The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

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Epidemiology of Alzheimer disease

Intranasal delivery to the central nervous system: Mechanisms and experimental considerations

Alzheimer's disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

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Alzheimer's Disease is Type 3 Diabetes—Evidence Reviewed

Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, β-amyloid, and cortisol. Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group ( p = 0.0374). Insulin-treated subjects also showed improved attention ( p = 0.0108) and functional status ( p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42), resulting in an increased Aβ40/42 ratio ( p = 0.0207). Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

https://n.neurology.org/content/neurology/71/11/866.full.pdf

Intranasal insulin improves cognition and modulates β-amyloid in early AD

Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

http://multivu.prnewswire.com/broadcast/36441/36441-RegerHenderson&Craft(2004)NeuroAging.pdf

Effects of β-hydroxybutyrate on cognition in memory-impaired adults

Background: Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid β-peptide (Aβ) in vitro in neuronal cultures and in vivo in the CSF of normal older adults. Objective: To determine whether insulin affected plasma Aβ levels and whether such effects differed for patients with AD compared with normal older adults. Methods: Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU · kg −1 · min −1 ) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU · kg −1 · min −1 ) and higher (1.67 mU · kg −1 · min −1 ) rate. Plasma insulin and Aβ were measured after 120 minutes of infusion. Results: Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Aβ levels at the middle (1.0 mU · kg −1 · min −1 ) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Aβ levels at the two higher doses (1.0 and 1.67 mU · kg −1 · min −1 ). Conclusions: These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid β-peptide (Aβ) elevation. Abnormal regulation of peripheral Aβ by insulin may contribute to AD risk.

Differential modulation of plasma β-amyloid by insulin in patients with Alzheimer disease

properties. Molecular modeling studies have indicated the central fused acridine ring undergoes favourable interactions within the catalytic site of AChE enzyme. Preliminary data on their ability to inhibit both AChE and BuChEs, their ability to chelate metals and antioxidant properties along with detailed enzyme-ligand binding investigations will be discussed. Conclusions: It is anticipated that our research should lead to the development of novel class of disease-modifying agents to treat AD by developing novel (i) heterocyclic small molecules possessing dual ChE (AChE/BuChE) inhibition; (ii) identify metal chelating and antioxidant pharmacophores in the design of small molecule therapeutics to treat AD.

G.S. Watson

Papers

Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

Effects of β-hydroxybutyrate on cognition in memory-impaired adults

Differential modulation of plasma β-amyloid by insulin in patients with Alzheimer disease

Intranasal insulin treatment response in Alzheimer's disease influenced by glucose-stimulated insulin secretion