Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

Abstract

BackgroundThe mainstay of therapy for many neurodegenerative dementias still relies on acetylcholinesterase inhibitors (AChEI); however, there is debate on various aspects of such treatment. A huge body of literature exists on possible predictors of response, but a comprehensive review is lacking. Therefore, our aim is to perform a systematic review of the predictors of response to AChEI in neurodegenerative dementias, providing a categorization and interpretation of the results.MethodsWe conducted a systematic review of the literature up to December 31st, 2021, searching five different databases and registers, including studies on rivastigmine, donepezil, and galantamine, with clearly defined criteria for the diagnosis of dementia and the response to AChEI therapy. Records were identified through the string: predict*AND respon*AND (acetylcholinesterase inhibitors OR donepezil OR rivastigmine OR galantamine). The results were presented narratively.ResultsWe identified 1,994 records in five different databases; after exclusion of duplicates, title and abstract screening, and full-text retrieval, 122 studies were finally included.DiscussionThe studies show high heterogeneity in duration, response definition, drug dosage, and diagnostic criteria. Response to AChEI seems associated with correlates of cholinergic deficit (hallucinations, fluctuating cognition, substantia innominate atrophy) and preserved cholinergic neurons (faster alpha on REM sleep EEG, increased anterior frontal and parietal lobe perfusion after donepezil); white matter hyperintensities in the cholinergic pathways have shown inconsistent results. The K-variant of butyrylcholinesterase may correlate with better response in late stages of disease, while the role of polymorphisms in other genes involved in the cholinergic system is controversial. Factors related to drug availability may influence response; in particular, low serum albumin (for donepezil), CYP2D6 variants associated with reduced enzymatic activity and higher drug doses are the most consistent predictors, while AChEI concentration influence on clinical outcomes is debatable. Other predictors of response include faster disease progression, lower serum cholesterol, preserved medial temporal lobes, apathy, absence of concomitant diseases, and absence of antipsychotics. Short-term response may predict subsequent cognitive response, while higher education might correlate with short-term good response (months), and long-term poor response (years). Age, gender, baseline cognitive and functional levels, and APOE relationship with treatment outcome is controversial.

Dementia Prevention and Treatment

“…It was also not known whether long-term use would accompany desired outcomes, such as delay in institutionalization. It is now established that response to CIs is complex and affected by many factors, including but not limited to signs of cholinergic deficit, stage of disease, rate of disease progression, presence of apathy, concomitant diseases, and education level . CIs are associated with modest but persistent cognitive benefits over several years and reduced mortality, and both CIs and memantine have demonstrated prolonged time to institutionalization and reduced caregiver burden …”

Emerging significance of butyrylcholinesterase

“…According to the cholinergic hypothesis, degeneration of cholinergic neurons in the basal forebrain results in cognitive dysfunction in AD[ 37 ]. Other conditions that occur via the cholinergic system include amyloid deposition, tau phosphorylation, neuroinflammation, and vascular damage (Pozzi et al [ 38 ], 2022). Acetylcholine, the neurochemical transmitter in the cholinergic synapses, is inactivated by AChE, and to a lesser extent by BuChE.…”

Involvement of an Aberrant Vascular System in Neurodevelopmental, Neuropsychiatric, and Neuro-Degenerative Diseases

“…However, the development of DMTs has been hindered by undetectable efficacy and the emergence of side effects in clinical trials. Therefore, at present, drug treatment for AD still relies on AChEIs [ 103 ].…”