Alzheimer’s disease (AD) is the most common type of dementia and typically manifests through a progressive loss of episodic memory and cognitive function, subsequently causing language and visuospatial skills deficiencies, which are often accompanied by behavioral disorders such as apathy, aggressiveness and depression. The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein (P-tau) in the neuronal cytoplasm is a remarkable pathophysiological cause in patients’ brains. Approximately 70% of the risk of developing AD can be attributed to genetics. However, acquired factors such as cerebrovascular diseases, diabetes, hypertension, obesity and dyslipidemia increase the risk of AD development. The aim of the present minireview was to summarize the pathophysiological mechanism and the main risk factors for AD. As a complement, some protective factors associated with a lower risk of disease incidence, such as cognitive reserve, physical activity and diet will also be addressed.

/pdf/alzheimer-s-disease-risk-factors-and-potentially-protective-2ayzkzyww7.pdf

Alzheimer's disease: risk factors and potentially protective measures.

Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer's drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer's diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment. 

/pdf/amyloid-b-based-therapy-for-alzheimers-disease-challenges-28xmf2dn.pdf

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

The relationship between stress and Alzheimer's disease.

Depression as a risk factor for Alzheimer's disease: Genes, steroids, cytokines and neurogenesis - What do we need to know?

Alzheimer’s disease (AD) has emerged as a key comorbidity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The morbidity and mortality of COVID-19 are elevated in AD due to multiple pathological changes in AD patients such as the excessive expression of viral receptor angiotensin converting enzyme 2 and pro-inflammatory molecules, various AD complications including diabetes, lifestyle alterations in AD, and drug-drug interactions. Meanwhile, COVID-19 has also been reported to cause various neurologic symptoms including cognitive impairment that may ultimately result in AD, probably through the invasion of SARS-CoV-2 into the central nervous system, COVID-19-induced inflammation, long-term hospitalization and delirium, and post-COVID-19 syndrome. In addition, the COVID-19 crisis also worsens behavioral symptoms in uninfected AD patients and poses new challenges for AD prevention. In this review, we first introduce the symptoms and pathogenesis of COVID-19 and AD. Next, we provide a comprehensive discussion on the aggravating effects of AD on COVID-19 and the underlying mechanisms from molecular to social levels. We also highlight the influence of COVID-19 on cognitive function, and propose possible routes of viral invasion into the brain and potential mechanisms underlying the COVID-19-induced cognitive impairment. Last, we summarize the negative impacts of COVID-19 pandemic on uninfected AD patients and dementia prevention.

/pdf/covid-19-and-alzheimer-s-disease-how-one-crisis-worsens-the-2sydnrxx3j.pdf

COVID-19 and Alzheimer's disease: how one crisis worsens the other.

Recent studies have found that those who suffer from posttraumatic stress disorder (PTSD) are more likely to experience dementia as they age, most often Alzheimer's disease (AD). These findings suggest that the symptoms of PTSD might have an exacerbating effect on AD progression. AD and PTSD might also share common susceptibility factors such that those who experience trauma-induced disease were already more likely to succumb to dementia with age. Here, we explored these two hypotheses using a mouse model of PTSD in wild-type and AD model animals. We found that expression of human familial AD mutations in amyloid precursor protein and presenilin 1 leads to sensitivity to trauma-induced PTSD-like changes in behavioral and endocrine stress responses. PTSD-like induction, in turn, chronically elevates levels of CSF β-amyloid (Aβ), exacerbating ongoing AD pathogenesis. We show that PTSD-like induction and Aβ elevation are dependent on corticotropin-releasing factor (CRF) receptor 1 signaling and an intact hypothalamic–pituitary–adrenal axis. Furthermore, we show that Aβ species can hyperexcite CRF neurons, providing a mechanism by which Aβ influences stress-related symptoms and PTSD-like phenotypes. Consistent with Aβ causing excitability of the stress circuitry, we attenuate PTSD-like phenotypes in vivo by lowering Aβ levels during PTSD-like trauma exposure. Together, these data demonstrate that exposure to PTSD-like trauma can drive AD pathogenesis, which directly perturbs CRF signaling, thereby enhancing chronic PTSD symptoms while increasing risk for AD-related dementia.

https://www.jneurosci.org/content/jneuro/35/6/2612.full.pdf

Posttraumatic Stress Disorder-Like Induction Elevates β-Amyloid Levels, Which Directly Activates Corticotropin-Releasing Factor Neurons to Exacerbate Stress Responses

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Posttraumatic Stress Disorder-Like Induction Elevates β-Amyloid Levels, Which Directly Activates Corticotropin-Releasing Factor Neurons to Exacerbate Stress Responses