Diabetes mellitus contributes to higher cerebrospinal fluid tau levels selectively in Alzheimer's disease patients with the APOE4 genotype

Abstract

Background and purpose Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using β amyloid (A: Aβ1‐42) and phosphorylated tau (T: p‐tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T–) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process. Methods For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping. Results A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T– patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t‐tau) levels compared to non‐DM patients (DM: 919.4 ± 444 vs. non‐DM: 773.1 ± 348.2; p = 0.04), but similar p‐tau (p = 0.72) and Aβ1‐42 levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t‐tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49–398.1; p = 0.01), but not in APOE E4‐ (p = 0.53). Conclusions The present study shows a clear dependency of CSF t‐tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4‐related and non‐related disease, with key implications for AD pathophysiology and treatment.

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

“…Intraneuronally, the lipid‐rich ER‐mitochondria interaction site (MAMs) is also regulated by tau [243]. Additionally, a significant association between T2D and CSF tau levels is detected in ApoE4 carriers but not in noncarriers [244].…”

Diagnostic, Prognostic, and Mechanistic Biomarkers of Diabetes Mellitus-Associated Cognitive Decline

“…That was subsequently confirmed by a study that indicated an increase in the rate of functional activity decline among patients with both diabetes and one of the AD risk variables, either genetic susceptibility, such as carrying the ApoE E4 allele, or CSF alterations of total tau and p-tau, but not CSF Aβ [ 131 ]. Additionally, DM was found to be associated with alteration only in CSF total tau level, but not in p-tau or Aβ in ApoE E4 carriers diagnosed with MCI or early dementia [ 17 ].…”

“…Besides the early changes in cerebral metabolism and brain structures that can be detected using brain imaging technology platforms [ 4 ], the most promising molecules identified so far are related to glucose metabolism, inflammation, neurodegeneration, vascular damage, and oxidative stress. Some of these molecules include C reactive protein (CRP) [ 12 ], interleukin-6 (IL-6) [ 13 ], leptin and interleukin-1 (IL-1 β) [ 14 ], homeostasis model assessment of the insulin resistance (HOMA-IR) score along with glycosylated hemoglobin (HbA1c) [ 15 ], advanced glycation end products (AGEs) [ 16 ], tau protein [ 17 ], glycogen synthase kinase 3β (GSK-3β) [ 18 ], brain-derived neurotrophic factor (BDNF) [ 19 ] and microRNAs [ 20 ]. In the following sections, we aim to evaluate the contributory risk factors and the potential pathophysiological mechanisms of cognitive disorders in diabetes, and to discuss the potential biomarkers related to the cognitive decline in T2DM patients.…”

Electroacupuncture improves cognitive impairment in diabetic cognitive dysfunction rats by regulating the mitochondrial autophagy pathway

“…The Journal of Physiological Sciences † Xia Ge and Ling Wang have contributed equally to this work and should be considered co-first authors tissues of DM patients [5]. Moreover, Aβ deposition in the brain leads to neuronal toxicity, affecting microcirculation [6].…”

“…Synaptic plasticity regulates learning and memory in patients with type 2 diabetes [ 3 , 4 ]. Amyloid-β (Aβ) peptide deposition and hyperphosphorylation of microtubule-associated protein tau have been reported in brain tissues of DM patients [ 5 ]. Moreover, Aβ deposition in the brain leads to neuronal toxicity, affecting microcirculation [ 6 ].…”