Early Alzheimer’s disease (AD) biomarkers’ start showing up during midlife, whereas late-life measures of AD, such as neuronal injury and astrogliosis biomarkers, are all associated with manifest dementia, according to new research from a team that looked at blood samples from over 1,500 people in both mid- and later-life. Neurofilament light (NNfL) had the strongest association with later in life actual dementia.
Their article was published in JAMA, July 28. The lead author is Yifei Lu, Gillings School of Global Public Health, University of North Carolina (UNC) at Chapel Hill.
As new drugs are introduced and in development, AD is increasingly becoming a treatable condition. Management includes early diagnosis with molecular confirmation and disease-modifying treatments initiated early in the disease course. Plasma biomarkers are being investigated for identifying AD neuropathology and neurodegeneration. These steps forward in Alzheimer’s disease were in part possible because of advances in the detection of amyloid and tau proteins. But detecting these markers required PET, which is impractical. New markers are being explored.
This study looked at 1525 participants from the U.S.-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993–1995, mean age 58.3 years) and late life (2011–2013, mean age 76.0 years; followed up to 2016–2019, mean age 80.7 years). They measured levels of plasma biomarker (amyloid-β 42 to amyloid-β 40 ratio, phosphorylated tau, NfL, and glial fibrillary acid protein.)
Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time.
The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011–2013 and had biomarker measurements in 1993–1995 and 2011–2013.
Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), NfL, and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform.
Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance.
The population was diverse. Among 1525 participants, 914 (59.9%) were women, and 394 (25.8%) were Black. A total of 252 participants (16.5%) developed dementia.
The data revealed decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a faster NfL increase.
Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia. All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association.
Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. According to this study, AD-specific biomarkers’ association with dementia starts in midlife and late-life measures of AD, neuronal injury, and astrogliosis biomarkers are associated with dementia.
