Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype

Abstract

Background: The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood.

Objective: To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes.

Methods: Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using alpha-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions.

Results: The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP.

Conclusion: These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.

Figure

Frequency of Lewy body pathology–positive cases by region in PSEN 1 and PSEN 2 mutation-associated dementia cases. Asterisks indicate P≤.05, χ² test; CG, cingulate gyrus; SN, substantia nigra.