Title: Neurodegeneration, Synaptic Dysfunction, and Gliosis are Phenotypic of Alzheimer Dementia
Legend: A substantial number of healthy older adults harbor AD pathology, namely beta amyloid plaques and neurofibrillary tangles (some reports suggest the number is as high as 40%), even in the absence of dementia. Why do people with comparable levels of pathology show differences in cognitive function? As shown in Figures A and B, individuals with dementia have greater neurodegeneration (↑NFL) and greater evidence of glial activation (↑ YKL-40) compared to people without dementia. The group of cognitively normal participants with elevated AD pathology (dark blue bars) had qualitatively intermediate levels of NFL and YKL-40, suggesting that they may eventually progress to greater levels of pathology and cognitive decline. Longitudinal follow-up is ongoing to address this question.
Citation: Merluzzi AP, Carlsson CM, Johnson SC, Schindler SE, Asthana S, Blennow K, Zetterberg H, Bendlin BB. (2018). Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia. Neurology, 31;91(5):e436-e443.
Abstract: Objective – To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. Methods – In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3–like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD–mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). Results – In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. Conclusions – These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding
provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.
About the Lab: Bendlin’s lab focuses on brain structure and function in middle and late age, especially in people with increased risk of developing AD due to parental family history, genotype and vascular risk factors. Understanding early brain changes in people who may go on to develop AD is expected to lead to earlier diagnosis, prevention, and the development of new therapies for AD. Her current projects use MRI as a tool to understand the effect of risk factors (parental family history, genotype, metabolic syndrome) on brain blood flow and structure. Additionally, she is funded to examine the relationship between cerebrospinal fluid biomarkers and brain structure to learn more about early mechanisms of brain damage in AD.