Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds.
Compounds/Drugs | Probable Mechanism of Action | Type of Research | Effects | References |
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Drugs/Substances | Dosage | Time-Dependent Therapy | Route of Administration | Diagnostic Tool/Tests | Patients | ||||||||||||
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Clinical Trials | Animal Model of Alzheimer’s Disease | In Vitro | |||||||||||||||
References | |||||||||||||||||
Bexarotene | ↓ ABCA1, ABCG1 expression ↑ ApoE lipidation |
+ | ↓ Soluble or insoluble Aβ ↓ Aβ plaques Improved memory ↑ HDL levels |
[11] | [19] | ||||||||||||
[ | 16 | ] | [ | 24 | ] | Improved cognitive function Improved baseline synaptic transmission and synaptic plasticity ↓ Astrogliosis and reactive microglia in both cortex and hippocampus ↑ Expression of APOE (limited to CA1 hippocampal) |
[13] | [21] | |||||||||
↓ Memory deficits ↓ Interstitial fluid Aβ level No effect on amyloid deposition |
[14 | ||||||||||||||||
Intranasal insulin | 10, 20, 40, or 60 IU or placebo five times a day | Cognition was tested 15 min after treatment and blood was drawn immediately after insulin/placebo administration and 45 min after treatment | Intranasal | Verbal declarative memory measures (Story Recall and Hopkins Verbal Learning Test) A test of selective attention (Stroop Color-Word test) A visual working memory measure (Self-Ordered Pointing Task) A test of psychomotor processing speed (Digit Symbol) |
Participants with (epsilon4+or epsilon4-) the APOE- epsilon4 allele with memory-impaired with either probable AD or amnestic MCI or multiple domain MCI with amnestic features (mean age of about 77) and cognitively normal older (epsilon4+or epsilon4-) as control groups (mean age of about 74) |
[41] | [47] | ] | [22] | ||||||||
Selenium or selenium with probiotic | Selenium (200 μg/day) plus probiotic (containing | Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum | ) (2 × 109 CFU/day each), selenium (200 μg/day) or placebo | For 12 weeks | Oral | Cognition was tested using the Mini-Mental State Examination (MMSE) biomarkers of inflammation and oxidative stress, metabolic profiles and plasma glucose |
Patients with AD (aged 55 to 100 years) | [111] | [94] | ↓ Soluble Aβ40 No effect on plaque burden that exhibit Aβ amyloidosis |
[15] | [23] | |||||
Citalopram | Dosing began at 10 mg/day with planned titration to 30 mg/day over 3 weeks based on response and tolerability or placebo | Psychosocial intervention plus either citalopram or placebo for 9 weeks | Oral | Assessment of agitation, hostility/uncooperativeness, and disinhibition—Neurobehavioral Rating Scale agitation subscale (NBRS-A) the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) Cohen-Mansfield Agitation Inventory (CMAI) Neuropsychiatric Inventory (NPI) Activities of daily living (ADLs) Caregiver distress; cognitive safety (MMSE) |
Patients with probable AD and clinically significant agitation | [55] | [117] | + | ↑ ApoE concentrations by 25% No effect on Aβ peptide metabolism Adverse reactions (non-significant) |
[16] | [24] | ||||||
No effect on amyloid burden in apoE4 carriers | |||||||||||||||||
Escitalopram | 20 mg or 30 mg/day or placebo | For 2 or 8 weeks | Oral | Lumbar punctures to sample CSF levels before and after treatment | Cognitively normal older adults (aged 50 to 84 years) | [58] | [120] | Significant correlation between ↑ serum Aβ1-42 and ↓ in brain amyloid in apoE4 noncarriers, significant adverse reactions |
[17] | [25] | |||||||
Resveratrol | up to 1 g by mouth twice daily (500 mg once daily (with a dose escalation by 500-mg increments every 13 weeks, ending with 1000 mg twice daily) | For 52 weeks | Oral | “M | agnetic microspheres internally coded with two fluorescent dyes to measure markers of neurodegeneration (Millipore, Cat#: HNABTMAG-68K) | ” | Patients with mild-moderate AD | [81][82][83] | [143,144,145 | ADCS-6253 | Directly activates ABCA1 expression | + | APOE4 knock-in only ↑ ApoE4 lipidation ↑ ABCA1 expression ↓ Aβ and phosphorylated tau |
[18] | [26] | ||
] | HJ6.3–monoclonal antibody against apoE | Blocking apoE and Aβ interaction | + | ↓ Soluble and insoluble Aβ ↓ Microglia ↓ Brain Aβ plaques ↑ Plasma Aβ ↓ Pro-inflammatory cytokines |
[22] | [30] | |||||||||||
Memory attention (Trail Making A) | Assessment of amyloid and tau accumulation in the brain (2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET) | Middle-aged and older adults without dementia (age 51 to 84 years) | HAE-4 | Blocking apoE and Aβ interaction | + | ↓ accumulation of Aβ in the brain | [23] | [31] | |||||||||
CN-105 | ApoE mimetic | + | ↓ Soluble Aβ ↓ Aβ plaques Improved memory |
[24] | [32] | ||||||||||||
Anti-APOE antisense oligonucleotides | Silencing APOE | + | ↓ Soluble APOE ↓ Soluble and insoluble Aβ ↓ Aβ plaques ↓ Dystrophic neurites |
[28] | [36] | ||||||||||||
Intranasal insulin | Reduced AHP | + | ↓ Cognitive impairment, improves memory in | [39] | [45] | ||||||||||||
+ | patients without (epsilon4-,) improves verbal memory | [41] | [47] | ||||||||||||||
Liraglutide | Glucagon-like peptide-1 analog Activation of protein kinase A (PKA) signaling pathway |
+ | Prevented the “ | loss of brain insulin receptors and synapses, and reversed memory impairment | ” induced by AβOs ↓ AD-related insulin receptor ↓ Synaptic and tau pathologies in specific brain regions |
[46] | [52] | ||||||||||
Probiotic therapy with the SLAB 51 cocktail | ↑ Intestinal metabolites of the short-chain fatty acid type | + | Impede the formation of toxic soluble amyloid aggregates ↑ Cognitive function ↓ Aβ aggregates ↓ Brain injuries Partial restoration of altered neuronal proteolytic pathway |
[109] | [87] | ||||||||||||
Dipeptides of tryptophan-tyrosine and tryptophan-methionine | Suppression of the inflammatory response of microglia ↑ Aβ phagocytosis | ||||||||||||||||
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[ | |||||||||||||||||
143 | |||||||||||||||||
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+ | Improve cognitive function | ↓ Hippocampal long-term potential deficit ↓ Memory impairment |
[110] | [89] | |||||||||||||
Selenium or selenium with probiotic | Anti-inflammatory and antioxidant effects ↑ Total glutathione and the quantitative insulin sensitivity check index (QUICKI) |
+ | ↓ High sensitivity C-reactive protein Improvement of lipidogram results ↑ Cognitive function |
[111] | [94] | ||||||||||||
VEGF | Anti-inflammatory effects | + | Improved spatial learning and memory along with ↓ Aβ levels |
[112] | [113] | ||||||||||||
+ | ↑ cell viability ↓ ROS production Improved mitochondrial structure and function ↑Number of mitochondria ↑ Stimulation of mitochondrial biogenesis |
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+ | ↓ Memory impairment ↑ Levels of choline acetyltransferase ↓ Aβ accumulation |
[113] | [114] | ||||||||||||||
Kisspeptin | Activates the hypothalamic-pituitary-gonadal axis | + | Induces mitophagy and autophagy processes | [114] | [112] | ||||||||||||
+ | ↑ Number of mitochondria ↑ Complex I activity ↑ ATP levels |
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+ | ↑ Spatial memory consolidation and retrieval Alleviated Aβ-induced memory impairment |
[115] | [116] | ||||||||||||||
Citalopram | Selective serotonin reuptake inhibitor | + | ↓ Levels of the mitochondrial fission genes ↑ Fusion, biogenesis, autophagy, mitophagy, and synaptic genes ↑ Number of mitochondria and cell survival rates |
[54] | [14] | ||||||||||||
+ | ↑ Cognitive impairment Cardiovascular side effects |
[55] | [117] | ||||||||||||||
Escitalopram | + | ↓ Aβ level in CSF | [57] | [119] | |||||||||||||
Selective serotonin reuptake inhibitor | ↓ Plaque load Inhibition of amyloid plaque growth |
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+ | ↓ Aβ42 level in CSF | [58] | [120] | ||||||||||||||
+ | Inhibition of tau hyperphosphorylation | [63][64] | [125,126] | ||||||||||||||
Resveratrol | Stimulating proteasomal proteolysis Stimulating factors such as expression of brain-derived neurotrophic factor precursor, neuronal growth factor, and neurotrophin 3 Anti-inflammatory, antioxidant and anti-apoptotic action Induces autophagy and mitophagy Activator of silent information regulator-1 (SIRT1) |
+ | ↓ Astrocyte and microglia activation and suppression of the inflammatory response in the hippocampus | [72][73][74][80] | [134,135,136,142] | ||||||||||||
+ | ↓ MMP-9 levels in CSF ↓ Aβ40 levels in CSF ↑ Macrophage-derived chemokine, fibroblast growth factor-2 and interleukin (IL)-4 levels ↓ Plasma concentrations of pro-inflammatory mediators, including IL-1r4, IL-12P40, IL-12P70, and TNF-α ↓ Brain volume (excluding CSF, brain stem, and cerebellum) ↑ Ventricular volume |
[81 | + | ↓ MMP-9 levels in CSF | [82][83] | [144,145] | |||||||||||
Curcumin | Affects Aβ plaque aggregation and tau protein hyperphosphorylation Antioxidant, anti-inflammatory, antidiabetic, antiviral, antiproliferative, antioxidant, pro-apoptotic as well as anti-amyloidogenic action Regulates levels of PS-1 and GSK-3β |
+ | Improvements in verbal and visual memory ↓ Tau accumulation in the amygdala |
[98] | [160] | ||||||||||||
+ | ↓ Aβ production ↓ Synaptic degradation Improving spatial learning ↓ Memory impairment |
[99] | |||||||||||||||
Curcumin | 90 mg or placebo twice daily—(180 mg/day) | for 18 months | Oral | Verbal (Buschke Selective Reminding Test [SRT]) Visual (Brief Visual Memory Test-Revised [BVMT-R]) | [161] | ||||||||||||
+ | Improving cognitive function ↓ Apoptosis and oxidative stress processes ↓ Aβ accumulation |
[102] | [164] | ||||||||||||||
+ | ↓ Aβ production | [101] | [163] |
Bexarotene | 225 mg or placebo twice daily | For 5 days | Oral | Applied “ | stable isotope labeling kinetics (SILK-ApoE and SILK-Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentration | s” in CSF | Healthy volunteers; aged 21 to 49 years (average 32 years old); with APOE ε3/ε3 genotype |
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98 | |||||||
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160 | |||||||
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