Table 1.

Role of BDNF in Alzheimer’s disease.

Observations		References
Alzheimer’s disease patients
Serum BDNF levels significantly decreased in early-onset and late-onset Alzheimer’s disease compared to age-matched healthy controls.		[32]
BDNF levels in platelet-rich plasma significantly decreased, which was correlated with moderate-to-severe stages of dementia.		[33]
Alzheimer’s disease patients have higher levels of peripheral BDNF, possibly due to a compensatory mechanism to fight early neurodegeneration or to the activation of immune cells.		[34]
BDNF serum levels are increased in subjects with MCI and decreased in subjects with Alzheimer’s disease.		[35]
There is a significant correlation between serum BDNF levels and medial temporal lobe atrophy.		[39]
Oxidative stress and Aβ decrease PKCϵ expression. A depression in PKCϵ reduces BDNF and MnSOD expression in hippocampal pyramidal neurons.		[42]
BDNF level was reduced in the sera and brains of Alzheimer’s disease patients.		[43]
Peripheral BDNF promoter methylation might be a diagnostic marker of Alzheimer’s disease risk.		[46]
There was a gender-related alteration in BDNF mRNA expression in brain tissues and a positive genetic association of rs6265 in BDNF with Alzheimer’s disease in females. There was a clear female-specific risk trend for the effect of BDNF rs6265 on Alzheimer’s disease-related endophenotypes.		[47]
The ApoE ε4 genotype is involved in regulating BDNF metabolism. The interaction between BDNF and ApoE genotype plays a critical role in Alzheimer’s disease pathogenesis.		[48]
There were dose-dependent genotype effects and significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex.		[49]
BDNF genetic variations increase the risk of Alzheimer’s-disease-related depression.		[50]
Prefrontal cortex BDNF gene expression is associated with aging, rs6265 carrier status, and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences.		[51]
BDNF-AS levels in the plasma of late-stage Alzheimer’s disease patients showed a significant increase compared to healthy subjects.		[52]
BDNF anti-sense RNA (BDNF-AS) promotes BACE1 expression and Alzheimer’s disease progression through the competitive binding of miR-9-5p.		[53]
Pro-BDNF levels are significantly associated with both amyloid load and pTau in the hippocampus.		[54]
Amnestic mild cognitive impairment (aMCI) patients
The interactions between DNA methylation (CpG5) of the BDNF gene promoter and the tag SNP (rs6265) play important roles in the etiology of amnestic mild cognitive impairment (aMCI) and its conversion to Alzheimer’s disease.		[55]
The elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to Alzheimer’s disease.		[56]
Patients with subjective cognitive decline (SCD) to mild cognitive impairment (MCI)
BDNF Val66Met increased the risk of progression from SCD to MCI and from MCI to Alzheimer’s disease in women only.		[57]
Cognitively unimpaired (CU) adults
The interaction between BDNF Met and APOE4 has a weak effect on amyloid-β plaque burden, and the longitudinal PET measurements of Alzheimer’s disease-related carriage have a weak effect on the decline in the cerebral metabolic rate for glucose (CMRgl) in cognitively unimpaired late-middle-aged and older adults, but there is no apparent effect on the rate of cognitive decline.		[58]
Animal model
13.5-month-old BDNFf/f and TrkBf/f mice	The deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of transcription factor C/EBPβ. This, in turn, results in the increased expression of δ-secretase, leading to both APP and Tau fragmentation by δ-secretase and neuronal loss.	[40]
Transgenic mouse models of human Tau expression	Tau at least partially mediates Aβ-induced BDNF downregulation. Therefore, Alzheimer’s disease treatments targeting Aβ alone may not be effective without considering the impact of Tau pathology on neurotrophic pathways.	[41]
P301L transgenic mice (a mouse model of tauopathy)	The BDNF level was reduced in the sera and brains of P301L transgenic mice. BDNF overexpression attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration, and reduced neuronal abnormality, but did not affect Tau hyperphosphorylation levels.	[43]
5xFAD mouse model of Alzheimer’s disease	Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties.	[45]
APPswe/PS1dE9 (APdE9) mice	BDNF gene mutations are deleterious for learning and memory. BDNF protein accumulates around amyloid plaques in the brains of APdE9 mice.	[59]
Cell culture
human Tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells	Tau at least partially mediates Aβ-induced BDNF downregulation. Therefore, Alzheimer’s disease treatments targeting Aβ alone may not be effective without considering the impact of Tau pathology on neurotrophic pathways.	[41]
Beta-amyloid-treated neural stem cells (NSCs)	BDNF overexpression improves the therapeutic potential of engrafted NSCs for Alzheimer’s disease via neurogenic effects and neuronal replacement.	[44]
SH-SY5Y cell line	BDNF anti-sense RNA (BDNF-AS) promotes BACE1 expression and Alzheimer’s disease progression through the competitive binding of miR-9-5p.	[53]
SH-SY5Y cell line	There is a synergistic toxic interaction between the amyloid-β peptide (Aβ1-42) and the pro-domains of both DNT1 and BDNF.	[60]