Therapeutic advances in Alzheimer’s disease: Current strategies and future possibilities

ABSTRACT

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder causing memory, cognitive, and behavioral impairments in older adults and poses a major worldwide health challenge. The pathophysiology of AD is highly complex and multifactorial, arising from interrelated processes such as amyloid-β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, mitochondrial impairment, and oxidative stress. In addition, both genetic predisposition and environmental or lifestyle factors play critical roles in disease susceptibility and progression. Despite decades of investigation, therapeutic options with robust disease-modifying potential remain limited. Based on published studies from 2021 to 2025, current treatments primarily focus on symptomatic management with cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and combined therapies, complemented by nonpharmacological interventions to support cognition and quality of life. Recently, advances in disease-modifying strategies, particularly monoclonal antibodies targeting Aβ, tau-directed therapies, and approaches modulating neuroinflammation, have generated cautious optimism for shifting the treatment paradigm. Importantly, emerging evidence suggests that specific herbal extracts with antioxidant, anti-inflammatory, and neuroprotective properties may serve as promising adjuncts to conventional therapy. Effective long-term management of AD may ultimately require multimodal strategies that integrate pharmacological, herbal, and lifestyle interventions with precision medicine approaches guided by biomarkers and neuroimaging. This minireview summarizes current therapeutic strategies, emerging advances, and persistent challenges, while highlighting future directions to enable earlier intervention and more effective modulation of disease progression.

INTRODUCTION

Alzheimer’s disease and public health impact

Alzheimer’s disease (AD) exerts a profound public health impact worldwide, with both prevalence and associated costs steadily rising as populations age. Between 1991 and 2021, the prevalence of AD and related dementias among adults aged 65 and older increased by 1.6 times, reaching about 49 million affected individuals in 2021, and projections point to even higher numbers in the coming decades [1]. According to estimates from the Chicago Health and Aging Project and U.S. Census data, approximately 7.2 million Americans aged 65 and older are living with AD in 2025 [2]. On the Asian continent, it is expected that low- and middle-income nations will account for more than 60% of all global AD cases [3]. Recent national surveys reveal that the prevalence of dementia among adults aged 65 and older is 8.69% in Taiwan, 9.5% in Japan, 8.5% in Malaysia, 8% in Bangladesh, 9.11% in China [4], and around 10% in Thailand [5].

AD substantially contributes to disability-adjusted life years and increases mortality, impacting not only patients but also families and health systems, evidenced by consistent annual rises in these rates across different age groups and regions. Furthermore, the financial burden includes growing direct costs, such as medical and long-term care, alongside indirect costs from reduced productivity of unpaid caregivers [1]. Collectively, these challenges underscore the urgent need to understand AD pathology better and to develop innovative, accessible therapies to mitigate its growing impact on individuals, society, and the economy.

For this minireview, the literature was surveyed across multiple biomedical databases, including PubMed, Scopus, Web of Science, and Google Scholar. The search primarily covered publications from 2015 to 2025, with particular emphasis on pharmacological and nonpharmacological therapeutic advances reported within the past 5 years. Search terms included “Alzheimer’s disease,” “antiamyloid immunotherapy,” “tau-targeted therapy,” “FDA-approved treatments for Alzheimer’s disease,” “small-molecule drugs,” “biomarkers of Alzheimer’s disease,” “herbal products in clinical trials,” and “lifestyle interventions.” Only English-language articles were considered. The literature selection prioritized peer-reviewed original research articles, late-phase clinical trials, consensus guidelines, and high-quality review articles, while including preclinical and early-phase studies to illustrate emerging mechanisms and exploratory therapeutic strategies.

PATHOPHYSIOLOGY OF A LZHEIMER’S DISEASE

The pathophysiology of AD centers on the buildup of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau, which together disrupt neuronal function and drive progressive cognitive decline [6]. These hallmark pathological features provoke chronic neuroinflammation, driven by the activation of microglia and astrocytes, as well as oxidative stress and mitochondrial dysfunction, which further contribute to neuronal injury and synaptic loss [7]. Synapses facilitate communication between neurons, which is necessary for encoding, storing, and recalling information [8]. In AD, synaptic loss is observed in multiple brain regions, including the cortex and hippocampus, which correlate with the severity and progression of the disease [7].

Excitotoxicity, resulting from excessive N-methyl-D-aspartate (NMDA) receptor activation, alterations in neurotransmitter systems (particularly acetylcholine and glutamate), and disturbances in protein clearance pathways, including the ubiquitin–proteasome and autophagy–lysosomal systems, have also been implicated in AD progression [9]. The onset of AD is influenced not only by molecular and cellular abnormalities but also by the interplay of genetic and lifestyle factors. Genetically, mutations in the amyloid precursor protein (APP), presenilin 1, and presenilin 2 genes drive early-onset familial AD, while the apolipoprotein E ε4 (APOE ε4) allele is the most substantial genetic risk factor for late-onset AD [10]. The National Institute on Aging (NIA) and recent clinical cohort studies reported that lifestyle and environmental factors, such as physical inactivity, poor diet, cardiovascular disease, diabetes, and smoking, also critically influence the risk of developing AD [11]. Interactions among Aβ, tau, inflammation, and these diverse risk factors drive a vicious cycle of neurodegeneration that leads to progression of brain atrophy and the clinical symptoms of AD [Figure 1].

Figure 1.

Overview of Alzheimer’s disease (AD) pathogenesis and risk factors. The figure illustrates the interconnected factors involved in AD. Extracellular amyloid-β plaques and intracellular neurofibrillary tangles are the hallmark pathologies that drive progressive brain atrophy and cognitive decline in AD. In addition, neuroinflammation, synaptic loss, and oxidative stress/mitochondrial dysfunction are depicted as core molecular processes interconnected with hallmark lesions. Genetic risk factors (APP, PSEN1, PSEN2, APOE ε4) and lifestyle/environmental factors (physical inactivity, poor diet, smoking, diabetes, and cardiovascular disease) are shown as key contributors that increase AD risk. Ultimately, the interplay between these molecular, genetic, and lifestyle influences drives AD-related neuropathological changes and symptoms of this disease

Although the amyloid cascade hypothesis has long guided AD research, its limitations are evident, as amyloid-PET burden explains only 5%–15% of variance in cognitive decline, and plaque removal alone has yielded limited clinical benefit [6]. This has shifted therapeutic focus toward soluble Aβ oligomers, whose synaptotoxic effects better align with clinical outcomes, with oligomer-targeting therapies demonstrating 25%–30% slowing of cognitive decline in early AD, supporting a multipathway disease model integrating amyloid toxicity with tau pathology and synaptic failure [12].

CLINICAL STAGING AND PATHOLOGICAL PROGRESSION OF ALZHEIMER’S DISEASE

Clinical stages

The AD continuum describes the trajectory from asymptomatic brain pathology to advanced dementia. According to the 2024 revised criteria [13], clinical stages are classified from 0 to 6, as shown in Table 1 [2,13]. Under the 2024 NIA–Alzheimer’s Association (AA) Revised Criteria, AD is defined biologically rather than solely by clinical symptoms. Accordingly, Stage 1 disease reflects the presence of objective biomarker evidence of Alzheimer’s pathology, rather than nonspecific or subjective subtle biomarker changes. Specifically, Stage 1 is characterized by abnormal Aβ biomarkers (A+) and/or tau biomarkers (T+), as defined within the ATN[V] framework, in individuals who may remain cognitively unimpaired. These biomarker alterations indicate early Alzheimer’s pathophysiology before overt neurodegeneration or clinical symptom manifestation. These numerical stages correspond to three broader clinical phases: Early, moderate (middle), and severe (late), which describe the progression of everyday symptoms [13]. Stages 0–1 display no symptoms, while at Stage 2, subtle cognitive, mood, or motivational changes appear. Early-stage AD, corresponding to Stage 3 (early functional impact) and Stage 4 (mild dementia with instrumental ADL dependence), features memory lapses, repetitive questioning, difficulty managing finances, disorientation, misplaced belongings, apathy, and depression [2,13]. Middle stage (Stage 5) is characterized by increased memory loss, struggles with personal care tasks such as brushing teeth and dressing, loss of recognition of familiar people, emotional lability, disorientation, sleep–wake disturbances, and behavioral changes, including suspiciousness, delusions, or repetitive movements [2,13]. Assistance is needed for most activities of daily living. Late stage (severe), aligning with Stage 6, is characterized by profound cognitive and physical decline [2,13]. Patients lose awareness of their surroundings, experience significant speech and swallowing difficulties, become entirely dependent, and physical complications such as immobility and aspiration pneumonia often occur. Integrating the 0–6 staging framework and the broader early–middle–late classification helps clinicians and researchers characterize progression, guide care planning, and target interventions.

Table 1.

Clinical trajectory of Alzheimer’s disease progression

Clinical stage	Symptoms
Stage 0	No symptoms; abnormal amyloid/tau biomarkers; preserved cognition
Stage 1	No symptoms; abnormal amyloid/tau biomarkers; preserved cognition
Stage 2	Subtle cognitive, mood, or motivational changes ≥6 months; independence maintained
Stage 3	Measurable cognitive impairment affecting complex daily tasks; basic independence preserved
Stage 4	Mild dementia; independent in basic activities but requiring assistance with instrumental tasks
Stage 5	Moderate dementia: help needed for daily care; memory, language, and behavioral changes are evident
Stage 6	Severe dementia; complete dependence; significant cognitive and physical decline, often with complications such as aspiration pneumonia

Pathological frameworks

Thal amyloid phase system

According to the 2012 NIA-AA guidelines, the ABC score is used to summarize the degree of AD neuropathological changes. The score integrates three key assessments: amyloid deposition measured by Thal phases (A), neurofibrillary tangle burden determined by Braak stage (B), and neuritic amyloid plaque density based on the Consortium to Establish a Registry for Alzheimer’s Disease criteria (C) [14].

Aβ deposits are not limited to the medial temporal lobe but also occur in diverse brain regions, including the allocortex, neocortex, striatum, hypothalamus, thalamus, basal forebrain nuclei, cerebellum, and brainstem. Post-mortem studies reveal five phases of Aβ deposition, with plaques first appearing in the neocortex (Phase 1), especially the temporal and occipital cortices, before spreading to other regions. Positron emission tomography (PET) imaging shows that, in AD mutation carriers, Aβ can accumulate throughout most cortical areas (except the sensorimotor cortex) as early as 15 years before symptom onset [15]. In Phase 2, Aβ pathology advances to the hippocampus and allocortical areas, such as the entorhinal cortex and the subiculum/CA1 region of the hippocampal formation, with occasional single deposits in related structures [16]. Phase 3 further spreads into subcortical nuclei, including the basal ganglia (striatum), thalamus, hypothalamus, and basal forebrain, along with additional amyloid-like deposits in the white matter and molecular layers of the cortex [16]. In 10%–45% of phase 3 cases, Aβ deposits can be found in the central gray matter, superior and inferior colliculi, hilus of the dentate gyrus (CA4), the red nucleus, and the subthalamic nucleus. Phase 4 involves the extension of Aβ to midbrain sites, such as the red nucleus, substantia nigra, and brainstem reticular formation, with plaques becoming more numerous in the medulla oblongata, pons, and select nuclei. The cerebellum typically remains unaffected [16]. By Phase 5, Aβ deposits are widely distributed throughout the brain, including the pons, the central and dorsal raphe nuclei, the locus coeruleus, the parabrachial nuclei, and the cerebellum, particularly in the molecular layer, indicating advanced amyloid pathology [16].

Braak staging system

The Braak staging system is a widely used method for assessing the severity and progression of AD based on the anatomical distribution of NFTs. Developed by Braak and Braak [17], this hierarchical system tracks the spread of tau pathology: Stages I–II, known as the transentorhinal stages, begin with tau aggregates in the transentorhinal area of the hippocampus (stage I) and become denser, then spread to the subiculum region of the hippocampal pyramidal cell layer (stage II) [18]. Early neuropathological changes in neurodegenerative diseases are often asymptomatic or manifest only as subtle cognitive alterations that may escape clinical detection. Although Clinical Dementia Rating (CDR) scores correlate positively with Braak neurofibrillary tangle staging [18], the correspondence between neuropathological burden and clinical presentation is not always linear. In elderly individuals, even the earlier Braak stages may not be entirely clinically silent, as subtle deficits in memory, executive function, or attention may become more apparent with advancing age and reduced cognitive reserve [19]. As tau aggregates expand from the transentorhinal region to the subiculum of the hippocampus and related limbic structures, the disease transitions into Stages III–IV, or limbic stages, with pathology advancing to the entorhinal cortex, hippocampal CA1 sector (Stage III), and spreading to the inferior temporal cortex and superior frontal areas (stage IV) [18]. Here, mild cognitive impairment (MCI) and memory issues begin to surface, with more consistent links to CDR scores and the clinical presentation of mild dementia [19]. In the later Braak stages V–VI, or neocortical stages, tau pathology encompasses the neocortex, including secondary association and primary cortical regions involved in higher-order functions such as language, sensory integration, and complex thinking [20]. At these stages, pronounced cognitive and functional deficits become apparent, and patients lose the ability to function independently, marking the fully developed stage of AD both pathologically and clinically.

PHARMACOLOGICAL TREATMENTS

Symptomatic pharmacological treatments for AD are aimed at alleviating cognitive and functional deficits without directly modifying the underlying neuropathology. They do not halt disease progression, nor do they modify or arrest the underlying neuropathological mechanisms responsible for AD development [2]. Instead, available therapies act primarily by enhancing cholinergic neurotransmission, modulating glutamatergic activity, and targeting pathological protein aggregation and clearance. These interventions aim to mitigate neurotransmitter deficits and maintain synaptic function, thereby providing temporary stabilization or modest improvement in cognitive performance and activities of daily living among affected individuals. Despite these benefits, their effects are largely symptomatic, offering only transient relief without altering the long-term trajectory of neuronal degeneration or cognitive decline. Table 2 summarizes the drug class, Food and Drug Administration (FDA) approval year, mechanism of action, clinical use (Stages 0–6), and common side effects for symptomatic pharmacological treatments.

Table 2.

Symptomatic pharmacological treatments for Alzheimer’s disease with Food and Drug Administration approval

Drug class	Drugs (FDA approval year)	Dosage, administration route	Mechanism of action	Clinical use (Stages 0–6)	Common side effects
Cholinesterase inhibitors	Donepezil (Aricept®, Adlarity®, 1996) [21]	Mild-moderate; 5–10 mg, QHS, PO Moderate-severe; 23 mg, QHS, PO 5–10 mg, 24 h, transdermal patch	Selective, reversible inhibition of acetylcholinesterase, ↑ synaptic acetylcholine	Stage 3 (MCI with functional impact), Stage 4 (mild dementia), Stage 5 (moderate dementia), and Stage 6 (severe dementia)	Nausea, diarrhea, vomiting, insomnia, muscle cramps, fatigue, and weight loss
	Rivastigmine (Exelon®, 2000) [2,22]	6–12 mg, BID, PO 4.6–13.3 mg, 24 h, transdermal patch	Inhibits acetylcholinesterase and butyrylcholinesterase, ↑ brain acetylcholine	Stage 3 (MCI with functional impact), Stage 4 (mild dementia), Stage 5 (moderate dementia), and Stage 6 (severe dementia)	Nausea, vomiting, diarrhea, dizziness, anorexia, muscle weakness, and fatigue
	Galantamine (Razadyne®), 2001) [23]	Extended release; 16–24 mg, QD, PO Immediate release; 8–12 mg, BID PO	Reversible inhibition of acetylcholinesterase, ↑ acetylcholine; allosteric modulation of nicotinic receptors	Stage 3 (MCI with functional impact) and Stage 4 (mild dementia)	Nausea, vomiting, diarrhea, insomnia, dizziness, decreased appetite, and headache
	Benzgalantamine (Zunveyl®, 2024) [24]	Delayed-release tablet; 32 mg, QD, PO	Prodrug of galantamine; Reversible inhibition of acetylcholinesterase, ↑ acetylcholine; allosteric modulation of nicotinic receptors	Stage 3 (MCI with functional impact) and Stage 4 (mild dementia)	Nausea, diarrhea, headache, decreased appetite, dizziness; and rare: bradycardia
NMDA receptor antagonist	Memantine (Namenda®, 2003) [25]	5 mg, QD, PO Immediate release; 20 mg, QD, PO Extended release; 7–28 mg, QD, PO	Uncompetitive NMDA receptor antagonist; reduces glutamate-induced excitotoxicity while preserving normal signaling	Stage 5 (moderate dementia) and Stage 6 (severe dementia)	Dizziness, headache, constipation, and confusion
Combination therapy	Memantine + Donepezil (Namzaric®, 2014) [26]	Extended release; 28 mg/10 mg, QD, PO	Dual action: enhances cholinergic activity (donepezil) and reduces glutamatergic excitotoxicity (memantine)	Stage 5–6 (moderate-to-severe dementia)	Combination of the above: nausea, dizziness, headache, and constipation
Antiamyloid immunotherapy	Aducanumab (Aduhelm®, 2021) [27]	10 mg/kg, Q4W, following titration, IV	Binds to soluble and insoluble forms of Aβ aggregates; promotes plaque removal	Stage 2 (MCI due to AD), Stage 3 (MCI with functional impact), and Stage 4 (mild dementia)	Edema, microhemorrhage, headache, confusion, dizziness, nausea; rare: seizures, stroke, and severe allergic reactions
	Lecanemab (Leqembi®, 2023) [28]	Initial; 10 mg/kg, Q2W, IV Maintenance; 10 mg/kg, Q4W, IV	Binds to soluble Aβ protofibrils and prevents plaque formation	Stage 2 (MCI due to AD), Stage 3 (MCI with functional impact), and Stage 4 (mild dementia)	Fever, nausea, chills, vomiting, dizziness, headache, falls, edema, and microhemorrhage
	Donanemab (Kisunla®, 2024) [29]	Titrated from 350–1400 mg, Q4W, IV infusion	Binds to an N-terminal pyroglutamate-modified form of Aβ at position 3 (pGlu3-Aβ)	Stage 2 (MCI due to AD), Stage 3 (MCI with functional impact), and Stage 4 (mild dementia)	Headache, infusion reactions, confusion, seizure, delirium, brain inflammation, stroke-like symptoms, edema, and microhemorrhage

NMDA: N-methyl-D-aspartate, ↑: Increase, Aβ: Amyloid-beta, MCI: Mild cognitive impairment, pGlu3-Aβ: Pyroglutamate-3 amyloid-beta, PO: Oral administration, IV: Intravenous infusion, QHS: Nightly, Q2W: Every two weeks, Q4W: Every 4 weeks, QD: Once daily, BID: Twice daily, FDA: Food and Drug Administration, AD: Alzheimer’s disease

Cholinesterase inhibitors

Cholinesterase inhibitorsact by inhibiting acetylcholinesterase, the enzyme responsible for degrading acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability and enhancing cholinergic neurotransmission. This mechanism targets the cholinergic deficit consistently observed in AD patients, contributing to memory and attention impairments [30]. Donepezil (Aricept®) received FDA approval in 1996 [31], followed by rivastigmine (Exelon®) in 2000 [2,22], galantamine (Razadyne®) in 2001 [23], and benzgalantamine, a prodrug of galantamine, in 2024 [24]. These medications are generally prescribed during MCI with early functional impact (Stage 3), mild dementia (Stage 4), moderate dementia (Stage 5), and severe dementia (Stage 6) [2,13]. Clinical trials demonstrate modest improvements in global cognition, activities of daily living, and caregiver burden [2]. However, their efficacy is often transient, with benefits diminishing as the disease progresses. Common side effects include gastrointestinal symptoms (nausea, vomiting, and diarrhea), headaches, dizziness, and muscle cramps, which may limit tolerability in some patients [2].

N-methyl-D-aspartate receptor antagonists

Memantine (Namenda^®), approved in 2003, is a low-to-moderate affinity, uncompetitive antagonist of the NMDA receptor, which regulates glutamatergic neurotransmission [25]. In AD, chronic excitotoxicity due to excessive glutamate release contributes to neuronal injury and cognitive decline [9]. Memantine confers neuroprotective effects and stabilizes cognitive performance by blocking pathological NMDA receptor activity while sparing normal synaptic signaling [31]. It is typically indicated for moderate to severe dementia (Stages 5–6), either as monotherapy or in combination with donepezil [32]. Clinical studies report that memantine improves global outcomes and prolongs functional independence in some patients [33]. The most reported adverse events associated with memantine in clinical trials include dizziness, headache, confusion, diarrhea, and constipation [34]. Less frequent but notable adverse events comprise fatigue, pain, hypertension, weight gain, hallucinations, aggressive behavior, vomiting, abdominal discomfort, and urinary incontinence [32].

Combination therapies

In 2014, the FDA approved a fixed-dose combination of memantine and donepezil (Namzaric^®), which targets both cholinergic and glutamatergic dysfunction [26]. Combination therapy is primarily indicated for individuals in Stage 5 and Stage 6 of AD [25,26]. Clinical trials demonstrate that this dual approach modestly improves cognition, global function, and daily living activities compared with monotherapy, although benefits are often temporary and vary among patients [25,35]. Common side effects include headache, dizziness, nausea, and constipation, consistent with the safety profiles of the individual agents [25]. Importantly, donepezil and memantine do not modify the underlying neuropathological process of AD. They are symptomatic agents that help maintain cognitive function and independence for a limited time, but they cannot slow, stop, or reverse disease progression [2,35].

Antiamyloid immunotherapy

Aducanumab (Aduhelm^®), approved in 2021 [27], followed by Lecanemab (LEQEMBI^®) in 2023 [28], and Donanemab (Kisunla^®) in 2024 [29] are monoclonal antibodies developed as antiamyloid therapies for AD, each designed to recognize and clear Aβ aggregates that are central to the disease’s pathophysiology. Aducanumab (10 mg/kg, IV infusion), approved earlier, also targets aggregated Aβ, but has faced greater scrutiny regarding its clinical efficacy due to mixed results in phase 3 trials, which showed discordant clinical benefit despite consistent reduction in Aβ plaques [36]. Lecanemab targets Aβ as it forms fibers, while donanemab binds more mature plaques, resulting in distinct pharmacological profiles and dosing regimens. Lecanemab (10 mg/kg) is an intravenous infusion administered biweekly [28], and donanemab (700 mg) monthly [37]. Clinical trials such as CLARITY-AD and TRAILBLAZER-ALZ2 have shown that both lecanemab [28] and donanemab [29] significantly reduce brain amyloid burden and modestly slow cognitive and functional decline in MCI (Stage 2) and early-stage AD (Stage 3–4), with improvements demonstrated in measures like CDR-Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), and Alzheimer’s Disease Composite Score.

In the CLARITY-AD trial, lecanemab reduced decline on the CDR-SB by 27% relative to placebo over 18 months, corresponding to a mean difference of − 0.45 points (95% CI, −0.67 to − 0.23; P < 0.001). Consistent effects were observed across secondary endpoints, with approximately 26% slowing of cognitive decline on the ADAS-Cog14 and 37% slowing of functional decline on the ADCS–MCI–ADL compared with placebo (P < 0.001) [28]. In the TRAILBLAZER-ALZ 2 trial, donanemab produced an approximately 29% relative slowing of decline on the CDR-SB over 76 weeks, with a mean difference of −0.67 points (95% CI, −0.95 to − 0.40; P < 0.001). On the integrated Alzheimer’s Disease Rating Scale, donanemab achieved a 35%–40% slowing of disease progression, corresponding to a mean difference of approximately 6.0 points (95% CI, ~3.2–8.7; P < 0.001) [29]. These clinical benefits must be weighed against treatment-related safety risks. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in approximately 12.6% of lecanemab-treated patients and 24% of donanemab-treated patients. In comparison, ARIA-H (microhemorrhage or superficial siderosis) was observed in 17.3% and 36.8%, respectively, compared with lower rates in placebo groups.

The most common adverse effects of all three medicines recorded include headache, diarrhea, infusion reactions, confusion, nausea, and falls, with the highest risk of developing ARIA-E and ARIA-H. Therefore, to ensure patient safety during antiamyloid immunotherapy, a baseline brain magnetic resonance imaging (MRI) is required to assess treatment eligibility and identify pre-existing cerebrovascular abnormalities. During treatment, scheduled MRI monitoring is recommended before infusions 2^nd, 3^rd, 4^th, and 7^th for donanemab and before infusions 5^th, 7^th, and 14^th for lecanemab, reflecting periods of increased risk of ARIA. If ARIA-E or ARIA-H is detected, treatment interruption or modification is guided by radiographic severity and clinical symptoms, with repeat MRI performed at approximately 4-week intervals until radiographic resolution or stabilization is confirmed [38].

Antitau therapies

Antitau therapies in AD are primarily investigated in patients with prodromal or mild dementia, targeting tau aggregation and propagation to slow disease progression. These therapies include monoclonal antibodies such as semorinemab [39], JNJ-63733657 [40], and MAPT Rx [41]. Semorinemab is a humanized IgG4 monoclonal antibody that specifically binds to the N-terminal domain of tau (amino acids 6–23) to prevent tau propagation across neurons. Recently, semorinemab advanced to phase 2 clinical trials, which allow treatment in Stages 2–4 (prodromal-MCI, mild, moderate AD); however, it has not been approved by the FDA [39] and was discontinued in early 2024 [42]. JNJ-63733657, also known as posdinemab, was developed by Johnson and Johnson and specifically targets tau phosphorylated at threonine 217 (p-tau217), a central player in the formation and spread of neurofibrillary tangles in AD. Beyond its role as a therapeutic target, p-tau217 has emerged as a highly informative blood-based biomarker, enabling blood-first strategies for selecting patients for antiamyloid immunotherapies. This approach can reduce the need for tau-PET imaging and lumbar puncture by 56.9%, while maintaining high sensitivity for identifying amyloid-positive individuals with elevated tau burden [43]. JNJ-63733657 has completed Phase 1 trials in prodromal and mild AD (Stage 2–3) [40] and is currently in a Phase 2b study (AuTonomy) assessing clinical efficacy and biomarker effects in early AD (NCT04619420). It also received the FDA Fast Track Designation, granted in 2025 [44]. MAPT Rx, also known as BIIB080, is an investigational antisense oligonucleotide therapy that received FDA Fast Track designation in April 2025. It works by binding specifically to the premessenger RNA of the MAPT gene in intron 9 to initiate ribonuclease H1-mediated degradation of the message, thereby reducing tau protein production in neurons. MAPT Rx delivered by intrathecal injection to treat mild AD and MCI due to AD (Stage 2–3) is in the phase 1b study (NCT03186989) [41]. It demonstrated that BIIB080 dose-dependently reduced soluble tau protein in cerebrospinal fluid (CSF) and decreased aggregated tau pathology in the brain as measured by PET [41]. The ongoing Phase 2 CELIA study (NCT05399888) is evaluating its efficacy in early-stage Alzheimer’s, with results anticipated in 2026 [45].

Overall, these medications are most effective in early to middle AD, helping to preserve memory and function temporarily. However, responses vary, and benefits are modest. Nonpharmacological approaches, such as cognitive stimulation, behavioral therapy, and caregiver education, are recommended as first-line treatments for behavioral and psychological symptoms, with medications used as adjuncts.

Others

Compared to biologics, small-molecule drugs are advancing as potentially more accessible and cost-effective therapies for AD. In 2022–2025, several promising disease-modifying small molecules have progressed to Phase 3 clinical trials. Notably, ALZ-801 (valiltramiprosate) is an oral prodrug of tramiprosate designed to inhibit Aβ oligomer formation by stabilizing soluble Aβ monomers. In Phase 2 studies, ALZ-801 significantly reduced amyloid-related cognitive decline, particularly among APOE ε4 homozygotes [46]. The ongoing Phase 3 APOLLOE4 trial (NCT04770220), initiated in 2021 and running through 2025, aims to confirm these benefits in a genetically defined AD population [47].

Another key small molecule is masitinib, an oral tyrosine kinase inhibitor first developed for oncology, which targets microglial activation and neuroinflammatory pathways relevant to AD [48]. A multicenter Phase 3 study (AB09004, NCT01872598) demonstrated that masitinib slowed cognitive decline and improved functional outcomes in patients with mild-to-moderate AD. The ongoing confirmatory Phase 3 trial (NCT05564169), launched in 2023, is currently assessing the drug’s long-term safety and potential as a disease-modifying agent [49].

Together, ALZ-801 and masitinib represent a diverse pipeline of small-molecule therapeutics targeting amyloid toxicity and neuroinflammation. Relative to biologics, these agents offer essential advantages in terms of oral administration, enhanced brain penetration, and cost efficiency. Small-molecule drugs typically exhibit higher blood–brain barrier (BBB) penetration due to their low molecular weight (400–500 Da), lipophilicity, and compatibility with passive diffusion or active transport mechanisms, enabling broader and more uniform distribution within the brain parenchyma. In contrast, monoclonal antibodies and other large-molecule biologics demonstrate markedly limited BBB penetration, generally estimated at approximately 0.1%–0.3% of circulating drug levels, and rely primarily on peripheral target engagement and indirect central effects [50]. As Phase 3 trial data become available between 2025 and 2026, these small molecules have the potential to reshape the landscape of disease-modifying treatments for AD [51].

Management of behavioral and psychological symptoms

BPSD, including mood disorders (depression and anxiety), agitation/aggression, and psychosis, affects up to 90% of individuals with dementia, varying in prevalence and severity across dementia subtypes and disease stages [52]. These symptoms substantially increase caregiver burden, accelerate institutionalization, and diminish patient quality of life [53]. Pharmacological treatment is typically reserved for cases where BPSD pose safety concerns or prove refractory to nonpharmacological interventions [54].

Second-generation antipsychotics, such as risperidone, olanzapine, and quetiapine, are frequently employed in the management of psychosis due to their comparatively lower incidence of adverse effects than first-generation agents [55]. Recent systematic review and network meta-analysis findings indicate that brexpiprazole demonstrates strong efficacy in treating BPSD, while aripiprazole ranks highest in acceptability and olanzapine lowest in tolerability [55].

Meta-analytic evidence indicates that three selective serotonin reuptake inhibitor–class antidepressants, including citalopram, S-citalopram, and sertraline, may hold therapeutic promise for AD relative to placebo [56]. However, a separate meta-analysis of randomized controlled trials found no significant benefit of antidepressant monotherapy for BPSD [57]. Specifically, no improvements were observed in agitation or cognitive outcomes, and current evidence does not support the effectiveness of most antidepressants for managing overall BPSD, especially agitation. Clinicians should remain cautious of adverse effects such as arrhythmia, dizziness, and diarrhea [57]. These findings underscore the need for further investigation into antidepressant use in AD, with emphasis on combination therapies over monotherapy and patient-specific approaches.

Valproic acid (VPA), an FDA-approved anticonvulsant and mood stabilizer, has attracted interest for its potential neuroprotective properties in neurodegenerative disorders, including AD. However, findings from large-scale, randomized, double-blind, placebo-controlled trials indicate that VPA not only failed to mitigate agitation, psychosis, or cognitive decline in AD but also exacerbated certain cognitive and functional impairments. Its adverse effects, such as sedation, gastrointestinal disturbances, and tremors, further limit its clinical utility in this population [58].

Importantly, pharmacological treatment should always follow a thorough assessment of underlying causes and be integrated into a broader care plan. Regular monitoring for efficacy and adverse effects is essential, and deprescribing should be considered when symptoms subside or the risks outweigh the benefits.

Herbal and natural products

Natural products and herbal medicines are adjunctive potentials because they are rich in bioactive molecules, such as polyphenols, flavonoids, alkaloids, and terpenoids, that exhibit multifaceted neuroprotective effects. These compounds act through antioxidants, anti-inflammatory, antiamyloid, and antitau mechanisms, supporting neuronal health and targeting multiple pathogenic pathways involved in neurodegenerative diseases [59].

Ginkgo biloba extract (EGb 761 or Ginexin-F^®) is a standardized extract with well-defined bioactive compositions including 24% flavonoid glycosides and 6% terpene lactones, with ginkgolic acids maintained below five ppm. It is well-known for its ability to scavenge free radicals, prevent mitochondrial dysfunction, activate JNK and ERK pathways, and inhibit neuronal apoptosis, largely due to flavonoids and terpenoids [60]. Phase 3 clinical trials and meta-analyses showed that EGb 761 is safe and provides modest but significant improvements in cognitive function, neuropsychiatric symptoms, and activities of daily living, particularly in patients with mild-to-moderate dementia [61]. In a 2025 clinical study of amyloid PET-positive AD patients, those receiving both donepezil and EGb 761 showed a statistically significant cognitive improvement and a greater reduction in plasma Aβ oligomers over 12 months. In contrast, the donepezil-only group exhibited minimal cognitive change [62].

Panax ginseng extract, including white, red, and fermented types, contains ginsenosides and gintonin that reduce Aβ formation and aggregation, mitigate oxidative stress, and stimulate neurogenesis, supporting cognitive functions in both animal models and AD patients [63]. Panax ginseng extract has been evaluated in multiple phase 2 and phase 3 clinical trials for AD. Recent phase 2/3 clinical trials have shown that oral Panax ginseng extract significantly improves cognitive function in patients with moderately severe AD, as evidenced by gains in both the Alzheimer’s Disease Assessment Scale (ADAS, commonly ADAS-Cog) and the Mini–Mental State Examination (MMSE) scores over 12–24 weeks when compared to controls [64]. In addition, findings suggest that administering Korean red ginseng extract for 24 weeks alongside standard AD medications (such as donepezil, galantamine, and rivastigmine) in patients with mild-to-moderate AD can progressively enhance cognitive function, with minimal side effects reported [65].

Centella asiatica extract has also shown neuroprotective effects in AD models [66]. Key compounds such as asiatic acid and asiaticoside exhibit strong antioxidant properties, reducing free radicals, H₂O₂,-induced cytotoxicity, and Aβ-related cell damage [67]. A Phase 1, randomized, double-blind, crossover study evaluated the oral bioavailability, pharmacokinetics, and acute safety of standardized Centella asiatica extract in older adults with mild dementia. The study found that the extract was safe, well-tolerated, and produced changes in NRF2 gene expression, supporting its biological activity, but this phase was not designed to test cognitive efficacy [68].

In AD mouse models, Melissa officinalis (lemon balm) extract has been shown to improve memory and learning, inhibit acetylcholinesterase activity, and potentially reduce neuroinflammation and beta-secretase expression, indicating multifaceted neuroprotective effects [69]. Phase 2 randomized controlled trials of Melissa officinalis extract containing rosmarinic acid in MCI have demonstrated significant improvements in agitation symptoms and modest enhancements of cognitive function compared to the placebo [70,71].

Despite encouraging findings from preclinical models, a substantial translational gap exists between animal studies and clinical efficacy in AD. Many neuroprotective agents that show robust benefits in rodent models have failed to demonstrate meaningful clinical efficacy in humans, reflecting differences in disease complexity, species-specific neurobiology, pharmacokinetics, dosing, and outcome measures. Accordingly, effects observed in animal models should be interpreted as mechanistic or hypothesis-generating evidence rather than proof of clinical benefit. Within this framework, herbal and natural products are best viewed as supportive or adjunctive approaches rather than disease-modifying therapies. Careful clinical consideration is warranted only for standardized extracts with defined bioactive profiles and supportive clinical trial data, such as EGb 761 [62]. In contrast, nonstandardized herbal preparations that lack consistent composition, batch-to-batch reproducibility, or clearly defined active compounds provide limited translational interpretability; evidence supporting these products is therefore confined mainly to preclinical or early-phase studies, and they should be regarded as investigational.

NONPHARMACOLOGICAL INTERVENTIONS

Based on the 2024 Lancet Commission on dementia prevention, intervention, and care [72] identifies 14 modifiable risk factors across the life course that substantially contribute to dementia risk, including low education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excessive alcohol consumption, traumatic brain injury, air pollution, social isolation, and newly highlighted factors such as untreated vision loss and elevated low-density lipoprotein (LDL) cholesterol. The Commission estimates that addressing these factors through targeted lifestyle, vascular, sensory, and environmental interventions could prevent or delay up to ~45% of dementia cases worldwide, underscoring the central role of lifestyle modification in AD prevention and care. Consistent with this framework, evidence indicates that age-related metabolic decline can exacerbate AD pathology; however, early adoption of nutrient-rich dietary patterns, particularly whole and minimally processed plant-based diets, such as the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean–DASH Intervention for Neurodegenerative Delay (MIND) diets, may help reduce disease risk and support healthy cognitive aging [73,74].

The Mediterranean diet (MedD)

In the 1960s, an American couple created Mediterranean diet (MedD), modeling it after the traditional eating habits of people living in Greece, southern Italy, and Spain in the mid-20^th century [75]. The MedD highlights plant-based eating, prioritizing vegetables, fruits, legumes, whole grains, and nuts, with olive oil as the main fat source. It allows moderate fish and dairy consumption, restricts red and processed meats, and permits moderate wine during meals if desired [76]. A meta-analysis of prospective cohort studies demonstrated that greater adherence to the MedD is significantly associated with a reduced risk of AD and cognitive decline in older adults [77]. The MedD enhances systemic antioxidant and anti-inflammatory responses, reduces insulin resistance, and supports cerebrovascular health, all of which are relevant to AD pathology [78].

The dietary approaches to stop hypertension

The DASH diet promotes whole grains, fruits, and vegetables, discourages salt, sugary drinks, and red meat, and omits alcohol [79]. It helps lower blood pressure [80] and cholesterol, key Alzheimer’s risk factors, which may reduce oxidative stress and inflammation [81]. Studies show that following the DASH diet may improve verbal memory, but it does not seem to affect executive function, processing speed, or visual memory [82]. In summary, the DASH diet shows promise in promoting cognitive health, though more evidence is necessary to substantiate its efficacy in preventing or slowing AD progression.

Mediterranean-dietary approaches to stop hypertension intervention for neurodegenerative delay diet

The MIND diet, developed by Morris et al., was designed to target age-related memory and thinking problems [83]. It combines features of the Mediterranean and DASH diets, highlighting foods that protect the brain, such as leafy greens, berries, whole grains, olive oil, nuts, and fish, while limiting red meat, butter, pastries, and fried foods [84]. Studies show that higher adherence to the MIND diet is linked to slower memory decline [85] and up to a 53% lower risk of AD, with moderate adherence reducing risk by about 35% [86]. Brain imaging studies also suggest that the MIND diet helps preserve brain structure [87]. However, future research combining genetic testing like APOE ε4 with diet studies may enable personalized nutrition plans for individuals at risk.

Physical activity in Alzheimer’s disease

Regular physical activity is strongly associated with a reduced risk of cognitive impairment and dementia [88]. Exercise enhances cardiovascular fitness and cerebral blood flow, stimulates neurogenesis, synaptogenesis, and neuroplasticity through increased brain-derived neurotrophic factor [89], and helps preserve brain volume in regions vulnerable to dementia, including the hippocampus, temporal, and frontal areas [90]. Physical activity also enhances brain network connectivity, upregulates PGC1α to promote gene expression and dendritic spine growth, and increases lactate production that supports myelination, memory formation, and neurotransmitter transport [89]. Collectively, these mechanisms contribute to slowing brain aging, protecting against cognitive decline, and reducing AD risk by 30%–45%, while inactivity is a major modifiable risk factor [72].

Western guidelines for lowering AD risk emphasize aerobic, resistance, balance, and dual-task exercises. Aerobic activities, such as running, walking, cycling, and swimming, enhance cardiovascular and brain health, while resistance and balance exercises improve strength and prevent falls [91]. Structured workouts and gym-based exercise are supported by strong evidence that physical activity reduces cognitive impairment and AD risk [90]. In contrast, many Asian countries emphasize traditional mind-body practices like Tai Chi and yoga, which integrate movement, breathing, and meditation to enhance balance, flexibility, strength, and social connection [92]. Taken together, exercise benefits multiple cognitive domains, including memory, attention, executive function, and sleep, serving as effective nonpharmacological strategies for AD prevention.

Efficacy of probiotics supplementation in Alzheimer’s disease

Recent studies highlight the pivotal influence of the gut–brain axis and gut microbiota in the development of AD, suggesting that alterations in intestinal microbial composition can modulate neuroinflammation, amyloid accumulation, and cognitive decline [93]. Probiotics, defined as live microorganisms that confer health benefits, are receiving increased attention for their ability to restore gut balance, mitigate neuroinflammatory processes, and enhance cognitive function [94]. Therefore, the following describes recent clinical and preclinical evidence regarding the efficacy of probiotics in AD treatment and explores possible mechanisms.

A randomized controlled trial (RCT) demonstrated that 12-week supplementation with Lactobacillus and Bifidobacterium strains improved MMSE scores and metabolic/inflammatory markers in AD patients compared to placebo. Meta-analyses pooling AD and MCI trials consistently show modest yet significant gains in global cognition and reductions in inflammation-related biomarkers [95]. For instance, one meta-analysis found that probiotic supplementation yielded cognitive improvements (standardized mean difference ~0.47) and reduced biomarkers such as C-reactive protein and malondialdehyde [96].

Although preclinical animal studies generally report promising results, probiotics—often strains of Lactobacillus and Bifidobacterium—have been shown in transgenic mouse models of AD to decrease neuroinflammation, reduce Aβ deposition, improve gut microbiota diversity, and enhance cognitive function, including long-term memory and spatial recognition. However, effects on tau pathology have been inconsistent [97]. In human RCTs, while some studies observe cognitive gains, others find nonsignificant results in certain cognitive domains, likely reflecting variability in probiotic strain selection, dosage, treatment duration, and patient disease stage. Notably, the benefit of probiotics appears more pronounced in early or mild cases of AD, possibly because advanced neurodegeneration is less amenable to intervention [98].

Overall, future studies should prioritize well-powered, multicenter RCTs with standardized probiotic strains, dosage, and duration, alongside the incorporation of biomarkers such as CSF amyloid/tau, neuroimaging, microbiome sequencing, and stratification by disease stage to better assess efficacy boundaries. Through rigorous design and mechanistic integration, probiotic therapy may evolve into a viable adjunct strategy in AD management.

CURRENT CHALLENGES AND FUTURE DIRECTIONS

AD has a complex pathogenesis involving Aβ accumulation, tau pathology, and chronic neuroinflammation, all interrelated and influenced by genetic, lifestyle, and environmental factors [6,11]. Consequently, AD treatment faces significant challenges: Symptomatic drugs only temporarily relieve symptoms but do not stop disease progression, efficacy is limited, costs are high, and side effects are a concern [2]. Recently FDA-approved antiamyloid immunotherapies benefit only select early-stage patients and can cause serious side effects [12,99], such as ARIA-E or ARIA-H, highlighting the need for improved biomarkers, personalized approaches, and greater safety.

Future directions for AD treatment are shifting toward multifaceted strategies targeting core disease mechanisms. Beyond antiamyloid and antitau therapies, therapeutic focus is expanding to include modulation of neuroinflammation, synaptic health, and metabolic dysfunction. Integration of genetic and biomarker-guided personalized medicine and combination approaches will be key to effective long-term management. Importantly, growing evidence supports the neuroprotective, antioxidant, and antiamyloid properties of selected herbal extracts [59]. Although rigorous clinical trials are needed, these natural compounds, along with dietary and lifestyle interventions [73,74], hold promise as safe, multitarget adjuncts to conventional therapy.

CONCLUSION

AD remains a significant public health challenge due to its multifactorial pathogenesis and limited disease-modifying therapies. Current management, centering on cholinesterase inhibitors and NMDA antagonists, provides only modest and transient benefits. Antiamyloid immunotherapies and emerging tau-directed drugs offer new possibilities, especially for early-stage patients, but challenges such as limited efficacy, high costs, and adverse effects, such as edema and microhemorrhage, persist. Notably, accumulating evidence supports the neuroprotective role of certain herbal extracts and adherence to brain-healthy dietary patterns as safe, multi-target adjuncts that may help slow cognitive decline. It suggests that integrating pharmacological advances, natural compounds, and lifestyle strategies will be vital for improving AD outcomes. Thus, continued research into novel drug targets and holistic prevention strategies is still urgently needed to slow progression and improve quality of life for AD patients and their families.

Declaration of generative AI use

The representative Figure 1 was created with illustrae.co and further edited by using Microsoft PowerPoint. ChatGPT, Perplexity, and Copilot were utilized for the literature review of the body text and to enhance the readability and language of the article, under strict monitoring and review. Following the use of these tools, the authors reviewed and edited the content needfully and take full responsibility for the content of the article.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Conflicts of interest

Prof. Ingrid Y. Liu, an editorial board member at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.

Funding Statement

The Buddhist Tzu Chi Medical Foundation “TCMF-SP 112-02” and the National Science and Technology Council (NSTC), Taiwan (Grant #: NSTC 113-2410-H-320-004-MY2).