Cognitive deficits in older adults attributable to Alzheimer's disease (AD) pathology are featured early on by hippocampal impairment. Among these individuals, deterioration in spatial navigation, manifested by poor hippocampus-dependent allocentric navigation, may occur well before the clinical onset of dementia. Our aim was to determine whether allocentric spatial navigation impairment would be proportional to right hippocampal volume loss irrespective of general brain atrophy. We also contrasted the respective spatial navigation scores of the real-space human Morris water maze with its corresponding 2D computer version. We included 42 cognitively impaired patients with either amnestic mild cognitive impairment (n = 23) or mild and moderate AD (n = 19), and 14 cognitively intact older controls. All participants underwent 1.5T MRI brain scanning with subsequent automatic measurement of the total brain and hippocampal (right and left) volumes. Allocentric spatial navigation was tested in the real-space version of the human Morris water maze and in its corresponding computer version. Participants used two navigational cues to locate an invisible goal independent of the start position. We found that smaller right hippocampal volume was associated with poorer navigation performance in both the real-space (β = −0.62, P < 0.001) and virtual (β = −0.43, P = 0.026) versions, controlling for demographic variables, total brain and left hippocampal volumes. In subsequent analyses, the results were significant in cognitively impaired (P ≤ 0.05) but not in cognitively healthy (P > 0.59) subjects. The respective real-space and virtual scores strongly correlated with each other. Our findings indicate that the right hippocampus plays a critical role in allocentric navigation, particularly when cognitive impairment is present.P ersons with Alzheimer's disease (AD) (1, 2) and with amnestic mild cognitive impairment (MCI) (3), who are known to be at higher risk for developing AD, experience difficulties with spatial navigation. Based on animal research, two basic navigation types were distinguished (4). Egocentric navigation is route or body centered and is dependent mainly on parietal cortices and caudate nucleus (4-8). The more flexible and complex allocentric type is world centered and it is dependent mainly on the hippocampus (5, 9). In humans, medial temporal lobe function is highly lateralized with the right hippocampus predominantly associated with spatial navigation and topographical memory (10). Recent research has underscored the importance of the hippocampus for spatial navigation in cognitively impaired subjects (11,12). For example, a case study of a patient with early AD (13) reported a distinct navigation deficit indicative of hippocampal atrophy. However, structural background of the allocentric navigation impairment has not yet been entirely elucidated, particularly in the real-space environment.The navigation disability in AD and MCI patients has been found to involve selective impairment of spatial cognition as...

ObjectiveIn a multi-center cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that amyloid-β and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.MethodsWe included 417 DLB patients (45–93 years, 31% women). Positivity on amyloid-β (A+) and tau (T+) biomarkers was determined by cerebrospinal fluid amyloid-β 1-42 and phosphorylated tau in the European cohort, and Pittsburgh compound-B and AV-1451 positron emission tomography in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, A+T+.ResultsA-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age and A+ and T+ increased with age both in women and men. A+ increased more in APOE ε4 carriers with age than in non-carriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable rapid eye movement sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.ConclusionsAlzheimer's disease pathologic changes are common in DLB and are associated with the clinical phenotype. Amyloid-β is associated with cognitive impairment and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.Classification of evidenceThis study provides Class II evidence that in patients with probable DLB, amyloid-β is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.