Comment on “The value of cholinesterase inhibitors for improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease: a systematic review and meta-analysis of on placebo-controlled RCTs”

Dear Editor, Alzheimer disease (AD), a complicated senile degenerative disease of the central nervous system, is the most common form of dementia.[1,2] Globally, there are 47.5 million AD patients; by 2030, that number is predicted to rise to about 82 million, and by 2050, it is predicted to exceed 152 million. The primary characteristic of AD is cognitive impairment, which has a significant impact on individuals, families, and society as a whole. The genesis of AD is yet unclear. AD has grown to be a significant public health problem in recent years that has a negative impact on people’s health and quality of life worldwide. Functional and neuropsychiatric evaluation scores may decline as a result of AD. A cholinergic deficit in AD is linked to the development of psychosis, according to convergent data from biochemical and neuroimaging research. As a result, cholinesterase inhibitors (ChEIs) have higher tolerance than benzodiazepines and antipsychotics and may be useful therapies for improving functional and neuropsychiatric evaluation scores in AD. In order to assess the safety and effectiveness of ChEIs for AD, Zhang et al[3] conducted a meta-analysis of RCTs. There were 12 RCTs involving 6908 individuals (Table 1). According to the findings of meta-analysis, AD patients who received ChEIs therapy often had better functional and neuropsychiatric evaluation scores without experiencing more adverse events. Table 1 - The characteristics of included studies. Author (year) Country and site Sample size (n) Severity of dementia Intervention Age (year) Duration Neurologic and cognitive test scores End points or outcomes Black SE (2007) Multinational, 98 sites 343 MMSE 1–12; FAST ≥ 6; MHIS≤ 6 Donepezil, 10 mg daily 78.0 ± 8.10 24 weeks SIB, CIBIC-Plus, MMSE, FAST, ADCS-ADL-sev, NPI, CBQ, RUSP Mean and LS change from baseline to endpoint, AEs Brodaty H (2005) Five countries at 93 sites 971 MMSE 10–24; ADAS-cog/11 ≥ 18 Galantamine 16 or 24 mg/day 76.5 ± 7.81 6 months ADAS-cog/11, CIBIC-Plus, ADCS-ADL, NPI Mean change from baseline, AEs Gault LM (2016) NR 438 MMSE 10–24; CSDD ≤ 10; MHIS≤4 ABT-126 25/50/75 mg, donepezil 10 mg, QD 74.2 ± 7.89 24 weeks ADAS, MMSE, WMS, ADCS-ADL total score, NPI-12- item total score mean change from placebo, AEs Gault LM (2015) Six countries at 27 sites 274 MMSE 10–24; CSDD ≤ 10; MHIS≤4 ABT-126 (5 or 25 mg once daily), donepezil 10 mg once daily 73.9 ± 7.92 24 weeks 11-item ADAS-Cog total score, ADAS-Cog 13-item total score, MMSE, CIBIS and CIBIC-Plus, NPI-12- item total score, ADCS-ADL total score LS and mean change from placebo, AEs Gold M (2010) One hundred thirty-four centers in 19 countries 693 MMSE 10-23 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil 72.5 ± 8.56 24 weeks ADAS-Cog total scores, CIBIC + scores, Change from baseline, AEs 71.7 ± 7.91 72.6 ± 8.63 72.9 ± 7.97 Haig GM (2014) Two countries in 21 sites 242 MMSE 10-24; CSDD≤10; MHIS≤4 ABT-288 1 mg or 3 mg, donepezil 10 mg, once daily 70.2 ± 8.32 12 weeks 13-item ADAS-Cog Total Score, 11-item ADAS-Cog Total Score, MMSE Total Score, NPI (12-item) Total Score, NPI (10-item) Total Score, ADCS-ADL Total Score Mean change from baseline, AEs Homma A (2008) Japan 325 MMSE 1–12; MHIS≤4; FAST ≥6 Donepezil 5 or 10 mg/day 79.7 ± 7.5 24 weeks SIB, CIBIC-plus, ADCS-ADL-sev, BEHAVE-AD LS mean change from baseline; AEs 78.0 ± 8.9 76.9 ± 7.9 Nakamura Y (2011) NR 855 MMSE 10–20 4.5 mg loading dose, 9 mg loading dose, 13.5 mg loading dose and 18 mg loading dose 74.5 ± 7.4 24 weeks ADAS J-cog scores, CIBIC-plus-J scores LS mean changes from baseline; AEs 74.3 ± 7.5 75.1 ± 6.9 74.6 ± 7.2 Rockwood K (2001) Six countries at 43 sites 386 MMSE 11–24 galantamine received 8 mg/day for 1 week, increasing to 16 mg/day for the2nd week and to 24 mg/day for the 3rd 74.6 ± 0.68 3 months ADAS-cog/11, ADAS-cog/13, NPI, DAD AEs 75.2 ± 0.45 Tariot PN (2001) US in 27 sites 208 MMSE 5–26 Donepezil, average daily dose of 9.5 mg/day 85.9 (65–102) 24 weeks Mean NPI-NH 12-item total scores Response, AEs 85.4 (64–98) Tariot PN (2000) United States, multicenter 978 MMSE 10-22 Galantamine 8 mg/day, 16 mg/day, 24 mg/day 77.1 ± 0.5 5 months ADAS-cog, CIBIC-plus, NPI, mean change from baseline, AEs 76.0 ± 0.6 76.3 ± 0.5 77.7 ± 0.4 Winblad B (2007) NR 1195 MMSE 10–20 Three active treatment target dose groups 73.6 ± 7.9 24 weeks ADAS-cog, ADCS-CGIC, ADCS-ADL, NPI, MMSE Mean changes at Week 24 to placebo, AEs 74.2 ± 7.7 72.8 ± 8.2 73.9 ± 7.3 ADAS, the Alzheimer’s Disease Assessment Scale; ADCS-ADL-sev, the Alzheimer Disease Cooperative Study – Activities of Daily Living – severe version; CBQ, the Caregiver Burden Questionnaire; CIBIC-Plus, Clinician’s Interview-Based Impression of Change-Plus caregiver input; CIBIS, the Clinician Interview-Based Impression of Severity; CSDD, Cornell Scale for Depression in Dementia; FAST, Functional Assessment Staging; MHIS, Modified Hachinski Ischemic Scale; MMSE, Mini-Mental State Examination; NPI, the Neuropsychiatric Inventory; NR, not report; RUSP, the Resource Utilization for Severe Alzheimer Disease Patients; SIB, Severe Impairment Battery; WMS, Wechsler Memory Scale. The hyperphosphorylation of tau protein, deposition of insoluble amyloid plaques, and the development of neurofibrillary tangles inside the cells are the main causes of AD, which is characterized by the death of brain cells. Other pathologies include neuroinflammation, anomalies in the vascular system, disorders in energy generation and mitochondrial function, disruption of synaptic connections and circuits, as well as epigenetic alterations are all linked to AD. Over the past century, a number of researches have been conducted, yet little is known about the causes of AD or effective treatments. It was discovered that AD with traumatic brain injury constituted a separate group from AD, probably with unique pathologic contributions beyond gray matter loss. This finding had significant implications for the diagnosis and treatment of AD in the existence of traumatic brain injury and suggested that models of AD, aging, and neural loss should take traumatic brain injury history into account. ChEIs, one of the available medications that corrects neurotransmitter imbalance, have been shown to be beneficial for AD and may be able to temporarily reduce dementia symptoms. High-quality data supporting the application of ChEIs to enhance functional and neuropsychiatric evaluation scores in AD patients was shown by this meta-analysis. Nevertheless, there are several limitations to the meta-analysis. First, there were differences in the medications and dosages used in the trials. However, subgroup analysis was not carried out due to sample size limitations. Second, the pharmacological intervention lasted from 12 weeks to 6 months. ChEIs’ effects evolved throughout time, which might have an impact on the outcomes. Future studies should thus dynamically monitor the efficacy of ChEIs and determine the optimal duration. This study was conducted in compliance with the Transparency in the Reporting of Artificial Intelligence – the TITAN guideline[4].