Readhead B, Klang E, Gisladottir U, Vandromme M, Li L, Quiroz YT, Arboleda-Velasquez JF, Dudley JT, Tatonetti NP, Glicksberg BS, Reiman EM. Heparin treatment is associated with a delayed diagnosis of Alzheimer's dementia in electronic health records from two large United States health systems. Mol Psychiatry. 2024 Oct 8; PubMed.
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University of Texas, Southwestern Medical Center
These results are indeed fascinating. It is important that a small, if statistically significant, effect was observed in two independent cohorts. We determined that heparin (and a heparin mimetic) blocks tau binding to cell-surface HSPG, thereby preventing uptake and seeding (Holmes et al., 2013; Stopschinski et al., 2018, 2020). This implication of HSPG in pathological tau propagation was complemented by studies indicating that ApoE carrying the protective Christchurch mutation appears to bind HSPG with lower affinity than normal. The question is whether the brief exposure to heparin catalogued in the study cohorts could possibly account for a difference in AD onset.
My sense is that the odds are low for two reasons and I think other explanations should be considered. First, heparin exposure is generally fairly brief, typically a matter of weeks around surgery or treatment for a blood clot, e.g., deep vein thrombosis, or cardiovascular problems. The study doesn’t say how long people were exposed, or whether those who had longer exposure had a greater benefit. It also doesn’t specify whether individuals were treated with low molecular weight or more traditional forms of heparin, which could have different effects on tau or ApoE. Perhaps future studies could do this. Second, the amount of heparin that extravasates from the intravascular space, where it is used for anticoagulation, to the brain parenchyma, where it would potentially block ApoE or tau interactions with neurons and glia, is likely very low, as heparin is relatively large and negatively charged, and would not be expected to cross the blood brain barrier to a significant extent.
References:
Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond MI. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3138-47. Epub 2013 Jul 29 PubMed.
Stopschinski BE, Holmes BB, Miller GM, Manon VA, Vaquer-Alicea J, Prueitt WL, Hsieh-Wilson LC, Diamond MI. Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus α-synuclein and β-amyloid aggregates. J Biol Chem. 2018 Jul 6;293(27):10826-10840. Epub 2018 May 11 PubMed.
Stopschinski BE, Thomas TL, Nadji S, Darvish E, Fan L, Holmes BB, Modi AR, Finnell JG, Kashmer OM, Estill-Terpack S, Mirbaha H, Luu HS, Diamond MI. A synthetic heparinoid blocks Tau aggregate cell uptake and amplification. J Biol Chem. 2020 Mar 6;295(10):2974-2983. Epub 2020 Jan 23 PubMed.
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