

Nelson says that the dementia research field, unlike oncology, has been inappropriately reluctant to give people imperfect medicines and the clinical trial culture needs to change so people are getting their risk assessed and have options for treatment while they are still asymptomatic. “Once you have symptomatic impairment, it is very challenging to get things rewired back... this is the big public health problem of our time.” 

Approved biomarkers exist that make it possible to distinguish individuals who are more likely to have pure Alzheimer’s, versus a mix of Alzheimer’s and LATE or neither dementia type, he points out. 

Hippocampal Sclerosis Of Aging 

A diagnosis of LATE is effectively an assumption based on individuals’ “screen fail” as candidates for an Alzheimer’s drug, says Nelson. “A lot of people that have a degenerative process in their brain don’t have the Alzheimer’s amyloidosis, which you can detect by biomarkers in blood or CSF [cerebrospinal fluid], or neuroimaging.” 

The world’s first clinical trial for LATE is currently underway at the University of Kentucky, which will provide a small group of people age 75 and up with Alzheimer’s disease “mimics" their only treatment option—Nicorandil, an anti-TDP vasodilatory drug approved in Europe and Asia (but not the U.S.) for heart failure and angina pain. Specifically, the placebo-controlled pilot study will test the safety and efficacy of the drug for “hippocampal sclerosis of aging.” 

The study is based on prior work elucidating a pharmacologically targetable mechanism for this common cause of cognitive decline and dementia. The potassium channel being modulated with Nicorandil appears to make the brain as well as the heart healthier, Nelson says. 

Thanks to the pandemic, the trial was put on hold for several years, says Nelson. Participants began receiving the drug only earlier this year, and their eligibility was based on brain changes seen on neuroimaging.  

Participants will be required to do a clinic visit about every three months for memory and thinking tests and to receive their study drug dose. Treatment will continue for 96 weeks. The study’s principal investigator is Gregory A. Jicha, M.D., Ph.D. 

It will be considerably more difficult to bring the clinical trial option to the larger group of people who have both Alzheimer’s and LATE, Nelson notes. “As of yet we don’t have a definitive biomarker for LATE.”  

Diversity Question 

Achieving a diverse clinical trial cohort is always a big challenge, says Nelson, although recruitment numbers are aligning well with the demographics of Kentucky that include a roughly 15% African American population. In the three-continent study, minorities accounted for about one-sixth (1,000 individuals) of the combined cohort which, on a truly global scale, leave people of color under-represented. 

That said, when dementia studies have been done with autopsy cohorts where the impacts of race and ethnicity are factored in, no differences in brain pathology have been seen between Blacks and Whites, he adds. Differences in incidence—in the U.S., for example, Blacks are nearly twice as likely to develop Alzheimer's and related dementias—can probably be attributed largely to socioeconomic status. 

“In general, at-risk populations have poorer control of diabetes and hypertension... problems that are highly likely to increase the speed and severity of how a given pathology is going to affect the brain.” It makes sense, then, that the higher dementia incidence rate is due to “environmental factors and... echoes of racism that have led people to be more leery of seeking a doctor’s help because doctors weren’t helpful in the past.”  

Cause For Hope 

While it may seem like “kind of a bummer” to think that Alzheimer’s is but one type of dementia-causing disease that can strike with age, embracing the idea of complexity is the best route to discovering useful treatments that can end the suffering, Nelson says. Without a good appreciation of the different underlying diseases, a treatment could do more harm than good—like using an asthma treatment (steroids) to treat pneumonia.  

The encouraging news is that some people live to be 100 with their brain “clear as a bell” without any sign of Alzheimer’s, LATE, or Lewy bodies, he says. “There is hope that we can bend and manipulate the environmental and genetic factors to come to a place where we have really healthy aging. Dementia is not an inevitability of aging but a disease we can prevent... we just need more shots on goal.”