O2‐04‐03: ApoE genotype and amyloid beta effects on cognition are mediated by cell injury (tau) and death (progressive atrophy)
Year: 2009
Type: article
Abstract: The amyloid hypothesis suggests a primary role for Aβ, although clinical symptoms are most closely associated with neurofibrillary formation and neuronal injury and loss. We hypothesized that CSF tau would therefore mediate the effect of CSF Aβ on cognitive performance (Figure). 313 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for whom baseline CSF, repeated MRI and repeated Cognitive measures were evaluated. Subjects included 70 AD, 152, MCI and 91 Cognitively normal individuals mean age 74.8 + 7.0 years. Baseline brain and hippocampal volumes were calculated as well as yearly rates of both measures using a fluid flow deformation method to determine jacobian determinant expansion or contraction for each image voxel. Cognitive measures included 1-year change in delayed story recall and ADAS-Cog. Multiple regression analysis was used to systematically test the effects of CSF Aβ, CSF Tau, baseline and change in brain volume on change in cognition at 1 year. Significant associations were found between the rate of change of cognitive measures and ApoE4 genotype, CSF Aβ, CSF Tau, baseline and rate of whole brain atrophy adjusting for age, education and gender (see table). The impact of CSF Aβ remained significantly associated with change in cognitive measures in a multiple regression model that included both CSF Aβ and ApoE genotype (p <0.0001). CSF Tau was also significantly associated with change in delayed story recall (p=0.0002) and ADAS-Cog (p<0.0001) when added to the model. In a model predicting change in ADAS-Cog which included baseline and change in whole brain volume as well as CSF Tau and Aβ, CSF Tau (p<0.0002), baseline, longitudinal brain atrophy (p<0.0001), but not CSF Aβ were significantly associated with change in ADAS-Cog. Conversely, in a model predicting change in delayed story recall, CSF Aβ (p < 0.0001), CSF Tau (p=0.013), baseline hippocampus (p < 0.0001), change in hippocampal (p =0.016) and brain volume (p<0.0011) were each significantly associated with rate of change in delayed story recall. CSF Aβ has both direct and mediated effects on specific cognitive domains. Reductions in both CSF Aβ and CSF tau, therefore, should be considered good markers of therapeutic efficacy in AD clinical trials.
Source: Alzheimer s & Dementia
Institution: University of California, Davis
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2054060353