Proteins Predict Signs of Alzheimer’s Disease

Protein indicators of subclinical peripheral heath in plasma were linked with markers of Alzheimer’s disease and neurodegeneration, cross-sectional proteomic analyses showed.

Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with plasma biomarkers of amyloid-beta, phosphorylated tau181 (p-tau181), neurofilament light (NfL, a measure of neuronal injury), and glial fibrillary acidic protein (GFAP, a measure of astrogliosis), even in people without cardiovascular or kidney disease, reported Keenan Walker, PhD, of the National Institute on Aging in Baltimore, and co-authors.

Proteomic indicators of body fat percentage, lean body mass, and visceral fat also were tied to p-tau181, NfL, and GFAP, Walker and colleagues wrote in the Annals of Neurology.

The study aimed to assess the possible effects of health traits, disease, and disease risk on blood-based biomarkers of Alzheimer’s and neurodegeneration, Walker noted.

“Plasma biomarkers of Alzheimer’s disease and neurodegeneration are now commonly used in research and increasingly used in the clinical setting, so it is important to understand how person-specific factors can affect these biomarkers,” he told MedPage Today.

Previous work by Walker and colleagues identified 38 proteins significantly associated with incident dementia within 5 years, with two proteins (SVEP1 and angiostatin) causally implicated in Alzheimer’s disease through Mendelian randomization.

In the current study, Walker and colleagues looked at 14 protein-based health indicators derived from plasma samples, plus plasma and PET measures of Alzheimer’s and neurodegeneration, in the Baltimore Longitudinal Study of Aging (BLSA). They also used data from the Atherosclerosis Risk in Communities (ARIC) study to see whether proteomic indicators that were correlated with Alzheimer’s biomarkers also predicted 25-year dementia risk.

A total of 706 BLSA participants were included in the primary analyses; all were cognitively unimpaired at the time of biomarker measurement. Mean age was about 68, 54% were women, and 67% were white.

Overall, BLSA participants had lower prevalence of heart ischemic disease and chronic kidney disease than Americans 65 and older, the researchers noted. The prevalence of heart failure was on par with the general population.

Higher kidney disease, secondary (but not primary) cardiovascular disease risk, and heart failure prognosis risk (preserved and reduced ejection fraction) were consistently linked to levels of plasma biomarkers indicative of greater Alzheimer’s pathology and neurodegenerative burden, after adjusting for age, sex, race, and education.

“Notably, the kidney disease risk associations and cardiovascular disease risk and heart failure prognosis associations remained largely similar when participants with evidence of kidney dysfunction (estimated glomerular filtration rate under 60) and cardiovascular disease (i.e., heart ischemic disease, congestive heart failure, or stroke) were excluded,” Walker and co-authors wrote.

Higher body fat percentage and visceral fat were associated with lower p-tau181, NfL, and GFAP. Greater lean body mass was associated with higher p-tau181 and lower NfL and GFAP. Among participants with positive amyloid PET, poor heart failure prognosis was positively correlated with higher cortical amyloid beta, after adjusting for demographics.

In the ARIC study of 11,285 people, a total of 2,063 (18.3%) had incident dementia over a median follow-up of 21.1 years. Increased dementia risk was associated with higher primary and secondary cardiovascular risk, as well as poorer heart failure prognosis, after adjustments for age, sex, race, study site, education, and APOE4 status.

“Importantly, these associations remained similar after excluding participants with coronary heart disease, stroke, and suspected heart failure (based on the use of heart failure medications) at the time of protein measurement,” Walker and co-authors observed.

The study had several limitations, the researchers acknowledged. The proteomic health indicators were constructed and validated in cohorts that consisted primarily of white participants, and it’s unclear whether they were optimal for the sizable subset of non-white participants in BLSA and ARIC. Some null results in the PET analyses were due to small sample sizes.

In addition, the primary analyses were cross-sectional and could not shed light on how changing peripheral health might influence Alzheimer’s biomarker progression.

Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study was supported by the intramural research program of the National Institute on Aging.

Walker reported no conflicts of interest. Some co-authors are employees of SomaLogic, which developed the protein-based health indicators used in the study and has a commercial interest in the results.

Primary Source

Annals of Neurology

Source Reference: Dark HE, et al “Proteomic indicators of health predict Alzheimer’s disease biomarker levels and dementia risk” Ann Neurol 2023; DOI: 10.1002/ana.26817.

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