Alzheimer’s disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid β protein (Aβ) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aβ and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aβ cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aβ aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aβ- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood–brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aβ-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aβ assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.

Most of neurodegenerative diseases (NDD) have no cure. The common etiology of neurodegenerations is unclear. Air pollutant-gaseous formaldehyde is notoriously known to induce demyelination and cognitive impairments. Unexpectedly, an amount of formaldehyde has been detected in the brains. Multiple factors can induce the generation and accumulation of endogenous formaldehyde. Excessive formaldehyde can induce oxidative stress to generate H ₂ O ₂ ; in turn, H ₂ O ₂ promote formaldehyde production. Clinical investigations have shown that an abnormal high level of formaldehyde but low level of coenzyme Q10 (coQ10) was observed in patients with NDD. Further studies have proven that excessive formaldehyde directly inactivates coQ10, reduces the ATP generation, enhances oxidative stress, initiates inflammation storm, induces demyelination; subsequently, it results in neurodegeneration. Although the low water solubility of coQ10 limits its clinical application, nanomicellar water-soluble coQ10 exhibits positive therapeutical effects. Hence, nanopackage of coQ10 may be a promising strategy for treating NDD.

Background: Mild cognitive impairment (MCI) is common in older adults and may progress to Alzheimer disease. Accessible behavioral measures are needed to identify subtle cognitive changes; tactile tasks may provide a low-cost approach. Objective: To examine whether tactile cognitive tasks can differentiate between older adults with MCI and healthy controls (HC), and to explore whether processing related to working memory may contribute to tactile task deficits. Methods: We recruited two independent cohorts of older adults. Cohort 1 completed a tactile angle size comparison task and a tactile angle sequencing task, while Cohort 2 completed a visual learning-recognition task. We analyzed group differences while controlling for age, sex, years of education, and scores on the Hamilton Anxiety Scale and Hamilton Depression Scale. We then calculated signal detection indices for the learning-recognition task. Results: After covariate adjustment, the tactile angle size comparison task did not show a significant group difference ( p =0.388). The tactile angle sequencing task significantly distinguished individuals with MCI from HC ( p <0.001). Receiver operating characteristic analyses showed acceptable-to-good discriminatory performance for the tactile tasks, with stronger performance for the sequencing task. In the learning-recognition task, individuals with MCI showed reduced discrimination sensitivity indexed by d ′. Conclusion: Tactile sequencing performance appears more sensitive to MCI-related impairment than simple tactile angle comparison. These findings suggest that complex tactile deficits in MCI may be partly associated with working-memory–related processing.