Progress of research and application of non-pharmacologic intervention in Alzheimer's disease

Deep brain stimulation (DBS)

DBS is an invasive technique that entails implanting electrodes into specific regions of the brain to administer electrical stimulation, which is controlled by an implanted pulse generator. In the context of treating AD, common brain targets for DBS include the fornix, ⁵⁰ the entorhinal cortex, ⁵¹ the vertical limb of the diagonal band, ⁵² and the ventral capsule/ventral striatum (VC/VS) region, ⁵³ among others.

Chronic DBS of the hippocampus in mammalian models with neurodevelopmental disorders shows an increase in neuronal count, encouraged neurogenesis, reduced neuropathological burden, and improved spatial learning, memory, and object recognition. ⁵⁴ In clinical studies, six AD patients who received chronic bilateral hippocampal DBS showed enhanced neural activity in memory circuits, suggesting a potential therapy for AD-related memory deficits. ⁵⁵ However, a double-blind randomized controlled trial (RCT) assessing DBS in mild AD patients did not yield significant differences in cognition or metabolism between the treatment and control groups overall. Subgroup analysis demonstrated slight cognitive improvement among patients aged 65 or older, juxtaposed with cognitive decline in younger patients after 12 months of DBS treatment. ⁵⁶ While chronic stimulation studies on the human entorhinal cortex are lacking, long-term DBS in rodent AD models targeting the bilateral entorhinal cortex has shown promising outcomes. This intervention has been associated with increased neurogenesis and a reduction in Aβ plaque load, indicative of potential therapeutic benefits. ⁵⁷ Furthermore, studies investigating olfactory cortex DBS (EC-DBS) have demonstrated its ability to rectify synaptic defects between layers II of the entorhinal cortex and CA1 of the hippocampus in AD mice. ⁵⁸ This correction has led to hippocampal neurogenesis and improved cognitive function. Notably, EC-DBS has shown efficacy in reducing Aβ plaque burden in various brain regions of early-stage AD mice, suggesting its potential as a treatment strategy in the early stages of the disease. ⁵¹ Additionally, vertical diagonal band DBS (VDB-DBS) therapy has exhibited the ability to restore reduced cholinergic neuron synaptic density in the dentate gyrus (DG) of the hippocampus. ⁵² Targeting the VC/VS region aims to modulate frontal networks and influence executive function in AD patients. It is also noted that neurons in the VC/VS region undergo neurodegeneration following temporal areas of the AD process, potentially rendering them more suitable targets for DBS modulation. ⁵³

Although DBS is generally considered safe and well-tolerated, there are unforeseeable risks associated with the invasive nature of the procedure and the potential for neurological or psychological side effects, such as the occurrence of depression in AD patients undergoing bilateral DBS treatment of the thalamic nuclei for epilepsy. ⁵⁹ Therefore, caution should be exercised in the use of DBS.

Transcranial magnetic stimulation (TMS)

TMS is an established non-invasive method for brain stimulation. Utilizing coils encased in plastic, the TMS apparatus is placed over the patient's scalp and generates electrical currents, creating a magnetic field within cranial tissues to administer targeted brain stimulation. ⁶⁰ rTMS involves administering a series of pulses with specific frequencies and consistent intensities. Particularly in the motor cortex, rTMS can modulate cortical excitability, inducing enduring neuroplastic changes. ⁶¹ Research suggests that rTMS therapy can mitigate the production of Aβ peptides, enhance neuronal plasticity, and reduce neuronal apoptosis, thereby potentially ameliorating cognitive function in AD patients. ⁶² Low-intensity rTMS (110% average resting motor threshold intensity, 1 Hz, LIMS) have been reported to trigger the activation of BDNF and tyrosine kinase receptor B (TrkB), upregulate synaptic protein marker levels, increase synaptic density and PSD thickening, and further reverse the spatial cognitive dysfunction in aging mice. ⁶³ It has also been reported that rTMS stimulated at a high frequency of 25 Hz improves the cognitive function of AD model mice through the PI3K/Akt/GLT-1 signaling pathway, reduces hippocampal Aβ_1–42 level, improves oxidative stress, and improves glucose metabolism. ⁶⁴

Research indicates that neuropathological abnormalities in AD predominantly localize to the posterior cortical regions of the brain. Specifically, amyloid plaques and neurofibrillary tangles initially appear within the precuneus, posterior cingulate cortex, splenium, and lateral posterior parietal cortices. Consistent findings from FDG-PET imaging studies reveal early regional metabolic reductions in these posterior regions among AD patients. This correlates with alterations in default mode network (DMN) connectivity, which is detectable through fMRI. ⁶² The precuneus, considered a key hub of the DMN, is prominently affected by tau pathology deposition and neuroinflammation, resulting in diminished functional connectivity or hypoactivation. Reports also indicate interpretative impacts attributed to localized atrophy in the precuneus among patients with mild cognitive impairment. It is noted that disconnection of the precuneus precedes and contributes to localized brain atrophy during the early clinical stages of AD. Precuneal atrophy reflects the consequences of brain disconnection, leading to the transition from mild cognitive impairment to AD. ⁶² Additionally, AD patients often exhibit reduced cortical thickness, along with abnormal activation and decreased functional connectivity during memory tasks. Given the critical role of precuneal activity in episodic memory retrieval, its impairment signifies typical clinical manifestations of AD. ⁶² rTMS exhibits varied therapeutic effects across different brain regions. Following rTMS treatment of 94 patients with mild to moderate AD, stimulation of the left dorsolateral prefrontal cortex (DLPFC) was found to yield more pronounced cognitive improvements compared to the right or bilateral stimulation. ⁶⁵ Another randomized controlled clinical trial indicated that high-frequency rTMS targeting multiple brain regions simultaneously enhances cognitive function in AD patients more effectively than stimulation of a single region. ⁶⁶

A 24-week trial, comprising a two-week treatment and a 22-week maintenance phase, was conducted on 50 Alzheimer's patients. ⁶⁷ They were randomly assigned to either active rTMS or sham stimulation. During treatment, the active group received intensive rTMS sessions five times a week for two weeks, while the sham group received simulated treatment. In the maintenance phase, the active group had weekly sessions for 22 weeks. The primary outcome measured was the change in the Clinical Dementia Rating Scale total score, with secondary outcomes including scores on various cognitive assessments. Neurophysiological changes in prefrontal cortex excitability and oscillatory activity were assessed using single-pulse TMS and EEG. Results showed stable scores in the active rTMS group compared to deteriorating scores in the control. The active group also performed better on secondary outcomes. Neurophysiological findings revealed sustained prefrontal cortex excitability and enhanced gamma oscillations in the active group. Another trial combining 20 Hz rTMS with cognitive training showed superior associative memory improvement compared to cognitive training alone. ⁶⁸ High-frequency rTMS, particularly targeting the bilateral DLPFC, showed promise in AD treatment compared to low-frequency rTMS. These findings highlight rTMS as a potential intervention, especially when combined with cognitive training, emphasizing the importance of frequency optimization.

Intermittent theta burst stimulation (iTBS), a novel time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with AD. ⁶⁹ The latest study found that iTBS can reduce oxidative stress, increase antioxidant capacity and decrease reactive astrocyte proliferation in AD model mice. ⁷⁰ Furthermore, iTBS can upregulate the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice, regulates mitochondrial respiration and function, and thus alleviates the cognitive impairment and pathology of AD. ⁷¹ A randomized clinical trial investigating personalized hippocampal network-targeted rTMS in early AD demonstrated significant improvements in cognitive and functional performance, as well as enhanced hippocampal-cortical connectivity, supporting rTMS as a promising intervention for AD treatment. ⁷²

Transcranial current stimulation (TCS)

Transcranial electric stimulation (tES) involves delivering weak electrical currents (1–2 mA) between two or more electrodes on the subject's scalp. There are two main forms of tES: tDCS and transcranial alternating current stimulation (tACS). tDCS is the most common choice for tES in the treatment of AD. tDCS delivers a current of 1 to 2 mA through electrodes placed on the scalp. Anodal tDCS typically increases excitability in the targeted area and surrounding cortical regions, while cathodal tDCS decreases excitability. tDCS modulates neuronal activity, altering the polarization state of membranes. tDCS is safe, well-tolerated, and cost-effective, leading to its increasing application over recent decades. The DLPFC has been a target of research due to its crucial role in executive functions. tDCS applied to the DLPFC may engage compensatory mechanisms for working memory performance, this can alter neuroplasticity due to prefrontal cortex damage. Some studies have found positive effects of tDCS on memory in AD patients. A double-blind randomized controlled trial found higher cognitive scores in AD patients after repeated treatments compared to a control group, with similar effects for both anodal and cathodal tDCS. ⁷³ tDCS can enhance cognitive reserve effects in mild to moderate AD patients, possibly connected to its effects on neurotransmitters such as acetylcholine and dopamine. tDCS interventions targeting the left temporal cortex (TC) and frontal cortex (FC) also show a trend toward improving memory and executive function decline. Studies have suggested that tDCS treatment of the TC region improved word recognition memory in suspected AD patients. Additionally, tDCS treatment targeting the temporal regions demonstrates potential effects on visual recognition memory. ⁷⁴

tACS delivers a current oscillating above and below zero with a specified stimulation intensity (i.e., peak-to-peak amplitude) and specific frequency. ⁷⁵ In contrast to tDCS, where the excitability threshold of neuronal membranes is modulated, ⁷⁶ tACS directly interacts with ongoing neural activity during cognitive or sensorimotor processes, resulting in the synchronization of brain network oscillations or rhythmic coordination.^75,77 In animal studies, tACS stimulation of AD model rats demonstrated improved memory impairment and decreased recognition ability induced by Aβ in the brain, suggesting that tACS can counteract Aβ-induced memory deficits. ⁷⁸ tACS therapy that targeted the stimulation of bilateral temporal lobes in mild to moderate AD patients for 1 h/day over 4 weeks resulted in significantly reduced phosphorylated tau protein and microglial activation post-treatment. However, there was no significant change in brain Aβ burden, indicating that tACS therapy may only improve certain aspects of AD pathology. ⁷⁹ Another study that applied tACS therapy to the medial temporal cortex and prefrontal region demonstrated increased scores on the Rey Auditory Verbal Learning Test (RAVLT) total recall, long-delayed recall, and face-name association scores in the treatment group, along with enhanced network connectivity of cholinergic neurotransmission within the cortex, suggesting significant improvement in memory capabilities in AD patients with tACS. ⁸⁰

In summary, tDCS mitigates neuropathological manifestations of neurodegenerative disorders like AD by modulating neuronal activity and excitability within the cerebral cortex. Conversely, tACS does not directly modulate neuronal excitability but instead integrates substantial neuronal clusters into localized oscillatory networks via entrainment and resonance mechanisms. This process consequently modulates internal computations within specific brain regions and orchestrates broader network activity, thus playing a regulatory role in cognitive functions.

Transcranial pulse stimulation (TPS)

Transcranial pulse stimulation (TPS) is an innovative noninvasive method for precise neuromodulation using brief, high-intensity ultrasound pulses (∼3 μs), repeated every 200–300 ms. ⁸¹ This technique offers superior spatial resolution, allowing it to effectively target deep neural structures within the human cortex. ⁸² TPS utilizes focused ultrasound frequencies that can penetrate up to 8 cm deep, reaching critical brain regions like the thalamus, positioned between 5 and 6.5 cm beneath the scalp. ⁸³ Computational models indicate that TPS can modify the electrical activity of both cortical and subcortical areas. Unlike transcranial-focused ultrasound stimulation, TPS circumvents issues such as tissue heating and standing wave effects by employing brief pulses without continuous or prolonged ultrasonic sequences.^84,85 It has been reported that stimulating areas related to depression (including extended dorsolateral prefrontal cortex) appear to alleviate depressive symptoms and induce functional connectivity (FC) changes in AD patients. ⁸⁶ TPS is promising in improving cognitive performance and reducing depressive symptoms in patients with AD. Therefore, TPS may be a safe adjunct therapy in the treatment of AD. ⁸⁷

Vagus nerve stimulation (VNS)

VNS encompasses both invasive and non-invasive modalities. In invasive VNS (iVNS), electrodes are surgically positioned along the left vagus nerve. These electrodes are intricately connected to the left vagus nerve within the brain and are linked to a pulse generator implanted in the left thoracic region. This setup facilitates the delivery of programmable electrical stimulation to the vagus nerve, thereby regulating brain network activity. Studies have demonstrated that iVNS exerts its effects by enhancing synaptic transmission, neural plasticity, and long-term potentiation (LTP) through modulation of the locus coeruleus (LC) and β-adrenergic receptors within the CA3 region of the hippocampal perforant pathway, ultimately leading to cognitive enhancement. ⁸⁸ A pioneering pilot study conducted in 2002 on AD patients showcased promising results. Following 3 months of treatment, approximately 90% of patients exhibited improvements in Mini-Mental State Examination (MMSE) scores, with 70% demonstrating enhanced performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Remarkably, even after 6 months of treatment, the response rate among AD patients remained consistently high at 70%. ⁸⁹ After these encouraging findings, the research team expanded their cohort and conducted a comprehensive 12-month follow-up study. Notably, after a year of iVNS intervention, approximately 70% of patients exhibited either stable or improved cognitive abilities. ⁹⁰

Non-invasive vagus nerve stimulation (nVNS) represents a non-invasive therapeutic approach, utilizing a portable device to administer electrical stimulation to the ear or neck, thereby indirectly activating the auricular branch of the vagus nerve. Research indicates that in cognitively healthy older adults, a single session of nVNS therapy yields improvements in associative memory compared to control groups. ⁹¹ While nVNS shows promise for AD treatment, comprehensive clinical evidence remains insufficient. ⁹² Currently, a double-blind, placebo-controlled crossover study is underway to assess the therapeutic efficacy of nVNS in patients with MCI. ⁹³

Sound and light therapy

Gamma (γ) waves, the fastest brainwaves within the human cortex, are orchestrated by the synchronized firing of a multitude of neurons, yielding a resonance frequency spanning from 25 to 100 Hz. Of these frequencies, there is an emphasis on the 40 Hz frequency due to its extensively investigated impact on cerebral function. Empirical findings show a prevalence of gamma rhythms within the hippocampus, hinting at its pivotal role in mediating the representation of human objects, facilitating visual feature integration, and orchestrating higher-order cognitive processes. This reveals the pivotal role of gamma-band synchronization in orchestrating a myriad of cognitive operations. ¹⁰⁰ One randomized controlled trial allocated individuals with mild to moderate AD into either an active treatment cohort (n = 14) or a sham surgical intervention group (n = 8). The active treatment arm received 40 Hz visual and auditory stimulation for one hour daily over six months, while the sham surgical cohort was exposed to high-frequency stimulation exceeding 90 Hz. Notably, the outcomes demonstrated that 40 Hz stimulation therapy reinstated cortical gamma oscillations, thereby culminating in significant enhancements in sleep architecture and functional independence among individuals afflicted with mild to moderate AD. ¹⁰¹

Using invasive optogenetic methods, researchers implanted optical fibers into the visual cortex of 5×FAD/PV-Cre mice, subjecting them to light stimuli of varying frequencies for one hour daily over seven days. Results revealed that 40 Hz light stimulation prompted the microglial transition to a phagocytic state, reducing Aβ_1–40 and Aβ_1–42 levels by 53.22% and 44.62%, respectively, in the visual cortex. Conversely, 8 Hz or random frequency stimulations showed no reduction in Aβ levels, indicating frequency-dependent therapeutic effects. ¹⁰² Morphological changes induced by 40 Hz stimulation, such as shortened microglial processes and enlarged soma diameter, were observed, enhancing phagocytic activity as evidenced by doubled Aβ co-localization. ¹⁰³ Non-invasive 40 Hz light flicker stimulation in AD mice for one hour daily over seven days induced gamma oscillations, decreased amyloid plaques and phosphorylated tau, boosted neuroprotective factor release, and mitigated neuronal damage and microglia-induced inflammation. Similarly, 40 Hz auditory stimulation was administered to P301S (Tau model) mice aged 8 months and CK-p25 mice aged 6 to 9 months, for 22 and 42 days respectively, results demonstrated improved synaptic function, reduced DNA damage in neurons, and alleviated inflammatory responses, suggesting its efficacy in neurodegenerative disease alleviation. ¹⁰⁴ Furthermore, 40 Hz flicker light stimulation enhanced mitochondrial ATP-sensitive potassium channel structure and function, mitochondrial respiratory chain enzyme activities (Complex I and IV), mitochondrial membrane potential (ΔΨm), and reduced mitochondrial reactive oxygen species (ROS) production, thus affecting mitochondrial potassium channels and respiratory chain. ¹⁰⁵ Additionally, 40 Hz auditory stimulation induced a 40 Hz auditory steady-state response and gamma oscillations, aiding cognitive functions and language learning memory capabilities. ¹⁰⁶ In 5×FAD mice experiments, seven days of 40 Hz auditory stimulation for one hour daily significantly reduced both soluble and insoluble Aβ_1–42 in the auditory cortex and hippocampus, increased microglia number and dendritic branching, and improved recognition and spatial memory capabilities. ¹⁰⁷ Similarly, 40 Hz auditory stimulation increased reactive astrocytes in the auditory cortex and hippocampal CA1 region of APP/PS1 mice, enhanced blood vessel diameter, and reduced amyloid protein load. ¹⁰⁸ Furthermore, 40 Hz auditory stimulation reduced highly phosphorylated tau tangles in tau pathology, 5×FAD, and APP/PS1 mouse models, indicating its broad efficacy in improving tau protein deposition.^109,110 In clinical trials, ten consecutive days of 40 Hz light flicker stimulation twice daily in mild to moderate AD patients did not reduce cortical amyloid protein load significantly, suggesting the limited efficacy of short-term visual stimulation. ¹¹¹ However, 40 Hz auditory stimulation interventions showed significant improvement in mental symptoms for mild to moderate AD patients, with cognitive abilities increasing with prolonged treatment duration, as assessed by the Saint Louis University Mental Status (SLUMS) test, emotional evaluation scale, and behavioral observation. ¹¹²

Research has shown that combining 40 Hz visual and auditory stimuli therapy yields better results than using either stimulus alone. This combined therapy enhances microglial cell responses, clears amyloid plaques, and leads to significant cognitive improvement. ¹⁰⁸ In mouse models, this therapy increased microglial cell count, reduced plaque numbers and volume, lessened brain atrophy, and boosted cognitive function. ¹⁰⁷ Cognito Therapeutics has developed a portable device for this therapy, where AD patients receive 40 Hz audiovisual stimulation for an hour daily for six months. Compared to a control group, treated patients showed reduced brain white matter atrophy, which has the potential to slow AD progression because white matter connects different brain regions. Analysis of AD patient data from the Cognito device treatment and the Alzheimer's Disease Neuroimaging Institute (ADNI) database revealed that treated patients experienced increased white matter volume, while those in the ADNI database had decreased volume during the same period. This suggests that the therapy may effectively reduce white matter atrophy. ¹¹³ Dr Mihaly Hajos from Cognito Therapeutics highlighted the device's safety, tolerability, and effectiveness in maintaining cognitive function, reducing brain atrophy, and improving sleep quality. The therapy's benefits extend beyond sensory areas, significantly reducing plaques in the medial prefrontal cortex. ¹¹³ Studies also found that continuous 40 Hz audiovisual stimulation for three months in mild AD patients improved brain network connectivity, sleep quality, memory, and slowed brain atrophy. ¹⁰⁸ Another trial showed decreased levels of certain proteins associated with AD and improved brain network connectivity after two months of therapy. ¹¹⁴

In summary, the ameliorating effects of AD pathological symptoms induced by 40 Hz gamma oscillations primarily stem from heightened microglial phagocytic activity, augmented vasodilation, and enhanced trans-endothelial cell phagocytosis. These mechanisms facilitate the clearance of pathological proteins, thereby decelerating AD progression and alleviating memory deficits. Additionally, the therapeutic efficacy of 40 Hz audio-visual stimulation surpasses that of singular visual or auditory interventions. Evidence from studies conducted on both AD mouse models and human patients suggests that undergoing 40 Hz audiovisual stimulation therapy yields decreases in neurodegeneration and brain atrophy, alongside increases in synaptic density and normalization of circadian rhythms. These beneficial effects culminate in improved cognitive function, underscoring the potential of 40 Hz audiovisual stimulation intervention as a promising avenue for AD therapy.

Music therapy (MT) represents a cost-effective and efficacious intervention for enhancing neurological, cognitive, and social functioning in patients. Through the stimulation of various brain regions, MT facilitates neuroplasticity, thereby promoting improvements across the aforementioned domains. Notably, research indicates that AD patients experience activation in supplementary motor areas and heightened connectivity among disparate brain regions following exposure to preferred musical stimuli.^115,116 Furthermore, music's ability to synchronize neural oscillations associated with learning and memory suggests its potential to foster enduring musical memories.^116,117 Moreover, musical stimulation elicits the release of diverse neurotransmitters, including excitatory agents and hormones such as cortisol, testosterone, and estrogen. ¹¹⁷ These biochemical responses influence the expression of receptor genes and associated proteins, potentially ameliorating the condition of AD patients. ¹¹⁸ For instance, estrogen plays a role in reducing Aβ deposition, demonstrating a neuroprotective effect. Additionally, music induces the release of dopamine, a neurotransmitter linked to emotional responses, which can contribute to the therapeutic impact of MT.^116,117 Empirical evidence, such as the study conducted by Satoh et al., underscores the efficacy of six months of MT in enhancing memory recall and alleviating neurological symptoms. Furthermore, the emotional valence of music, ranging from cheerful to poignant, elicits varied effects on AD patients’ cognitive and emotional states. ⁹⁴ Notably, Garcia et al.'s findings suggest that emotionally evocative music can evoke memories in AD patients. ¹¹⁹ Additionally, familiar or preferred musical selections can enhance memory and linguistic capabilities. ¹²⁰ Arroyo-Anllo et al.'s research highlights the role of familiar music in augmenting self-awareness among AD patients. ⁹⁶ Importantly, MT demonstrates efficacy in mitigating symptoms such as anxiety, depression, and agitation, fostering a more positive behavioral repertoire in affected individuals. By promoting engagement in activities and reducing negative behaviors, such as wandering or aggression, MT cultivates a sense of accomplishment and belonging among AD patients. ⁹⁵

Olfactory stimulation therapy

In individuals afflicted with AD, olfactory dysfunction manifests across a spectrum of severity. In the early stages of AD pathology particularly, degenerative processes target key olfactory structures such as the olfactory bulb and piriform cortex, notably impacting the anterior olfactory nucleus, where a proliferation of neurofibrillary tangles is observed. This degeneration disrupts the intricate connectivity between the hippocampus and cerebral cortex, impeding the transmission of crucial signaling factors necessary for complex olfactory processing. ¹²¹ It is also noted that this impairment is correlated with declines in linguistic learning and memory retention capabilities.

Olfactory stimulation therapy emerges as a promising intervention with neuroprotective properties, attenuating the deleterious effects of Aβ accumulation in the brain and serving as an efficacious strategy for ameliorating neurological dysfunction. ¹²² During such therapy sessions, a network of interconnected brain regions including the olfactory cortex, hippocampus, amygdala, lateral cortex, olfactory bulb, and piriform cortex is directly engaged and activated. ¹²³ Notably, fMRI studies demonstrate robust activation within the amygdala and hippocampus, regions integral to memory processing. Given the amygdala's role within the limbic system as a pivotal hub for emotion regulation and memory consolidation, its involvement underscores the emotional resonance evoked by olfactory stimuli. Moreover, research indicates that olfactory cue memory elicits activation within the limbic system and temporal lobe structures, encompassing regions such as the middle temporal gyrus, bilateral superior temporal gyrus, temporal-parietal cortex, anterior olfactory cortex, cerebellar tonsil, and right insula, among others. ¹²⁴ Consequently, odors wield a potent capacity to evoke vivid memories. Glachet et al.^97,98 conducted a seminal investigation probing the impact of olfactory stimulation therapy on the autobiographical memory of past events and the imaginative faculties regarding future scenarios in AD patients. Employing a diverse array of aromas tailored to individual patient preferences, the study demonstrated that olfactory stimulation therapy significantly enhanced the vividness and clarity of both memories and future projections. This observed augmentation is attributed to the unique ability of odors to enhance autobiographical specificity, facilitated by the close anatomical proximity of neurons linking the olfactory bulb and limbic system. ¹²⁵ Furthermore, the activation of the amygdala-hippocampal complex underscores its pivotal role in retrieving emotionally laden memories, ¹²⁴ thus elucidating the mechanisms underpinning odor-induced autobiographical memory enhancement.

Photothermal therapy

In the realm of therapeutic interventions for AD, photothermal therapy (PTT) has garnered increasing attention owing to its precise temporal and spatial control. Leveraging photothermal materials hold promise in modulating Aβ aggregation, thereby presenting therapeutic avenues for AD. ¹²⁶ These materials utilized in PTT encompass various nanomaterials adept at absorbing photon energy and converting it into heat. The research underscores the efficacy of long-wave near-infrared light (NIR) in targeting deep-seated Aβ pathology within the brain. ¹²⁷ Given the temperature-dependent nature of Aβ formation, localized temperature fluctuations wield considerable influence over Aβ aggregation dynamics. Consequently, a spectrum of photothermal materials has been scrutinized for AD intervention, of which gold nanoparticles are one of the most prominent. ¹²⁸ Gold nanoparticles, spanning gold nanospheres (AuNSs) and gold nanorods (AuNRs), epitomize the preeminent plasmonic nanomaterials underpinning PTT research. ¹²⁸ Formulated Aβ-AuNPs conjugates, synthesized by coupling AuNPs with truncated Aβ peptides, exhibit a propensity for precipitating Aβ aggregates. Subsequent exposure to intense femtosecond laser pulses swiftly increases the temperature of AuNPs, inducing the formation of vapor nanobubbles (VNBs) around the surfaces of AuNPs. These VNBs undergo rapid collapse, unleashing high-pressure shock waves that disrupt Aβ aggregates. ¹²⁹ Distinguished by reduced cytotoxicity and heightened surface plasmon resonance effects, polyethylene glycol-coated AuNRs (AuNRs-PEG) wield superior efficacy compared to AuNPs. ¹²⁶ Under 800 nm femtosecond laser irradiation, transient mechanical forces acting upon AuNRs-PEG surfaces impede pre-formed Aβ fibrils, prompting their fragmentation into smaller entities marked by diminished β-sheet structures. ¹³⁰ Moreover, lipid-stabilized AuNRs, endowed with negative charges, fulfill dual roles: selectively binding to cationic Aβ sequences via electrostatic interactions facilitated by anionic liposomes, thereby thwarting Aβ fibrillogenesis, and fostering thermal dissolution of mature Aβ fibrils into smaller fragments through localized hotspot generation upon exposure to 800 nm near-infrared light. ¹³¹ Additionally, near-infrared light-responsive AuNSs have been utilized in modulating fibrous Aβ formation and disassembling Aβ deposits. Ruthenium-complex-modified penetration (Pen) peptides, loaded onto PEG-stabilized AuNSs (Ru@Pen@PEG-AuNSs), not only inhibit Aβ aggregation but also disrupt Aβ fibrils effectively. This dual-action mechanism mitigates Aβ-induced cell apoptosis while facilitating the restoration of neuronal dendritic growth and branching. ¹³² Furthermore, metal nanomaterials endowed with plasmonic photothermal properties, including silver triangular nanoplates and Fe3O4 nanoparticles, have emerged as potent agents for the rapid dissolution of Aβ fibrils. Noteworthy investigations highlight the capacity of silver triangular nanoplates to degrade Aβ fibrils within a remarkably short timeframe under near-infrared light irradiation. ¹³³ The process of anchoring carbon nitride (C3N4) nanodots onto Fe3O4@mesoporous silica nanoparticles and modifying them with benzothiazole aniline has yielded an intelligent nanosystem boasting metal ion chelation capabilities and targeted therapy potential. This sophisticated platform orchestrates Aβ aggregation induction and facilitates the decomposition of mature Aβ fibrils under near-infrared light irradiation, showcasing promise for AD intervention at the nanoscale level. ¹³⁴

Body temperature stands as one of the earliest documented metabolic metrics, and its modulation plays a crucial role in the paradigm of healthy aging. Across the aging continuum, individuals frequently encounter disruptions in body temperature regulation, manifesting as a progressive decline in average body temperature. This physiological shift results in diminished heat generation and compromises the organism's capacity to uphold its core temperature, indicative of a gradual attenuation in the efficacy of the thermoregulatory mechanism. The waning proficiency in temperature regulation among older demographics can be attributed in part to the age-related decline in the metabolic activity of brown adipose tissue (BAT). ¹³⁵ Compelling research underscores a potential nexus between the incremental emergence of metabolic perturbations and the onset of AD within the aging population. ¹³⁶ Moreover, the exponential rise in AD incidence among individuals grappling with temperature regulation anomalies underscores the tantalizing prospect of temperature modulation interventions as a potential avenue for ameliorating AD pathology.

Neutral thermal refers to the condition where, within a certain range of environmental temperatures, animals do not require additional heat production to maintain core body temperature beyond the energy generated by basal metabolism. For example, the core temperature of mice is approximately 28 °C, while the core temperature of humans ranges between 36.5 to 37.5 °C, with rectal measurements most closely reflecting core temperature. In the neutral thermal zone, mammals can generate enough heat through metabolism to counteract temperature decreases, thereby maintaining a stable body temperature even without physical activity. By maintaining a neutral thermal environment, cognitive function and neuropathology can be improved in AD mice and AD patients. Research has found that exposing 3×Tg-AD mice to a warm environment of 28 °C for 7 days resulted in an average increase of 0.95 °C in rectal temperature. ¹³⁷ Furthermore, intervention with a neutral thermal environment was found to restore their recognition memory function as observed through object recognition tasks and light-dark box experiments. ¹³⁷ Another study exposed type 2 diabetes db/db mice to temperatures of 34 to 35 °C for 1 h and found that rectal temperatures of the mice returned to levels comparable to the control group, with a significant improvement in phosphorylation sites of tau protein. ¹³⁸ For elderly individuals experiencing skeletal muscle function decline, thermotherapy can enhance their function and mitochondrial energy metabolism. A clinical study demonstrated that pulsed short-wave diathermy could increase muscle temperature, thereby reducing muscle atrophy and preventing mitochondrial dysfunction. ¹³⁹ Additionally, passive heating can improve reduced cerebral blood flow and blood-brain barrier dysfunction in AD patients. A study found that thermotherapy can improve skin microvascular function, increase pulse wave velocity, and reduce vessel wall thickness, thus aiding in maintaining cerebral blood flow and blood-brain barrier function. ¹⁴⁰ Moreover, sauna bathing has been found to increase core body temperature, lowering the risk of dementia such as AD.^141,142 Research on Drebrin protein suggests that a neutral thermal environment can increase its expression. ¹³⁷ Drebrin protein plays a significant role in synaptic plasticity by influencing dendritic spine morphology and structure, thereby regulating memory function.^143,144 The increase in temperature in a neutral thermal environment can also increase the expression of LRP1 transport protein, thereby reducing insoluble Aβ₄₂ levels in the cerebral cortex, which is beneficial for improving the pathological process of AD.^145,146

Moreover, a decrease in core body temperature can trigger excessive phosphorylation of tau. ¹³⁷ BAT serves as the principal thermogenic tissue in mammals. By stimulating BAT thermogenesis to uphold body temperature, it can rectify thermoregulatory and metabolic aberrations, thereby impeding cold-induced tau hyperphosphorylation. ¹³⁶ In a study involving aged C57BL6/129SvJ mice exposed to 4 °C cold for 24 h, a significant increase in tau phosphorylation was observed in the cortical region of their brains, accompanied by markedly elevated levels of soluble tau pThr181 and pThr231. ¹³⁶ Similarly, subjecting 3×Tg-AD mice to 4 °C cold for 24 h led to heightened tau phosphorylation increased soluble Aβ protein concentration, and synaptic protein loss in the cortical region of their brains. ¹³⁷ Furthermore, aged (15-month-old) 3×Tg-AD mice that were subjected to 4 °C cold exposure for 4 h per day, 5 days per week, for 4 weeks demonstrated that repeated short-term cold exposure could augment BAT thermogenesis, ameliorate glucose tolerance, and shield mice from cold-induced tau hyperphosphorylation. Notably, in mice exposed to repeated short-term cold, the expression of silencing regulatory protein 3 (SIRT3) in BAT increased. SIRT3, expressed in BAT mitochondria under fasting or cold exposure conditions, effectively stimulated BAT thermogenesis during repeated short-term cold exposure. ¹⁴⁷ Additionally, when AD mice were exposed to 4 °C cold for 3 h per day for 3 days, it was discovered that cold exposure could counteract AD-induced lipid metabolism changes, indicating the potential protective effect of brief cold exposure intervention against AD. ¹⁴⁸ In summary, a thermoneutral environment primarily increases Drebrin content and reduces insoluble Aβ in the cerebral cortex, while repeated short-term exposure to 4 °C induces BAT thermogenesis, improves thermoregulation and metabolic defects, and blocks cold-induced tau hyperphosphorylation. This suggests that correcting thermoregulatory defects may have therapeutic implications for AD.

Multisensory stimulation has shown promise in enhancing cognitive and emotional well-being among individuals with AD, while also mitigating psychological symptoms such as depression and anxiety, thereby improving overall quality of life. The design of multisensory environments, exemplified by Snoezelen rooms and therapeutic gardens, integrates visual, olfactory, tactile, and auditory elements, potentially playing a pivotal role in the daily care of AD patients. The Snoezelen approach, tailored for AD patients, focuses on directly stimulating the senses rather than simply providing environmental enrichment for patient activities. Conversely, therapeutic gardens encourage physical interaction with natural elements. ¹⁴⁹ Research supporting the effectiveness of Snoezelen interventions suggests a moderate impact in reducing various challenging behaviors associated with AD. However, studies, such as the one conducted by Goto et al., ¹⁴⁹ have demonstrated varying effects on AD patient behavior between Snoezelen activity rooms and therapeutic gardens. While the therapeutic gardens have shown positive changes, Snoezelen rooms have sometimes elicited more negative responses from participants. Investigations by Rivasseau et al. ¹⁵⁰ have delved into the therapeutic effects of different sensory stimuli in therapeutic gardens, highlighting their potential to enhance cognitive function and alleviate psychological symptoms in AD patients, ultimately fostering interpersonal connections and communication. Additionally, Gueib et al. ¹⁵¹ have observed enhancements in self-awareness among AD patients engaging in multisensory therapeutic garden activities. In our study, we explored the effects of a multifaceted intervention involving voluntary wheel running, involuntary treadmill running, and auditory and visual stimuli on neuroregeneration and behavioral outcomes in an AD mouse model. The findings revealed a significant reduction in toxic proteins and promotion of neuronal regeneration following the four-week intervention, underscoring the potential of multifaceted interventions as non-invasive therapeutic strategies against AD oligomer neurotoxicity. ⁶

VR technology facilitates the creation of a richly immersive, dynamic, and interactive virtual environment that closely mirrors real-life experiences. In their work, Park et al. ¹⁵² leveraged VR technology for game-based training in dementia patients. Comparative analysis of pre-and post-treatment outcomes demonstrated notable enhancements in balance, emotional well-being, and overall quality of life among participants with cognitive decline who underwent VR-based therapy. MT holds promise for augmenting the emotional well-being of individuals with AD, and when integrated with VR technology, it offers enhanced focus and improved training and therapeutic outcomes. Incorporating calming music into VR training sessions can assist patients in immersing themselves more deeply into the virtual environment. In a study by Optale et al., ¹⁵³ 36 patients engaged in VR visual and auditory training, followed by a six-month intervention featuring soothing background music. Evaluation of participants’ linguistic proficiency, cognitive function, and depressive symptoms indicated that VR training significantly bolstered cognitive function, language proficiency, and memory among those in the treatment cohort.

An increasing body of research has confirmed the benefits of utilizing sensory and multisensory stimulation in enhancing memory and alleviating behavioral symptoms in AD patients. These approaches have been validated in AD patients, with studies demonstrating their safety and efficacy. However, the mechanisms underlying the improvement of memory and behavioral symptoms through sensory stimulation are still being explored. Moreover, these treatment modalities have garnered significant attention in clinical trials, particularly in their potential to enhance patients’ quality of life.