Abstract
Background: Higher age comes with a multitude of changes in the brain, but the role of different neuropathological processes in cognitively normal older adults is far from fully understood. A substantial number of cognitively normal older adults show biomarker evidence of brain pathologies often associated with Alzheimer’s disease (AD), but the implications are not fully established. Furthermore, cognitively normal older adults often show hippocampal atrophy and memory decline, which are hallmarks of AD dementia. Older age is also a risk factor for delirium, a condition characterized by an acute disturbance in attention, awareness, and cognition. Delirium has epidemiologically been strongly linked to dementia, however the neuropathological processes underlying this relationship are not understood.
Aims: The overall aim was to increase knowledge about the role of different neuropathological processes in delirium and in cognitively normal older adults using AD-associated cerebrospinal fluid (CSF) biomarkers reflecting core AD pathology (Aβ42 reflecting Aβ deposition, T-tau reflecting neurodegeneration, P-tau reflecting tauopathy) and novel biomarkers (NFL reflecting axonal damage, YKL-40 reflecting neuroinflammation, and FABP3 reflecting neuronal damage). More specifically, we wanted to assess relationships between biomarkers, test whether subgroups of individuals with similar biomarker profiles could be identified using clustering analyses, and examine the relationship between biomarkers and longitudinal hippocampal atrophy and relationships between biomarker-based subgroups and longitudinal hippocampal atrophy and memory change, respectively, in cognitively normal older adults. We also wanted to examine whether the core AD biomarkers are related to delirium.
Methods: CSF from cognitively normal older adults (n=99) was assessed for CSF Aβ42, Ttau, P-tau, NFL, YKL-40, and FABP3, and CSF from hip fracture patients (n=129) was assessed for CSF Aβ42, T-tau, and P-tau. Delirium was assessed pre- and postoperatively in hip fracture patients, and the diagnosis of dementia at admission was based upon clinical consensus. Hippocampal volume and memory in cognitively normal adults was assessed across multiple follow-up examinations over up to 6 years.
Main results: The novel biomarkers NFL, YKL-40, and FABP3 were linked to T-tau and Ptau, but not to Aβ42. Concentrations of NFL, YKL-40, and FABP3 differed between at least two biomarker subgroups identified by clustering analyses with a relatively large effect size. High NFL levels predicted higher hippocampal atrophy rate in cognitively normal older adults, independently of core AD biomarkers, and also in subgroups unlikely to have preclinical AD. A clustering-based subgroup characterized by high concentrations of T-tau, P-tau, and FABP3 showed more memory decline than biomarkers groups with less abnormal biomarker levels, whereas biomarker groups based on only Aβ42 and P-tau showed no differences in memory trajectories. The core AD biomarkers (low CSF Aβ42, high CSF T-tau, low Aβ42/T-tau, low Aβ42/P-tau) were significantly associated with delirium in patients without dementia.
Conclusion: We have shown that CSF biomarkers previously associated with AD are also associated with delirium, hippocampal atrophy, and memory decline in individuals without dementia. Our findings suggest that neuronal damage, axonal damage, and neuroinflammation are accompanying tauopathy and neurodegeneration, but not Aβ deposition, in this group. Our results further suggest that it is meaningful to use the three novel biomarkers for characterization of brain states in cognitively normal older adults, and that addition of novel biomarkers improve prediction of memory decline compared to classification based on biomarkers of Aβ deposition and tauopathy only. Moreover, our findings suggest that a high degree of neurodegeneration and tauopathy is associated with more hippocampal atrophy and greater memory decline in cognitively normal adults. Lastly, our findings in the hip fracture cohort suggests that AD pathologies may underlie the interrelationship between delirium and dementia, and raises the question of whether delirium is an early symptom of AD.