Changes in Alzheimer’s Pathology Don’t Match Clinical Trends

While recent studies have suggested a decrease in the incidence of clinical dementia in the United States, there does not seem to have been a corresponding reduction in neurodegenerative pathologies, a new study shows. 

The researchers say their results have “important implications in terms of understanding dementia,” and suggest that “any improvements over time in clinical dementia are likely associated with improved resilience to pathology.”

The study was published online February 20 in JAMA Neurology.

Lead author Francine Grodstein, ScD, Rush Alzheimer’s Disease Center, Chicago, Illinois, explained that resilience to Alzheimer’s pathology is characterized by individuals having no clinical symptoms of dementia despite having significant pathology that would be expected to be associated with such symptoms.

“We believe that certain factors can predispose to this resilience to developing dementia, one of the main ones being education — the idea of ‘use it or lose it.’ But resilience could also be affected by other psychological, biological, or behavioral factors such as anxiety,” she added.

“It does not appear likely from our research that changes in pathology completely explain any changes in clinical dementia, and more research to better understand resilience to pathology is really important,” Grodstein told Medscape Medical News

“Our results certainly support the growing appreciation in understanding cognitive resilience as a preventative strategy against dementia,” she said.

Reduction in Cerebrovascular Pathology

The study also found that although most Alzheimer’s pathologies did not seem to change over time, there was a marked reduction in cerebrovascular atherosclerosis pathology.

“Reductions in cerebrovascular pathology are very encouraging and show that we really need to continue to emphasize public health and medical efforts to reduce stroke and stroke risk factors, such as diabetes, obesity, and hypertension,” Grodstein stated.  

“While these reductions could partly contribute to the suggested reductions in clinical dementia being reported, our guess is that this doesn’t completely explain the trend, and cognitive resilience may also be playing a role,” she commented.  

“There has been a lot of interest recently in trying to change Alzheimer’s pathology and so far, at least, it has not been very successful. In parallel, there is also significant interest in cognitive resilience. If we cannot change the pathology, perhaps we can figure out how we might change resilience to that pathology.”

In the study, the authors explain that in recent years, several studies have indicated the incidence of dementia in the US may be declining, but data are not entirely consistent.

However, studies of dementia incidence cannot clearly establish mechanisms by which disease rates may be changing, and to identify risk reduction strategies, characterizing mechanisms is essential, they say.

“Evaluating neuropathology trends provides insight into changes in pathways related to dementia. Additionally, since neuropathology is ubiquitous in aging brains (including those with and without clinical dementia), examining trends in neuropathologies may reflect a wider breadth of disease states than can be observed when focusing on clinical dementia,” they note.   

Grodstein explained that the researchers used data from unique cohorts of individuals who had agreed to be followed throughout their life and also post-mortem, giving unique data on brain pathology over time.

For the current study, the researchers examined trends over time in neuropathologies in the two US cohorts, with autopsy data from 1997-2022 with up to 27 years follow-up. Specifically, they looked for any differences in neuropathologies in 1554 individuals with birth years in four different time periods: 1905-1914; 1915-1919; 1920-1924; and 1925-1930.

Results showed that across year of birth groups, no differences were found in prevalence of pathologic Alzheimer’s diagnosis or in mean levels of global Alzheimer’s pathology.

In contrast, cerebral atherosclerosis and arteriosclerosis were dramatically lower over time; for example, age-standardized prevalence of moderate to severe atherosclerosis ranged from 54% among those born from 1905-1914 to 22% for 1925-1930.

“We looked at several different neurogenerative pathologies and found no evidence that they have been decreasing over time. This is really important information and suggests that changes in pathology are not the reason for any possible change in clinical disease,” Grodstein said. “The inference of that is that there is pathology but there’s also increasing appreciation of resilience to pathology.”

“Since neurodegenerative pathologies appear to be the strongest pathologic determinants of cognition and clinical dementia,” the researchers write, “any possible decrease in dementia over time, including our finding of better cognitive function and small (albeit nonsignificant) decreases in clinical Alzheimer dementia, is likely explained by nondegenerative pathways.

“For example, enhanced resilience to neuropathology over time is plausible. Indeed, several cohorts have reported that controlling for education, a marker of cognitive resilience, attenuates apparent time trends in dementia incidence, providing evidence that changes in cognitive resilience may be an effective path to reducing dementia,” they note.

Other results showed an unexpected increase over time in tau tangle density. Noting that tau pathology appears to be a primary pathologic driver of cognitive decline and dementia, the researchers say that this finding “further supports the likelihood of an increase in resilience to pathology over time.”

On the reduction in cerebrovascular disease observed in the study, the researchers say: “This likely reflects concomitant decreases in clinical vascular morbidity and mortality, which began approximately in the mid-1900s.”

The authors add: “Further, the striking reduction in brain atherosclerosis and arteriolosclerosis highlights the impact on brain aging of nationwide efforts to improve vascular health and the importance of redoubling these efforts since recent data suggest that stroke rates are leveling, possibly due to sustained increases nationally in obesity and type 2 diabetes.”

This work was supported by the National Institute on Aging. Grodstein reports no relevant financial relationships.

JAMA Neurol. Published online February 20, 2023. Abstract

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