News on AD biomarkers

New insights into biomarkers for Alzheimer’s disease (AD) were shared in 3 studies.

One study evaluated the ability of EEG alone or with resting state functional MRI (rsfMRI) to characterise mild cognitive impairment (MCI) subjects with an AD-like cerebrospinal fluid (CSF) biomarker profile [1]. A total of 39 AD, 86 MCI, and 86 healthy subjects underwent EEG and/or rsfMRI. MCI subjects were differentiated into phosphorylated tau/Aβ_1-42 ratio ≥0.13 (MCI-ATpos) and <0.13 (MCI-ATneg). In AD patients, delta and theta densities were increased, and alpha2 and beta1 densities decreased. MCI-ATpos individuals had higher theta density than MCI-ATneg individuals. After the application of rsfMRI networks to current source density analysis, the alpha2 band could distinguish MCI-ATpos patients from MCI-ATneg, AD, and healthy individuals. The authors concluded that theta frequency was the most sensitive to AD-like CSF biomarker profile. These results emphasise the role of the alpha2 band as a biomarker for neurodegeneration correlating with disease progression.

A new biomarker that could reflect beta-secretase 1 (BACE1) activity and cognitive alteration in AD patients is Neuregulin1 (Nrg1). Nrg1 is a presynaptic BACE1 substrate that can activate postsynaptic ErbB4 receptors. Neuritic plaques are associated with Nrg1 accumulation in AD [2]. CSF Nrg1 levels were evaluated in 172 individuals: 56 had AD, 21 MCI-AD, 32 non-AD MCI, and 36 non-AD dementia; the other 27 were neurological controls [3]. In AD and MCI-AD patients, CSF Nrg1 concentrations were significantly enhanced. Nrg1 levels correlated positively with tau, phosphorylated tau, Aβ_1-40, and BACE1 levels, and negatively with Mini-Mental State Examination (MMSE) scores and frontal battery scores. The authors concluded that Aβ-induced neurotoxicity induced synaptic demise with increased CSF BACE1 and Nrg1 levels. They postulate that lack of neuroprotection may be linked to decreased Nrg1 brain levels.

New research supports the systematic use of the concentration ratio of Aβ_1-42 to Aβ_1-40 (Aβ_1-42/1-40 ratio) as an amyloid biomarker in diagnosing AD [4]. A French group found significant differences in amyloid status according to the ATN system (A+/A-) in CSF between absolute values of Aβ_1-42 and of Aβ_1-42/1-40 ratio. The modification of the amyloid status (A- or A+) after Aβ_1-42/1-40 ratio calculation was analysed in CSF of 738 subjects with a mean age of 69 years. Of patients deemed A+ after Aβ_1-42 measurement, 67% became A- after Aβ_1-42/1-40 ratio calculation (P<0.0001), while 18% of A- subjects became A+ (P<0.0001). These findings confirm the recent suggestion that the Aβ_1-42/1-40 ratio may be more specific to distinguish AD and should be used when analysing CSF AD biomarkers [5].

1. Agosta F, et al. EPR1001, EAN 2020.
2. Chaudhury AR, et al. J. Neuropathol. Exp. Neurol. 2003;62(1):42-54.
3. Mouton Liger F, et al. EPR2004, EAN 2020.
4. Tisserand C, et al. EPR2009, EAN 2020.
5. Hansson O, et al. Alzheimers Res Ther. 2019;11(1):34.

Posted on 8 September, 202022 February, 2021