Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstrates that the induction of T2D/insulin resistance (IR) can promote the accumulation of Alzheimer’s disease (AD) pathological features. However, the association of T2D with pathological and clinical phenotypes in humans is unclear. Here we investigate the relationship of indices of IR (HOMA-IR) and pancreatic β-cell function (HOMA-B) with cognitive performance across several domains (Verbal/Visual Episodic Memory, Executive Function, Language and a measure of Global cognition) and AD biomarkers (CSF Aβ42, T-tau/P-tau, hippocampal volume and neocortical Aβ-amyloid burden). We reveal that HOMA-IR (p < 0.001) incrementally increases across diagnostic groups, becoming significantly elevated in the AD group compared with cognitively normal (CN) adults. In CN adults, higher HOMA-IR was associated with poorer performance on measures of verbal episodic memory (p = 0.010), executive function (p = 0.046) and global cognition (p = 0.007), as well as with higher CSF T-tau (p = 0.008) and P-tau (p = 0.014) levels. No association was observed with CSF Aβ or imaging modalities. Together our data suggest that IR may contribute to reduced cognitive performance and the accumulation of CSF tau biomarkers in cognitively normal adults.

Human pancreatic islet amyloid polypeptide (hiApp) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hiApp heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hiApp promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D. Epidemiological and clinical evidence suggests a strong association between Type 2 diabetes (T2D) and Alzheimer's disease (AD), with T2D patients having a significantly higher risk of developing AD compared to non-diabetic individuals 1-3. Both AD and T2D share common pathogenic markers including inflammation, oxidative stress, metabolic dysfunction and accumulation of the amyloidogenic proteins including beta amyloid (Aβ) and pancreatic islet amyloid polypeptide (IAPP or amylin) 4,5. Aβ is the main component of senile plaques in the AD brain 6. Similar to Aβ, human IAPP (hIAPP) containing deposits are observed in the T2D pancreas 7. The accumulation of aggregated Aβ or hIAPP in the brain and pancreas has been shown to be associated with cell dysfunction and death 8,9. Aβ is produced via the N-terminal proteolytic cleavage of amyloid precursor protein (APP) by BACE1 and at the C-terminus by γ-secretase, with the final Aβ length varying from 39 to 43 amino acids 10. Aβ42 is the central component of senile plaques observed in the AD brain and is considered the main neurotoxic form 11,12. hIAPP is cleaved from the pre-pro form of IAPP and subsequently converted into a 37-amino acid structure by pancreatic β-cell secretory granules 7. Mature hIAPP modulates insulin-sensitive glucose uptake and

Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstratesEpidemiological studies indicate that Type 2 diabetes (T2D) is associated with an increased risk of dementia [1][2][3][4][5] . Clinical studies using cross-sectional designs support this association by showing that cognition is worse in patients with T2D as compared to matched controls without T2D 6,7 . Furthermore, studies of structural magnetic resonance imaging (MRI) show that in T2D cognitive impairment is associated with greater levels of vascular