Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia.

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-amyloid (Aβ): those with low p-tau/Aβ and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ 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/Aβ and Aβ/Aβ 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.