Biomarkers in cerebrospinal fluid (CSF) associated with Alzheimer’s disease are detectable in early middle age, and are associated with future amyloid deposits and cognitive decline, according to research published in JAMA Neurology.
It was previously not known how early Alzheimer’s pathologies begin to develop in cognitively normal middle-aged adults. However, the detection of biomarkers in CSF may allow researchers to target asymptomatic individuals in new drug trials to try and prevent future cognitive decline.
Courtney L. Sutphen, of Washington University in St. Louis, and colleagues analyzed data from a cohort of 169 cognitively normal middle-aged volunteers who were enrolled in the Adult Children Study. The cohort underwent CSF collection and longitudinal clinical assessment at three-year intervals between January, 2003 and November, 2013. A subset of 74 volunteers also underwent amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) over the same period. CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).
The researchers found no consistent longitudinal patterns in Aβ40, however longitudinal reductions in Aβ42 were found in some volunteers as early as early middle age (45-54 years). Low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques, especially in volunteers of mid middle age (55-64 years). Total tau, P-tau181, and VILIP-1 dramatically increased in some volunteers during mid and late middle age, while YKL-40 increased consistently throughout middle age. The patterns were more prevalent in volunteers with the APOE4 gentoype and seemed to be linked to future cognitive decline based on the Clinical Dementia Rating.
Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.
While there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001).