Abstract
IntroductionApolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid-β (Aβ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of Aβ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology. MethodsWe analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without Aβ copathology. ResultsThe ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of Aβ pathology. DiscussionWe conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD-tau pathology, independent of Aβ.
Highlights
Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer’s disease (AD), with ApoE4 thought to enhance and accelerate amyloid-b (Ab) pathology
We found that the ApoE4 genotype lowered age at clinical onset in patients with dementia and tau pathology, and was a strong effect once the confounding effects of amyloid b pathology were taken into account
ApoE4 carrier status increased the likelihood of Ab pathology, both in cases with tau and TDP43 pathology: for the tau1 ApoE41 patients with frontotemporal dementia (FTD) and available neuropathology data, 15 of 21 (71.4%) had Ab copathology compared with 11/42 (26.2%) ApoE42 tau1 cases; for the TDP1 ApoE41 FTD cases, 8/13 (61.5%) had Ab copathology compared with 10/47 (21.3%) of ApoE42 TDP1 cases
Summary
We reviewed the literature searching for “ApoE” and “frontotemporal dementia” or “FTD”, establishing that other than Shi et al (Nature, 2017) little information on the effects of ApoE on primary tauopathies and FTD was available. Shi et al established a primary effect of ApoE4 on tau pathology and neurodegeneration, independent of amyloid b (Ab) pathology
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