BACKGROUND

The apolipoprotein E (, gene; apoE, protein) ε4 allele is the most common identified genetic risk factor for typical late-onset sporadic Alzheimer's disease (AD). Each ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, ε3.

METHODS

We have employed hyperspectral fluorescence imaging with an amyloidspecific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either ε3 or ε4.

RESULTS

As expected ε4/ε4 tissues had significantly larger load of CAA than ε3/ε3. isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in ε3/ε3 tissue had small spherical cores and large corona while amyloid plaques in ε4/ε4 tissues had large irregular and multilobulated plaques with relatively smaller corona. Despite the different morphologies of their cores, the p-FTAA stained ε3/ε3 amyloid plaque cores had spectral properties identical to those of ε4/ε4 plaque cores.

CONCLUSIONS

These data support the hypothesis that one mechanism by which the ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in brain. ε4 is associated with a higher density of amyloid plaques (as compared to ε3). We speculate that multilobulated -associated plaques arise from multiple initiation foci that coalesce as the plaques grow.