Using redescription mining to relate clinical and biological characteristics of cognitively impaired and Alzheimer’s disease patients

Abstract

Based on a set of subjects and a collection of attributes obtained from the Alzheimer’s Disease Neuroimaging Initiative database, we used redescription mining to find interpretable rules revealing associations between those determinants that provide insights about the Alzheimer’s disease (AD). We extended the CLUS-RM redescription mining algorithm to a constraint-based redescription mining (CBRM) setting, which enables several modes of targeted exploration of specific, user-constrained associations. Redescription mining enabled finding specific constructs of clinical and biological attributes that describe many groups of subjects of different size, homogeneity and levels of cognitive impairment. We confirmed some previously known findings. However, in some instances, as with the attributes: testosterone, ciliary neurotrophic factor, brain natriuretic peptide, Fas ligand, the imaging attribute Spatial Pattern of Abnormalities for Recognition of Early AD, as well as the levels of leptin and angiopoietin-2 in plasma, we corroborated previously debatable findings or provided additional information about these variables and their association with AD pathogenesis. Moreover, applying redescription mining on ADNI data resulted with the discovery of one largely unknown attribute: the Pregnancy-Associated Protein-A (PAPP-A), which we found highly associated with cognitive impairment in AD. Statistically significant correlations (p ≤ 0.01) were found between PAPP-A and clinical tests: Alzheimer’s Disease Assessment Scale, Clinical Dementia Rating Sum of Boxes, Mini Mental State Examination, etc. The high importance of this finding lies in the fact that PAPP-A is a metalloproteinase, known to cleave insulin-like growth factor binding proteins. Since it also shares similar substrates with A Disintegrin and the Metalloproteinase family of enzymes that act as α-secretase to physiologically cleave amyloid precursor protein (APP) in the non-amyloidogenic pathway, it could be directly involved in the metabolism of APP very early during the disease course. Therefore, further studies should investigate the role of PAPP-A in the development of AD more thoroughly.

Hypoglycaemia in type 2 diabetes exacerbates amyloid‐related proteins associated with dementia

“…PAPPAs are known to cleave insulin‐like growth factor binding proteins, and overexpression of PAPPA‐2 has been shown to play a role in Aβ peptide accumulation in AD 49 . Increased serum levels of PAPPA‐1 have been reported in subjects with T2D 50 and this is in accord with their suggested shared pathophysiology 51 .…”

Prenatal development of the human entorhinal cortex

“…The major developmental events in EC structure and connectivity have broad implications for understanding its normal function, hemispheric asymmetry, modular variability, age-related changes (Šimić et al, 2005) as well as deficits in brain diseases, such as epilepsy, autism spectrum disorder, schizophrenia, or Alzheimer's disease (Bažadona et al, 2020;Babić Leko et al, 2021;Jazvinšćak Jembrek et al, 2015;Kobro-Flatmoen et al, 2021;Mladinov et al, 2016;Mihelčić et al, 2017;Palmen et al, 2004;Polšek et al, 2011;Šimić et al, 1997;2014;2017;Špeljko et al, 2011;Španić et al, 2019).…”

Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia

“…PAPPAs cleave IGF-binding proteins, and PAPPA-2 overexpression promotes Aβ peptide accumulation in AD. 23 Increased circulatory PAPPA-1 has been reported in subjects with T2D, 24 perhaps reflective of the common underlying protein misfolding pathophysiology. 25 IGF proteins, once cleaved, negatively modulate the acute phase response, 26 27 and thus PAPPA also serves as an anti-inflammatory mediator.…”