The NLRP3 inflammasome is a multiprotein complex involved with the innate immune system and activates procaspase-1, which in turn induces production of proinflammatory cytokines IL-1β and IL-18. 13, 14 Other approaches attempt to reduce microglial cytokine production.
#TRANSLATE PRO CODEM AD BIBERI TRIAL#
For example, GC021109, which was shown to be safe in a phase 1 trial of patients with AD, promotes microglial phagocytosis by binding to the microglial P2Y6 receptor. It is worth emphasizing a few recent efforts that target specific aspects of inflammation. 12 Currently, there are 12 ongoing clinical trials testing anti-inflammatory interventions ( table 1), 7 of which are repurposed drugs (e.g., antiviral, antibiotic, and rheumatoid arthritis medications) and 1 is a biologic (plasma). 11 However, randomized clinical trials of broad-spectrum anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (e.g., naproxen, aspirin, celecoxib) and others (e.g., prednisone, statins, rosiglitazone) have thus far failed to improve cognitive outcomes in patients with AD. 8 Furthermore, in middle-aged and older adults, higher levels of systemic inflammatory markers (e.g., C-reactive protein, interleukin –6, fibrinogen) are associated with cortical thinning, 9 lower and greater declines in regional cerebral blood flow, 10 and poorer cognitive functions, including executive function and learning and memory. Inflammaging refers to the low-grade, chronic, systemic inflammation associated with aging in the absence of overt infection and is a significant risk factor for morbidity and mortality in the elderly. 7īecause the mechanisms underlying AD and related dementias are complex and multifactorial, greater exploration of targets beyond these 2 pathologic markers is warranted. 6 Therapeutic attempts to remove or decrease the production of Aβ have appeared promising in preclinical and early-phase trials, but have been largely unsuccessful in altering the progression of AD in later-phase clinical trials. Of phase 3 trials, 52% (13/25) are pursuing these targets (12 targeting amyloid and 1 targeting tau). The current drug development pipeline strongly reflects focus on these 2 major pathologic proteins, with 32.5% of the currently ongoing 126 AD clinical trials targeting either Aβ (30/126, 23.8%) or tau (11/126, 8.7%). 5 Clearly, pathologic and clinical findings indicate that sporadic AD and related dementias are age-related diseases.Īlthough Aβ plaques and neurofibrillary tangles are pathologic markers of AD, it is not known if these pathologies represent valid drug targets or if these targets alone are sufficient to treat AD. 4 Medial temporal tauopathy also begins in middle age and overt cognitive impairment coincides with increased neurofibrillary tangle burden. While Aβ can be detected in early adulthood even in cognitively healthy people, elevated amyloidosis begins in the 6th decade of life and increases linearly into old age. The accumulation of plaques and tangles occurs over many decades, in association with aging. Pathologic hallmarks of AD include senile plaques comprising β-amyloid (Aβ) proteins along with many other misfolded proteins and neurofibrillary tangles formed by hyperphosphorylated tau protein aggregates. An increased incorporation of extensive knowledge regarding biological gerontology into research on AD would likely increase our productivity in developing new drugs for AD. Processes that are altered with aging that have been implicated in AD include inflammation, impaired autophagy, mitochondrial dysfunction, vascular problems, epigenetic changes, and synaptic loss ( figure). The leading risk factor for sporadic Alzheimer disease (AD) is also aging. Thus, targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases. 1 Intriguingly, these 7 processes are highly intertwined with one another.
3 The trans-NIH Geroscience Interest Group Summit discussed 7 processes that contribute to biological aging: macromolecular damage, epigenetic changes, inflammation, adaptation to stress, and impairments in proteostasis, stem cell regeneration, and metabolism.
Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases. 1 In fact, morbidity rates increase steadily to middle age, then increase at a much steeper rate such that it is twice as high in people over 80 compared to 60- to 64-year-olds, a phenomenon related to the Gompertz curve. The increase in lifespan, however, has been accompanied by an increase in age-related chronic diseases, including type 2 diabetes mellitus, cardiovascular disease, cancer, osteoporosis, and neurodegenerative diseases. Advances in medicine, public health, and education have resulted in increased human lifespan, and the elderly population has grown dramatically worldwide.
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