Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ε4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ε4 homozygote and an apoE ε3 homozygote. The apoE ε4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ε4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.
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†Yadong Huang and William W. Seeley contributed equally to this work. We thank S. DeArmond for expertise with neuropathological examination, K. Possin for assistance deriving normative data for neuropsychological tests, S. Ordway for editorial review, and J. Carroll for graphics support. Financial Disclosure: None reported. Funding/Support: This work was supported by NIH grants P01 AG022074 (Y.H.), AG023501 (B.L.M. and W.W.S.), the Consortium for Frontotemporal Dementia Research, and the McBean Family Foundation (K.A.V.). Address correspondence to Dr. W. W. Seeley, Memory and Aging Center, University of California, 350 Parnassus Ave., Ste 905, San Francisco, CA 94143-1207, USA. (E-mail: firstname.lastname@example.org).
- Apolipoprotein E
- Frontotemporal dementia
- Motor neuron disease