Nonpharmacological treatment options for Alzheimer’s disease: from animal testing to clinical studies
Nonpharmacological treatment options for Alzheimer’s disease: from animal testing to clinical studies
Despite extensive pharmacological approaches, there is no curative therapy for Alzheimer’s disease (AD) or other types ofdementias. While current pharmacological options alleviate some symptoms of AD, they can lead to various adverse effects. Hence,nonpharmacological treatment options for AD are often considered with the assumption that they are safe, effective, and economic inmanaging patients. Furthermore, studies on animal models have suggested that environmental exposures like diet, music, or rewardrelatedactions can stimulate neuronal regeneration and differentiation without using any pharmacological factors. The aim of thisreview is to provide a summary of nonpharmacological treatment options for the management of cognitive, emotional, and behavioralsymptoms of AD. In addition, this review provides an overview of the challenging and encouraging experiences and recent studies andproblems in cognitive training related to animal models. Nonpharmacological studies of AD are discussed in this literature review interms of animal models, physical activity, brain stimulation, and the role of social communication.
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- Albarracin, SL, Stab B, Casas Z, Sutachan JJ, Samudio I et al.
(2012). Effects of natural antioxidants in neurodegenerative
disease. Nutritional Neuroscience 15 (1): 1-9. doi:
10.1179/1476830511Y.0000000028
- Ambrée O, Leimer U, Herring A, Görtz N, Sachser N et al. (2006).
Reduction of amyloid angiopathy and Aβ plaque burden after
enriched housing in TgCRND8 mice. American Journal of
Pathology 169 (2): 544-552. doi: 10.2353/ajpath.2006.051107
- Annweiler C (2014). Vitamine D et maladie d’Alzheimer : d’une
curieuse idée à une possibilité de traitement. Biologie
Aujourd’hui 208 (1): 89-95 (in French). doi: 10.1051/
jbio/2014005
- Azad N, Rasoolijazi H, Joghataie MT, Soleimani S (2011).
Neuroprotective effects of carnosic acid in an experimental
model of Alzheimer’s disease in rats. Cell Journal 13 (1): 39-44.
- Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H et al.
(2015). Summary of the evidence on modifiable risk factors
for cognitive decline and dementia: a population-based
perspective. Alzheimer’s and Dementia 11 (6): 718-726. doi:
10.1016/j.jalz.2015.05.016
- Beauquis J, Pavía P, Pomilio C, Vinuesa A, Podlutskaya N et al. (2013).
Environmental enrichment prevents astroglial pathological
changes in the hippocampus of APP transgenic mice, model of
Alzheimer’s disease. Experimental Neurology 239: 28-37. doi:
10.1016/j.expneurol.2012.09.009
- Braidy N, Behzad S, Habtemariam S, Ahmed T, Daglia M et al.
(2017a). Neuroprotective effects of citrus fruit-derived
flavonoids, nobiletin and tangeretin in Alzheimer’s and
Parkinson’s disease. CNS & Neurological Disorders - Drug
Targets 16 (4): 387-397. doi: 10.2174/18715273166661703281
13309
- Braidy N, Jugder BE, Poljak A, Jayasena T, Mansour H et al. (2016).
Resveratrol as a potential therapeutic candidate for the
treatment and management of Alzheimer’s disease. Current
Topics in Medicinal Chemistry 16 (17): 1951-1960. doi: 10.217
4/1568026616666160204121431
- Braidy N, Jugder BE, Poljak A, Jayasena T, Nabavi SM et al. (2017b).
Molecular targets of tannic acid in Alzheimer’s disease. Current
Alzheimer Research 14 (8): 861-869. doi: 10.2174/1567205014
666170206163158
- Cacciatore I, Marinelli L, Fornasari E (2016). Novel NSAID-derived
drugs for the potential treatment of Alzheimer’s disease.
International Journal of Molecular Sciences 17: 1035. doi:
10.3390/ijms17071035
- Cass SP (2017). Alzheimer’s disease and exercise. Current
Sports Medicine Reports 16 (1): 19-22. doi: 10.1249/
JSR.0000000000000332
- Chakraborty S, Bandyopadhyay J, Chakraborty S, Basu S (2016).
Multi-target screening mines hesperidin as a multi-potent
inhibitor: implication in Alzheimer’s disease therapeutics.
European Journal of Medicinal Chemistry 121: 810-822. doi:
10.1016/j.ejmech.2016.03.057
- Chen WW, Zhang X, Huang WJ (2016). Role of physical exercise in
Alzheimer’s disease. Biomedical Reports 4 (4): 403-407. doi:
10.3892/br.2016.607
- Cornejo A, Aguilar Sandoval F, Caballero L, Machuca L, Muñoz
P et al. (2017). Rosmarinic acid prevents fibrillization and
diminishes vibrational modes associated to β sheet in tau
protein linked to Alzheimer’s disease. Journal of Enzyme
Inhibition and Medicinal Chemistry 32 (1): 945-953. doi:
10.1080/14756366.2017.1347783
- Cotel MC, Jawhar S, Christensen DZ, Bayer TA, Wirths O (2012).
Environmental enrichment fails to rescue working memory
deficits, neuron loss, and neurogenesis in APP/PS1KI
mice. Neurobiology of Aging 33 (1): 96-107. doi: 10.1016/j.
neurobiolaging.2010.02.012
- Cotelli M, Manenti R, Petesi M, Brambilla M, Rosini S et al. (2014).
Anodal tDCS during face-name associations memory training
in Alzheimer’s patients. Frontiers in Aging Neuroscience 6: 38.
doi: 10.3389/fnagi.2014.00038
- Ebrahimi K, Majdi A, Baghaiee B, Hosseini SH, Sadigh-Eteghad
S (2017). Physical activity and beta-amyloid pathology in
Alzheimer’s disease: a sound mind in a sound body. EXCLI
Journal 16: 959-972. doi: 10.17179/excli2017-475
- El Haj M, Jardri R, Larøi F, Antoine P (2016). Hallucinations,
loneliness, and social isolation in Alzheimer’s
disease. Cognitive Neuropsychiatry 21 (1): 1-13. doi:
10.1080/13546805.2015.1121139
- Eliasova I, Anderkova L, Marecek R, Rektorova I (2014). Noninvasive
brain stimulation of the right inferior frontal gyrus
may improve attention in early Alzheimer’s disease: a pilot
study. Journal of the Neurological Sciences 346: 318-322. doi:
10.1016/j.jns.2014.08.036
- Essa MM, Vijayan RK, Castellano-Gonzalez G, Memon MA, Braidy
N et al. (2012). Neuroprotective effect of natural products
against Alzheimer’s disease. Neurochemical Research 37: 1829-
1842. doi: 10.1007/s11064-012-0799-9
- Farzi MA, Sadigh-Eteghad S, Ebrahimi K, Talebi M (2019). Exercise
improves recognition memory and acetylcholinesterase activity
in the beta amyloid-induced rat model of Alzheimer’s disease.
Annals of Neurosciences 25: 121-125. doi: 10.1159/000488580
- Feng Y, Wang X (2012). Antioxidant therapies for Alzheimer’s
disease. Oxidative Medicine and Cellular Longevity 2012:
472932. doi: 10.1155/2012/472932
- Ghofrani S, Joghataei MT, Mohseni S, Baluchnejadmojarad T,
Bagheri M et al. (2015). Naringenin improves learning and
memory in an Alzheimer’s disease rat model: Insights into the
underlying mechanisms. European Journal of Pharmacology
764: 195-201. doi: 10.1016/j.ejphar.2015.07.001
- Ghosh S, Basak P, Dutta S, Chowdhury S, Sil PC (2017). New insights
into the ameliorative effects of ferulic acid in pathophysiological
conditions. Food and Chemical Toxicology 103: 41-55. doi:
10.1016/j.fct.2017.02.028
- Habtemariam S (2016). Protective effects of caffeic acid and the
Alzheimer’s brain: an update. Mini-Reviews in Medicinal
Chemistry 17 (8): 667-674. doi: 10.2174/13895575166661611
30100947
- Herring A, Ambrée O, Tomm M, Habermann H, Sachser N et
al. (2009). Environmental enrichment enhances cellular
plasticity in transgenic mice with Alzheimer-like pathology.
Experimental Neurology 216: 184-192. doi: 10.1016/j.
expneurol.2008.11.027
- Hsu WY, Ku Y, Zanto TP, Gazzaley A (2015). Effects of noninvasive
brain stimulation on cognitive function in healthy aging and
Alzheimer’s disease: a systematic review and meta-analysis.
Neurobiology of Aging 36 (8): 2348-2359. doi: 10.1016/j.
neurobiolaging.2015.04.016
- Hu N, Yu JT, Tan L, Wang YL, Sun L et al. (2013). Nutrition and
the risk of Alzheimer’s disease. BioMed Research International
2013: 524820. doi: 10.1155/2013/524820
- Jedrziewski MK, Ewbank DC, Wang H, Trojanowski JQ
(2014). The impact of exercise, cognitive activities, and
socialization on cognitive function. American Journal of
Alzheimer’s Disease & Other Dementias 29 (4): 372-378. doi:
10.1177/1533317513518646
- Jensen CS, Bahl JM, Østergaard LB, Høgh P, Wermuth L et al.
(2019a). Exercise as a potential modulator of inflammation in
patients with Alzheimer’s disease measured in cerebrospinal
fluid and plasma. Experimental Gerontology 121: 91-98. doi:
10.1016/j.exger.2019.04.003
- Jensen CS, Simonsen AH, Siersm V, Beyer N, Frederiksen KS et al.
(2019b). Patients with Alzheimer’s disease who carry the APOE
ε4 allele benefit more from physical exercise. Alzheimer’s and
Dementia: Translational Research and Clinical Interventions 5:
99-106. doi: 10.1016/j.trci.2019.02.007
- Khedr EM, El Gamal NF, El-Fetoh NA, Khalifa H, Ahmed EM et
al. (2014). A double-blind randomized clinical trial on the
efficacy of cortical direct current stimulation for the treatment
of Alzheimer’s disease. Frontiers in Aging Neuroscience 6: 275.
doi: 10.3389/fnagi.2014.00275
- King JB, Jones KG, Goldberg E, Rollins M, MacNamee K et al.
(2019). Increased functional connectivity after listening to
favored music in adults with Alzheimer dementia. Journal of
Prevention of Alzheimer’s Disease 6 (1): 56-62. doi: 10.14283/
jpad.2018.19
- Liu J, Liu Z, Zhang Y, Yin F (2015). A novel antagonistic role of
natural compound icariin on neurotoxicity of amyloid β
peptide. Indian Journal of Medical Research 142 (2): 190-195.
doi: 10.4103/0971-5916.164254
- Liu Q, Chen Y, Shen C, Xiao Y, Wang Y et al. (2017). Chicoric acid
supplementation prevents systemic inflammation-induced
memory impairment and amyloidogenesis via inhibition
of NF-κB. FASEB Journal 31 (4): 1494-1507. doi: 10.1096/
fj.201601071R
- Liu X, Zhou J, Abid MDN, Yan H, Huang H et al. (2014). Berberine
attenuates axonal transport impairment and axonopathy
induced by calyculin a in N2a cells. PLoS One 9 (4): e93974.
doi: 10.1371/journal.pone.0093974
- Liu Y, Pukala TL, Musgrave IF, Williams DM, Dehle FC et al. (2013).
Gallic acid is the major component of grape seed extract that
inhibits amyloid fibril formation. Bioorganic and Medicinal
Chemistry Letters 23 (23): 6336-6340. doi: 10.1016/j.
bmcl.2013.09.071
- Marinelli L, Fornasari E, Di Stefano A, Turkez H, Arslan ME et
al. (2017). (R)-α-Lipoyl-Gly-l-Pro-l-Glu dimethyl ester as
dual acting agent for the treatment of Alzheimer’s disease.
Neuropeptides 66: 52-58. doi: 10.1016/j.npep.2017.09.001
- Martorell M, Forman K, Castro N, Capó X, Tejada S et al. (2016).
Potential therapeutic effects of oleuropein aglycone in
Alzheimer’s disease. Current Pharmaceutical Biotechnology
17: 994-1001. doi: 10.2174/1389201017666160725120656
- Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G
(2016). Therapies for prevention and treatment of Alzheimer’s
disease. BioMed Research International 2016: 1-17. doi:
10.1155/2016/2589276
- Moneim A (2015). Oxidant/antioxidant imbalance and the risk of
Alzheimer’s disease. Current Alzheimer Research 12 (4): 335-
349. doi: 10.2174/1567205012666150325182702
- Morris MC, Tangney CC, Wang Y, Sacks FM, Barnes LL et al. (2015a).
MIND diet slows cognitive decline with aging. Alzheimer’s and
Dementia 11 (9): 1015-1122. doi: 10.1016/j.jalz.2015.04.011
- Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA et al.
(2015b). MIND diet associated with reduced incidence of
Alzheimer’s disease. Alzheimer’s and Dementia 11 (9): 1007-
1014. doi: 10.1016/j.jalz.2014.11.009
- Nakajima A, Aoyama Y, Shin EJ, Nam Y, Kim HC et al. (2015).
Nobiletin, a citrus flavonoid, improves cognitive impairment
and reduces soluble Aβ levels in a triple transgenic mouse
model of Alzheimer’s disease (3XTg-AD). Behavioural Brain
Research 289: 69-77. doi: 10.1016/j.bbr.2015.04.028
- Nigam SM, Xu S, Kritikou JS, Marosi K, Brodin L et al. (2017).
Exercise and BDNF reduce Aβ production by enhancing
α-secretase processing of APP. Journal of Neurochemistry 142:
286-296. doi: 10.1111/jnc.14034
- Nithianantharajah J, Hannan AJ (2006). Enriched environments,
experience-dependent plasticity and disorders of the nervous
system. Nature Reviews Neuroscience 7: 697-709. doi: 10.1038/
nrn1970
- Olajide OJ, Yawson EO, Gbadamosi IT, Arogundade TT, Lambe E
et al. (2017). Ascorbic acid ameliorates behavioural deficits
and neuropathological alterations in rat model of Alzheimer’s
disease. Environmental Toxicology and Pharmacology 50: 200-
211. doi: 10.1016/j.etap.2017.02.010
- Pagoni A, Marinelli L, Di Stefano A (2020) Novel anti-Alzheimer
phenol-lipoyl hybrids: synthesis, physico-chemical
characterization, and biological evaluation. European
Journal of Medicinal Chemistry 186: 111880. doi: 10.1016/j.
ejmech.2019.111880
- Park YJ, Ko J, Jeon S, Kwon YH (2016). Protective effect of genistein
against neuronal degeneration in ApoE-/- mice fed a high-fat
diet. Nutrients 8 (11): 692. doi: 10.3390/nu8110692
- Peng X, Xing P, Li X, Qian Y, Song F et al. (2016). Towards
personalized intervention for Alzheimer’s disease. Genomics,
Proteomics & Bioinformatics 14 (5): 289-297. doi: 10.1016/j.
gpb.2016.01.006
- Persson T, Popescu BO, Cedazo-Minguez A (2014). Oxidative stress
in Alzheimer’s disease: Why did antioxidant therapy fail?
Oxidative Medicine and Cellular Longevity 2014: 427318. doi:
10.1155/2014/427318
- Rezai-Zadeh K (2005). Green tea epigallocatechin-3-gallate
(EGCG) modulates amyloid precursor protein cleavage and
reduces cerebral amyloidosis in Alzheimer transgenic mice.
Journal of Neuroscience 25 (38): 8807-8814. doi: 10.1523/
JNEUROSCI.1521-05.2005
- Riello R, Frisoni GB (2001). Music therapy in Alzheimer’s disease:
is an evidence-based approach possible? Recenti Progressi
in Medicina 92 (5): 317-321 (in Italian with an abstract in
English).
- Rietjens IM, Boersma MG, Haan L, Spenkelink B, Awad HM
et al. (2002). The pro-oxidant chemistry of the natural
antioxidants vitamin C, vitamin E, carotenoids and flavonoids.
Environmental Toxicology and Pharmacology 11: 321-333.
doi: 10.1016/S1382-6689(02)00003-0
- Rossi Dare L, Garcia A, Alves N, Ventura Dias D, de Souza MA
et al. (2019). Physical and cognitive training are able to
prevent recognition memory deficits related to amyloid beta
neurotoxicity. Behavioural Brain Research 365: 190-197. doi:
10.1016/j.bbr.2019.03.007
- Sabogal-Guáqueta AM, Muñoz-Manco JI, Ramírez-Pineda
JR, Lamprea-Rodriguez M, Osorio E et al. (2015). The
flavonoid quercetin ameliorates Alzheimer’s disease
pathology and protects cognitive and emotional function
in aged triple transgenic Alzheimer’s disease model
mice. Neuropharmacology 93: 134-145. doi: 10.1016/j.
neuropharm.2015.01.027
- Sachdeva AK, Chopra K (2015). Lycopene abrogates Aβ
(1–42)-mediated neuroinflammatory cascade in an
experimental model of Alzheimer’s disease. Journal of
Nutritional Biochemistry 26 (7): 736-744. doi: 10.1016/j.
jnutbio.2015.01.012
- Shal B, Ding W, Ali H, Kim YS, Khan S (2018). Antineuroinflammatory
potential of natural products in attenuation
of Alzheimer’s disease. Frontiers in Pharmacology 9: 548. doi:
10.3389/fphar.2018.00548
- Shinohara M, Yamada M (2015). Vitamin E and Alzheimer’s disease.
Brain and Nerve 67 (12): 1509-1513 (in Japanese with an
abstract in English).
- Silva GJJ, Bye A, el Azzouzi H, Wisløff U (2017). MicroRNAs as
important regulators of exercise adaptation. Progress in
Cardiovascular Diseases 60 (1): 130-151. doi: 10.1016/j.
pcad.2017.06.003
- Soni M, Orrell M, Bandelow S, Steptoe A, Rafnsson S et al. (2019).
Physical activity pre- and post-dementia: English Longitudinal
Study of Ageing. Aging and Mental Health 23 (1): 15-21. doi:
10.1080/13607863.2017.1390731
- Stephen R, Hongisto K, Solomon A, Lönnroos E (2017). Physical
activity and Alzheimer’s disease: a systematic review. Journals
of Gerontology Series A, Biological Sciences and Medical
Sciences 72 (6): 733-739. doi: 10.1093/gerona/glw251
- Talarek S, Listos J, Barreca D, Tellone E, Sureda A et al. (2017).
Neuroprotective effects of honokiol: from chemistry to
medicine. BioFactors 43 (6): 760-769. doi: 10.1002/biof.1385
- Terada A, Yoshida M, Seko Y, Kobayashi T, Yoshida K et al. (1999).
Active oxygen species generation and cellular damage by
additives of parenteral preparations: selenium and sulfhydryl
compounds. Nutrition 15: 651-655. doi: 10.1016/S0899-
9007(99)00119-7
- Türkez H, Arslan ME (2018). Neuroprotective effects of leucomicine
sesquiterpene on differentiated SH-SY5Y neuroblastoma cell
line. Neuroendocrinology 107: 35-36.
- Van Dijk A, van Weert JCM, Dröes RM (2012). Does theatre improve
the quality of life of people with dementia? International
Psychogeriatrics 12: 99-116. doi: 10.1017/S1041610211001992
- Van Dijk AM, van Weert JCM, Dröes RM (2012). Theater als
contactmethode in de psychogeriatrische zorg: effecten op
gedrag, stemming en kwaliteit van leven van mensen met
dementie. Tijdschrift Voor Gerontologie En Geriatrie 43 (6):
283-295. doi: 10.1007/s12439-012-0042-9
- Verret L, Krezymon A, Halley H, Trouche S, Zerwas M et al. (2013).
Transient enriched housing before amyloidosis onset sustains
cognitive improvement in Tg2576 mice. Neurobiology of
Aging 34: 211-225. doi: 10.1016/j.neurobiolaging.2012.05.013
- Wolf SA, Kronenberg G, Lehmann K, Blankenship A, Overall R et
al. (2006). Cognitive and physical activity differently modulate
disease progression in the amyloid precursor protein (APP)-
23 model of Alzheimer’s disease. Biological Psychiatry 60 (12):
1314-1323. doi: 10.1016/j.biopsych.2006.04.004
- Yu SY, Zhang M, Luo J, Zhang L, Shao Y et al. (2013). Curcumin
ameliorates memory deficits via neuronal nitric oxide synthase
in aged mice. Progress in Neuro-Psychopharmacology
and Biological Psychiatry 45: 47-53. doi: 10.1016/j.
pnpbp.2013.05.001
- Yu XL, Li YN, Zhang H, Su YJ, Zhou WW et al. (2015). Rutin inhibits
amylin-induced neurocytotoxicity and oxidative stress. Food &
Function 6 (10): 3296-3306. doi: 10.1039/C5FO00500K
- Zhang R, Zhang J, Fang L, Li X, Zhao Y et al. (2014). Neuroprotective
effects of sulforaphane on cholinergic neurons in mice
with Alzheimer’s disease-like lesions. International Journal
of Molecular Sciences 15 (8): 14396-14410. doi: 10.3390/
ijms150814396