Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer’s Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer’s disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

In participants with no epsilon4 alleles, the age-specific prevalence of AD reached a maximum and then declined after age 95. In epsilon4 heterozygotes a similar maximum was noted earlier at age 87, in homozygotes at age 73. Female sex was a risk factor for AD only in those with epsilon4. The epsilon4 allele accounted for 70% of the population attributable risk for AD.

Use of vitamin E and vitamin C supplements in combination is associated with reduced prevalence and incidence of AD. Antioxidant supplements merit further study as agents for the primary prevention of AD.

The incidence of AD in the Cache County population increased with advancing age, but then peaked and declined among the extremely old. The presence of APOE-epsilon 4 alleles accelerated onset of AD, but did not appreciably alter lifetime incidence apparent over a span of 100 years.

Background: Recent reports suggest that antihypertensive (AH) medications may reduce the risk of dementing illnesses.Objectives: To examine the relationship of AH medication use with incidence of Alzheimer disease (AD) among the elderly population (aged 65 years and older) of Cache County, Utah, and to examine whether the relationship varies with different classes of AH medications.Methods: After an initial (wave 1) multistage assessment (1995 through 1997) to identify prevalent cases of dementia, we used similar methods 3 years later (wave 2) to identify 104 incident cases of AD among the 3308 survivors. At the baseline assessment, we obtained a detailed drug inventory from the study participants. We carried out discrete time survival analyses to examine the association between the use of AH medications (including angiotensin converting enzyme inhibitors, ␤-blockers, calcium channel blockers, and diuretics) at baseline with subsequent risk of AD.Results: Use of any AH medication at baseline was associated with lower incidence of AD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.41-0.98). Examination of medication subclasses showed that use of diuretics (adjusted hazard ratio, 0.57; 95% confidence interval, 0.33-0.94), and specifically potassiumsparing diuretics (adjusted hazard ratio, 0.26; 95% confidence interval, 0.08-0.64), was associated with the greatest reduction in risk of AD. Corresponding analysis with a fully examined subsample controlling for blood pressure measurements did not substantially change our findings.Conclusions: These data suggest that AH medications, and specifically potassium-sparing diuretics, are associated with reduced incidence of AD. Because the latter association is a new finding, it requires confirmation in further study.

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk.

Although statin use might be less frequent in those with prevalent dementia, we found no association between statin use and subsequent onset of dementia or AD. Further research is warranted before costly dementia prevention trials with statins are undertaken.