In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Abstract

In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMRglc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Any means to reinstate the homeostatic regulation between Tau and insulin signalling can then be considered of therapeutic interest. This could be directly achieved by activating IRs or targeting downstream pathways using PTP1B inhibitors [221], GLP-1 receptor agonists [162, 222, 223], or intranasal insulin administration [224, 225]. Alternatively, one could imagine that strategies aimed at clearing pathological forms of Tau (such as Tau immunotherapy) [226, 227] could allow reestablishment of proper brain insulin signalling.…”

Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases

“…The drug liraglutide has been shown to protect the brain from the AD disease progression in an 18 FDG-PET imaging study. The AD typical reduction of brain activity and energy utilization was prevented by liraglutide, indicating that the drug reversed the IR in the brain and normalized brain function (Gejl et al, 2016). A phase II clinical trial is currently ongoing (Holscher, 2014a).…”

Effects of incretin-based therapies on neurocognitive function in humans: A systematic review of the literature

“…In a 6-month double-blinded trial, liraglutide produced increased cerebral metabolism of glucose versus placebo in multiple regions of interest [7], although the study was not powered to detect clinical outcomes. In an open-label study in 19 patients with comorbid affective disorder, 4 weeks of liraglutide was associated with improvements in multiple cognitive domains, although the study was uncontrolled [10].…”

“…However, as only three studies reported such data [6][7][8], all with varying study populations, meta-analysis was not performed.…”