Acupressure as Long-term Intervention to Slow the Progression of Early/Mild Alzheimer's Disease

Overview

This is an assessor-blinded, randomized controlled trial. A total of 188 older adults aged 60-85 years with early/mild AD will be recruited from care and attention homes for the elderly and elderly activity centers. Participants will be randomly assigned to receive least acupressure control (LAC, n = 94) and Comfy Acupressure for the Elderly (CAE, n = 94), administered by caregivers (i.e., trained research assistants), for 3 sessions a week for 12 months. The primary outcome is the change in the Montreal Cognitive Assessment (MoCA) score from baseline. The secondary outcomes include functional independence, psychological well-being, sleep quality, and health-related quality of life. The outcomes will be assessed at baseline and once bimonthly thereafter, totaling 7 sessions. A linear mixed-effect model will be applied to compare the primary and secondary outcomes. Three blood samples will be collected at baseline, 6 months, and 12 months, respectively, and the baseline blood sample will be immediately measured for the measurement of plasma Aβ42, Aβ40, p-tau181, and p-tau217, blood glial fibrillary acidic protein (GFAP) and neurofilament light chain protein (NfL). Repeated two-way variance (ANOVA) will be used to detect significant differences in blood biomarkers between the two groups. Linear regression will be conducted to examine inter-correlations between clinical outcomes and biomarker levels. Health and social care resource use will additionally be recorded at baseline, 6 months, and 12 months for the economic evaluation to examine the cost-effectiveness of the CAE intervention compared with LAC.

Alzheimer's disease (AD) - impacts, symptoms, and diagnosis: AD is the most common type of dementia, accounting for 3/4, that affects millions of people worldwide. About 100,000 elderly aged ≥65 years are suffering from AD in Hong Kong and will increase to 280,000 by 2036. These have led to dramatically increasing burdens on families, societies, and public healthcare systems. The symptomatological diagnostic criteria for AD include: (1) the cognitive impairment involves at least two of the following domains: learning and memory, reasoning and task, visuospatial abilities, language functions, changes in personality and behavior; (2) the symptoms gradually occur over months and years, not suddenly over hours or days; (3) a clear-cut history of worsening of cognition by report or observation; and (4) the initial and most prominent cognitive deficits are evident on history and examination. On the other hand, multiple amyloid (Aβ) and tau products have been validated to predict the risk and the progression of AD. In particular, the plasma Aβ42/40 ratio, p-tau181, and p-tau217 are core biomarkers that are strongly associated with the risk, onset, and progression of AD. An Aβ42/40 ratio of ≥0.170 indicates a lower risk of AD, 0.150-0.169 for intermediate risk, and \<0.150 for higher risk. A normal plasma level is 0.49-3.29 pg/ml for p-tau181 and ≤0.15 pg/ml for p-tau217. Plasma p-tau181 and p-tau217 levels increase with age, and higher levels are associated with more severe AD. These biomarkers are thus specifically suitable for the assessment of the outcomes of early and long-term intervention. Additionally, blood glial fibrillary acidic protein (GFAP) and neurofilament light chain protein (NfL) often serve as biomarkers for neuroinflammation associated with the etiology of AD. Acupressure for AD and dementia: Although there are various classes of pharmacological agents available for the treatment of AD, the clinical efficacy is limited and even ineffective. This situation has led to the development of non-pharmacological approaches, particularly for early intervention to prevent the progression of AD. As a convenient therapy, acupressure is increasingly introduced into the management of various cognitive disorders, and demonstrated for particular benefits in improving activities of daily living, agitation, anxiety, depression, and sleep disturbances in older adults living with dementia. Acupressure also improved cognitive function and quality of life in older adults living with mild cognitive impairment. These studies suggest that acupressure may be an effective preventive approach to AD. However, it is unknown about the efficacy of acupressure as an early and long-term intervention to prevent AD. It is also unknown about the neuropathological mechanisms underlying acupressure in mitigating AD-associated amyloid (Aβ) and tau accumulation. Besides, acupressure also considerably improved functional dependence, mood, and sleep disorders in older adults living with cognitive impairment. Putative mechanisms of acupressure effects: It is thought that the therapeutic effects of acupressure are achieved mainly via neurophysiological and neurochemical mechanisms. As a form of mechanical stimulation with particular physical touch, acupressure effectively rebalanced sympathetic and parasympathetic activities of the autonomic nervous system and modulated functions of multiple brain regions (such as the prefrontal cortex and limbic system) via activating tactile receptors and local sensory nerve endings of the skin and muscles. It also broadly regulated various neurotransmitters, particularly stimulating the release of serotonin, dopamine, endorphins, and oxytocin, in turn improving mood, cognitive function, and behavioral responses. Meanwhile, acupressure lowered levels of cortisol, a hormone related to stress response. In addition, acupressure activated tactile receptors in the skin and then transmitted relaxation signals to the brain, promoting emotional relaxation and calmness. These effects could explain the robust effects of acupressure in reducing stress-associated disorders and anxiety. There are thus reasons to believe that acupressure could serve as an effective intervention in preventing and improving cognitive deterioration of older people. Related studies of investigators: The investigators have published three randomized controlled trials of acupressure for insomnia disorder and stress-related symptoms. Moreover, the investigators have developed caregiver-administered acupressure called 'Comfy Acupressure for the Elderly (CAE)' (https://www.youtube.com/watch?v=pAqNIZPKmnM), and confirmed that CAE effectively improved the quality of life and sleep quality of frail older adults, and reduced their pain intensity and frequency. Between October 2020 and August 2024, the investigators further completed a randomized controlled trial of evaluating the effectiveness of CAE in community-dwelling older people living with various types of dementia. A total of 118 who were aged above 65 years participated in the study. All participants had a clinical diagnosis of dementia with mild to moderate severity. Participants were randomized to receive routine care alone as a control (n = 59) and plus CAE (n = 59) for 12 weeks. CAE was conducted for 3 sessions a week by caregivers at nursing homes. The primary outcome was baseline-to-endpoint changes in the Montreal Cognitive Assessment (MoCA) score. The secondary outcomes included the Forward and Reverse Digit Span test for cognitive function. The discontinuation rate was 10.2% (12/118). The CAE group had significantly greater improvement than the routine care control group from baseline to 12 weeks on MoCA score (mean difference \[MD\] = 1.62, 95% confidence interval \[CI\] = 0.37, 2.88, P = 0.012), Forward Digit Span (MD = 1.58, 95% CI = 0.34, 2.81, P = 0.013), and Reverse Digit Span (MD = 0.70, 95% CI = 0.04, 1.36, P = 0.038). Subgroup analysis revealed that CAE had significantly greater improvement on MoCA in participants with mild cognitive impairment and mild dementia, but not on moderate dementia. The mean difference between CAE and the routine care control was 1.67 ± 3.63 (standard deviation \[SD\]), which will be used for sample size calculation. These results proved the effectiveness of CAE in reducing cognitive deterioration of older adults, particularly with early/mild dementia, necessitating further conducting a long-term intervention study in preventing the progression of early/mild AD.