Douglas Galasko, United States of America
University of California, San Diego NeurosciencesAuthor Of 1 Presentation
AGE-OF-ONSET-RELATED COGNITIVE VARIABILITY IN ALZHEIMER’S DISEASE (AD) IS MEDIATED BY THE DISTRIBUTION OF TANGLE PATHOLOGY RATHER THAN CONCOMITANT NON-AD PATHOLOGY
Abstract
Aims
Alzheimer’s disease (AD) is characterized by age-of-onset-related heterogeneity in initial patterns of cognitive deficits with non-memory-predominant presentations more likely with earlier onset. We sought to determine if this heterogeneity is related to differences in concomitant pathologies (Lewy Bodies, TDP-43 inclusions, vascular) or distributions of neurofibrillary tangle pathology across limbic and cortical regions.
Methods
Baseline neuropsychological testing from 121 cases with autopsy-confirmed, severe AD pathology (Braak V-VI) was examined. Estimated age of onset ranged from 50 to 87. Testing occurred on average 4.2±2.7 years after onset and 6.4±3.1 years before death. Memory, Language, Executive, and Visuospatial domain scores were generated. Concomitant Lewy body, TDP-43, and vascular pathology was staged, and the ratio of Midfrontal Cortex/Hippocampal CA1 tangles (“MF/HP tangle ratio”) was calculated as a proxy for tangle distribution.
Results
The MF/HP tangle ratio decreased with increasing age of onset (p = 1.5x10-5) consistent with a more neocortical tangle distribution with earlier onset. TDP-43 (p=.02) and vascular (p=0.003), but not Lewy body pathology, increased with age of onset, as did Executive (p=.02) and Visuospatial (p=2.2x10-4), but not Memory or Language scores. Mediation analyses showed that the relationship between age of onset and Executive scores was mediated by the tangle ratio (p=0.008), but not Lewy body, TDP-43, or vascular pathology. The relationship with Visuospatial scores was not mediated by any of the 4 pathology measures.
Conclusions
Age-of-onset-related variability in initial cognitive deficit profiles is mediated by age-related differences in the distribution of tangle pathology in AD and not by concomitant Lewy body, TDP-43, or vascular pathology.