Mounting evidence that alterations in brain-derived neurotrophic factor (BDNF) levels and signaling may be involved in the etiopathogenesis of Alzheimer’s disease (AD) has suggested that its blood levels could be used as a biomarker of the disease. However, higher, lower, or unchanged circulating BDNF levels have all been described in AD patients compared to healthy controls. Although the reasons for such different findings are unclear, methodological issues are likely to be involved. The heterogeneity of participant recruitment criteria and the lack of control of variables that influence circulating BDNF levels regardless of dementia (depressive symptoms, medications, lifestyle, lack of overlap between serum and plasma, and experimental aspects) are likely to bias result and prevent study comparability. The present work reviews a broad panel of factors, whose close control could help reduce the inconsistency of study findings, and offers practical advice on their management. Research directed at elucidating the weight of each of these variables and at standardizing analytical methodologies is urgently needed.

Increasing experimental evidence indicates that synaptic alterations play a key role in cognitive decline in Alzheimer's disease (AD). Functional and structural synaptic changes progressively take place, beginning in the early phase of AD, mainly triggered by intracellular accumulation of soluble amyloid-β (Aβ) oligomers. These peptides also accumulate within mitochondria, heavily affecting their function and morphology, particularly in synaptic compartments. To better understand the role of mitochondrial impairment in synaptic alterations during the early stages of AD, a morphological investigation was performed by means of electron microscopy in the hippocampus of 3 month-old Tg2576 and transgene-negative littermate mice. In the stratum moleculare of CA1 pyramidal cells (SMCA1) of transgenic animals compared to controls, we found significantly larger and less numerous synapses, with a significantly reduced fraction of the perforated subtype, as well as significantly smaller and more numerous mitochondria. In contrast, no differences between the two groups of mice were found in the inner molecular layer of the dentate gyrus. The reduction of synaptic contacts in SMCA1 indicates a precocious vulnerability of this region, and the synaptic enlargement may reflect a compensating process aimed at maintaining the overall contact density. Accordingly, mitochondrial modifications may represent a plastic reactive phenomenon aimed at sustaining the increased energy needs for synaptic remodeling, since mitochondrial morphology was perfectly preserved and smaller mitochondria are metabolically more efficient. Thus, morphological changes occurring at synaptic level in SMCA1 of 3 month-old Tg2576 mice might reflect a precocious vulnerability associated with a residual plastic reactivity which may slow down functional alterations.