Risultati per: Identificata la causa della progressione dell’Alzheimer nel cervello

Stroke, Volume 55, Issue Suppl_1, Page ATP312-ATP312, February 1, 2024. Traumatic brain injury (TBI) afflicts 70 million people worldwide annually and is the 3rd overall risk factor for developing Alzheimer’s disease (AD), behind genetics and aging. In patients with AD, a history of TBI is associated with a 3-4 year earlier onset of cognitive impairment. TBI and AD share many pathologies, including blood brain barrier dysfunction, neuroinflammation, and protein aggregation. Yet, the underlying mechanism of this relationship is not understood, and there are no treatments that protect patients from accelerated AD after TBI. We recently reported that tau, a microtubule binding protein essential for neuronal health, is acetylated after TBI. Acetylation impairs tau binding to microtubules, leading to its mis-localization into the cell soma and pathological aggregation. Acetylated tau is also elevated early in AD, and acetylated tau was significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesize that TBI-induced tau acetylation drives the acceleration of AD. To study this phenomenon, we developed a mouse model of TBI that accelerates AD-like pathology and cognitive impairment in 5xFAD mice, and amyloid-driven AD model. Our unique model of multimodal TBI produces a complex and reproducible brain injury with neurodegeneration and neurobehavioral impairment, beginning with acute axonal degeneration and persisting chronically with blood-brain barrier degradation and nerve cell death. This model of TBI also produces the same systemic metabolic alterations that are reported in TBI patients. TBI causes learning deficits in young 5xFAD mice that are not seen in either sham-injured 5xFAD mice or in wild type littermates subjected to TBI. TBI also accelerates amyloid deposition in 5xFAD mice. We hypothesize that TBI will also worsen blood brain barrier function in 5xFAD mice. Importantly, 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Preliminary data suggests that treatment with the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the enzyme that acetylates tau, reduces acetylated tau and rescues behavior deficits after TBI in 5xFAD mice.

Annals of Internal Medicine, Ahead of Print.

Annals of Internal Medicine, Ahead of Print.

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New England Journal of Medicine, Volume 390, Issue 1, Page 55-62, January 2024.

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In Reply Amyloid-related imaging abnormalities are a common adverse event for individuals with Alzheimer disease receiving amyloid-targeting therapies. In their Letter, Drs Pomara and Imbimbo thoughtfully explore the possibility that APOE-mediated breakdown of the blood-brain barrier could lead to increased concentrations of donanemab in the CSF and thus increase incidence of amyloid-related imaging abnormalities (edema and effusions). This hypothesis is important to consider.

To the Editor The TRAILBLAZER-ALZ 2 trial provided additional evidence that the APOE4 genotype is a risk factor for amyloid-related imaging abnormalities, especially cerebral edema and effusion. These findings are consistent with those from other clinical trials of β-amyloid–targeting monoclonal antibodies in patients with Alzheimer disease. During donanemab treatment, amyloid-related imaging abnormalities of edema/effusion were observed in only 15.7% of APOE ε4 noncarriers but in 22.8% of heterozygous carriers and 40.6% of homozygous APOE ε4 carriers. These neuroimaging abnormalities were mostly asymptomatic and resolved in approximately 10 weeks. In approximately 1.6% of donanemab-treated participants, amyloid-related imaging abnormalities resulted in serious outcomes such as brain bleeding or swelling and even death, which occurred in 3 participants. A JAMA Editorial and other groups have recommended that APOE genotyping be performed to assess risk for amyloid-related imaging abnormalities before initiating treatment with this class of monoclonal antibodies. Among persons diagnosed with Alzheimer disease, up to 60% carry at least 1 APOE ε4 allele and are consequently at increased risk of amyloid-related imaging abnormalities. Thus, it is unclear how determination of the APOE genotype alone will guide donanemab treatment of this large subgroup of patients with Alzheimer disease. In the donanemab trial and in studies with other monoclonal antibodies, APOE ε4 carriers and noncarriers have received the same drug dose regimen. Cerebrospinal fluid (CSF) donanemab drug levels were not reported. Thus, it is unknown whether pharmacokinetic factors, such as higher CSF drug exposure, may have contributed to the higher risk of amyloid-related imaging abnormalities in APOE ε4 carriers. Increased amyloid burden associated with APOE ε4 and a more pronounced immune response have generally been suggested as factors contributing to the increased amyloid-related imaging abnormalities associated with this genotype. However, there is evidence that the APOE ε4 genotype may also be associated with a disruption of the blood-brain barrier. Breakdown of the blood-brain barrier may result in increased drug entry into the central nervous system that could have important safety implications because adverse events are generally dose-dependent. We would be grateful if Dr Sims and colleagues could discuss any data or insights they may have on the possible role of higher CSF donanemab levels in the increased risk for amyloid-related imaging abnormalities associated with the APOE ε4 genotype. If the hypothesized association is confirmed, determination of the APOE ε4 genotype together with emerging biomarkers of blood-brain barrier disruption, such as CSF and plasma-soluble platelet-derived growth factor receptor β, could provide a target for more individualized donanemab dose regimens to minimize the risk of serious amyloid-related imaging abnormalities.

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