Journal Article

Alzheimer’s and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline

Davatzikos, Christos, Moghekar, Abhay R., Resnick, Susan M., Walker, Keenan A., Lewis, Alexandria, An, Yang, Joynes, Cassandra, Duggan, Michael R., Dark, Heather E., Erus, Guray

2024

Overview

Background Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer’s disease (AD) pathology (amyloid-β [Aβ 42/40 ], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOE ε4 status, and plasma amyloid-β status modified these associations. Methods Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. Results Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aβ 42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aβ 42/40 (higher Aβ burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOE ε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aβ burden, as was the association of higher GFAP with memory decline. Conclusions Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Advertising executives / Aged / Aged, 80 and over / Alzheimer Disease - blood / Alzheimer Disease - diagnostic imaging / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - blood / Amyloid beta-protein / Analysis / Apolipoproteins / Atrophy - pathology / Biological markers / Biomarkers - blood / Biomedical and Life Sciences / Biomedicine / Brain / Brain - diagnostic imaging / Brain - pathology / Brain atrophy / Care and treatment / Cognitive decline / Cognitive Dysfunction - blood / Cognitive Dysfunction - pathology / Diagnosis / Female / Geriatric Psychiatry / Geriatrics/Gerontology / Glial Fibrillary Acidic Protein - blood / Health aspects / Humans / Longitudinal Studies / Magnetic Resonance Imaging / Male / Medical research / Medicine, Experimental / Middle Aged / Neurodegenerative Diseases - blood / Neurodegenerative Diseases - diagnostic imaging / Neurodegenerative Diseases - pathology / Neurofilament Proteins - blood / Neurology / Neurons / Neuropsychological Tests / Neurosciences / Peptide Fragments - blood / Plasma biomarkers / tau Proteins - blood / tau Proteins - cerebrospinal fluid