Discoveries Made Possible By You - Spring 2021

May 20, 2021

Science Updates, News

Explore some of the studies that used data from research participants in the UW ADRC or the Adult Changes in Thought Study and were made possible in part by funding from the National Institute on Aging. Find more highlighted studies on our Discoveries Made Possible by You page.

Medications and Dementia Risk

Glucose-Dementia Association Is Consistent Over Blood Pressure/Antihypertensive Groups. Zhou J et al. March 2021 / Shelly Gray, Zachary Marcum, Douglas Barthold, Wayne McCormick, Susan McCurry, Eric B. Larson, Paul Crane

High glucose levels in the body are associated with dementia risk in people with and without diabetes. However, little is known about how this association might be affected by high blood pressure (antihypertensive) treatments. Most studies on modifiable dementia risk factors so far have considered each factor in isolation. These researchers wanted to test the hypothesis that hypertension and antihypertensive treatments may modify these links between glucose levels and dementia. They analyzed data generated from the Adult Changes in Thought Study, a population-based longitudinal cohort study of community-dwelling older adults in Seattle, who are enrolled at age 65 and followed to autopsy. These data included glucose measures, diabetes and antihypertensive treatments, and blood pressure data on 3,056 participants, with a mean age of 75.1 years, without diabetes treatment and 480 with diabetes.

The researchers found that higher glucose levels were associated with greater dementia risk among people, both with and without treated diabetes, in line with previous work. However, hypertension and antihypertensive treatments did not appear to affect the association between glucose and dementia risk in the ACT Study. This finding suggests that taking high blood pressure medications may not make a difference in the dementia risk linked to high glucose levels, for older adults. Future studies are still needed to examine this question among midlife adults and to see if there is any variation in results when different types of antihypertensive treatments are tested individually.

If untreated, hypertension is also a cardiovascular contributor to dementia. When hypertension can’t be managed with exercise, stress reduction, and diet, several antihypertensive medicines are available. Another 2021 ACT study suggests that some medicines might be better than others at reducing dementia risk. The findings support that angiotensin II-stimulating medicines are potentially better than angiotensin II-inhibiting medicines for reducing dementia risk.


Genetics and African American Ancestry

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis. Kunkle BW, et al. January 2021 / Eric B. Larson, Paul Crane, Thomas J. Grabowksi, Walter Kukull, Thomas Bird, C. Dirk Keene, Shubhabrata Mukherjee, Elaine Peskind, Gail Jarvik, Wayne McCormick, Susan McCurry, Murray Raskind, Debby Tsuang, Chang-En Yu

In this study, the researchers analyzed genetic data from the Alzheimer Disease Genetics Consortium to compare the DNA sequences from more than 8,000 African Americans, with and without Alzheimer’s disease. The UW ADRC, along with multiple ADRCs, contributes genetic data to this project. The researchers found that the main biological pathways linked to Alzheimer’s risk in African Americans largely overlapped with those in non-Hispanic white individuals, but several disease-associated genetic loci in these pathways differed. A genetic locus (plural: loci) is the specific, fixed position on a chromosome where a particular gene is located. This finding suggests that these pathways, including those responsible for immune response, intracellular transport, nervous system development, and fat metabolism, are not ethnicity-specific and are important in understanding Alzheimer’s disease risk across ethnic groups. But, differences in the genetic loci in these pathways could prove to be additional targets for further investigation into ethnic difference in risk. 

The researchers also found a link between kidney system development and Alzheimer’s risk in African Americans, suggesting another novel disease mechanism to explore. African Americans are three times more likely to experience kidney failure than non-Hispanic whites. They are also more likely to have both dementia and kidney disease. Further research to understand this connection will be important for the prevention and treatment of Alzheimer’s disease for African Americans.

This study provides new insights about the biological pathways and genetic factors that contribute to the development of Alzheimer’s in African Americans, and more importantly shows how the genetic loci can differ significantly between ethnic groups. Understanding these differences is essential to develop effective treatments for African Americans and to understand the biology underlying observed health disparities.


Therapeutic Targets

The association of circulating amylin with β-amyloid in familial Alzheimer's disease. Ly H et al. January 2021 / Angela Hanson

Current therapeutic strategies to treat or prevent dementia are aimed at trying to interrupt the accumulation of amyloid beta protein, a hallmark pathology of Alzheimer’s disease. Another growing approach in the field aims to intervene earlier in the process. One example involves targeting levels of certain proteins circulating in the blood that can interact, or ‘cross-seed,’ with amyloid beta protein and initiate a disease process. Specifically, cross-seeding is a biological event in which a protein can trigger the aggregation of different species of amyloid beta, forming toxic amyloid. Recent data from multiple research teams suggest that one of these potential modifiers of Alzheimer’s pathology is amylin protein, which is a metabolic hormone  that is produced in the pancreas and circulates in the blood.

This study out of the University of Kentucky assessed whether circulating human amylin cross-seeds with amyloid beta early in the course of Alzheimer’s disease. The researchers used brain and spinal fluid samples from individuals affected by familial Alzheimer’s disease, and unaffected controls from the UW ADRC and other centers. In their analysis, the team found evidence for cross-seeding between amylin and amyloid beta in the brains of participants affected by familial Alzheimer’s disease. They also found, in a rat model of human Alzheimer’s, that suppressing amylin protected against Alzheimer’s-associated effects, while intravenous injection of human amylin worsened Alzheimer’s pathology.

These results demonstrate a role of circulating amylin in early Alzheimer’s disease and suggest that restoring the proper physiological balance of amylin may reduce Alzheimer’s pathology. The researchers suggest that development of anti-amylin drugs may improve the lives of familial Alzheimer’s disease mutation carriers and slow the progression of sporadic Alzheimer’s disease. 


Air Pollution and Alzheimer’s Neuropathology

Fine Particulate Matter and Markers of Alzheimer’s Disease Neuropathology at Autopsy in a Community-Based Cohort. Shaffer R et al. February 2021/ Rachel M. Shaffer, Ge Li, C. Dirk Keene, Caitlin S. Latimer, Paul K. Crane, Eric B. Larson, Joel D. Kaufman, Marco Carone, Lianne Sheppard

Air pollution contains solids or liquid droplets so small that they can be inhaled and cause bodily damage. Particles less than 2.5 micrometers in diameter, also known as fine particulate matter (PM2.5), pose risks to health, including brain health. Growing evidence links fine particulate matter exposure to Alzheimer’s disease, possibly through oxidative stress and inflammation. Researchers at the ADRC and Adult Changes in Thought Study (ACT) have published the first evaluation of the association between long term exposure to fine particulate matter and Alzheimer’s disease neuropathologies, using older adult brain autopsy samples.

The researchers leveraged extensive air pollution exposure data to examine their research question. They used a newly developed air pollution exposure prediction model, specifically developed from Puget Sound air monitoring data and study-collected low-cost sensor measurements. This model provided estimates of fine particulate matter exposures at the study participant home residences from 1978 to 2018. They found that 94% of the individuals had experienced 10-year exposures below the EPA national ambient air quality standard, meaning they had relatively low exposure concentrations of fine particulate air pollution. These individuals also mostly self-identified as white and middle class, with relatively low rates of co-occurring health problems.

Researchers analyzed autopsy specimens from 832 deceased participants enrolled in the ACT study. They found a suggestive increase in the odds of having more serious Alzheimer’s pathology, as defined by neuritic plaques, in those participants with relatively higher exposures to fine particulate matter. However, when the researchers looked at other neuropathological markers relevant to Alzheimer’s, such as tau tangles, results were conflicting, rendering the overall study findings inconclusive. 

The researchers suggest that because of the low variation of air pollution levels at the residences, the study may not have had enough statistical power to estimate adverse neurological effects of the low exposures experienced by the cohort. They also suggest that the known risk of Alzheimer’s disease linked to fine particulate matter may be related to mechanisms other than the formation of tau tangles and amyloid plaques. Finally, more advanced statistical methods are needed to untangle these autopsy findings from the well-understood premature death associated with particulate matter exposure.  Going forward, ADRC and ACT researchers aim to enroll and follow individuals from more diverse populations with different risk factor profiles to see whether or not these results can be generalized more broadly. •