P1‐492: selective vulnerability of the cholinergic system in alzheimer's disease subtypes

Patterns of neurofibrillary tangle density and distribution in cortical and limbic regions reveals distinct neuropathologic subtypes of Alzheimer's disease (AD) (Murray 2011). Further investigation into hippocampal sparing (HpSp), typical, and limbic predominant AD subtypes demonstrated striking differences in demographics and clinical progression. Little is known, however, about possible differences in the major source of corticolimbic innervation, the nucleus basalis of Meynert (nbM). Given the importance of the nbM and potential symptomatic benefit of acetylcholinesterase inhibitor (AChEi) therapy, we sought to investigate 1) selective vulnerability of the nbM and 2) clinical benefit of AChEi on clinical progression across AD subtypes. The FLorida Autopsied Multi-Ethnic (FLAME) cohort was investigated in this study. Neurofibrillary tangle counts were assessed in the nbM with thioflavin-S florescent microscopy. Histologic sections including the nbM were digitally scanned and neuronal density was analyzed using a custom-designed macro using Aperio systems. We assessed 94 cases of HpSp AD, 601 of typical AD, and 114 of limbic predominant AD, as well as 64 non-demented normals. Available medical records were reviewed and response to AChEI treatment was assessed in a subset of 407 cases and controls using the Mini Mental State Examination. Neuronal loss and density of neurofibrillary tangles in the nbM was greatest in HpSp AD (Figure 1), followed by typical and limbic predominant AD (p<0.001). Similar to previous findings, HpSp AD cases had the lowest frequency of coexisting Lewy body disease (p=0.003), youngest age of onset (p<0.001), and highest frequency of an atypical (non-memory) presentation (p<0.001). The treated HpSp AD (-4.9 points/year) and typical AD groups (-1.1 points/year) showed a slower rate of cognitive decline compared to the untreated HpSp (-7.1 points/year) and typical cases (-1.6), although not significant (p=0.141 and p=0.245, respectively). Limbic predominant did not show a difference (p=0.901).