Alzheimer disease pathology can be found in the brains of older persons without dementia or mild cognitive impairment and is related to subtle changes in episodic memory.

Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid ␤-peptide (A␤) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to A␤ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to A␤ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with ␣-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by A␤. Our findings suggest a sequence of events in the pathogenesis of AD in which A␤ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.amyloid ͉ apoptosis ͉ hippocampus ͉ lipid peroxidation ͉ sphingomyelin C hanges that occur in the brain during aging increase the risk of Alzheimer's disease (AD), a disorder involving the progressive deposition of amyloid ␤-peptide (A␤) and associated degeneration of neurons in brain regions involved in learning and memory (1). Two factors that are believed to contribute to neuronal dysfunction and degeneration in AD are increased oxidative stress and increased production of neurotoxic forms of A␤ (2). Alterations in lipid metabolism may also play roles in AD because the risk of AD is affected by inheritance of different isoforms of apolipoprotein E (3), changes in cholesterol metabolism can affect A␤ production in cell culture and in vivo (4-6), and drugs that lower cholesterol levels may reduce the risk of AD (7,8). However, a direct link between alterations in the metabolism of cholesterol and other membrane lipids in AD has not been established, and it is not known whether and how such lipid alterations might lead to neuronal dysfunction and death.Membrane microdomains that are rich in cholesterol and sphingolipids play important roles in various cellular signaling pathways (9, 10). Sphingomyelin is a major source of ceramides, lipid mediators that are generated when sphingomyelin is cleaved by sphingomyelinases, enzymes activated by inflammatory cytokines (11) and oxidative stress (12). Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a form of programmed cell death called apoptosis (13). Ceramides have been implicated in the pathological death of neurons that occurs in ischemic stroke (14) and Parkinson's disease (15). In the present study, we document significant increases in levels of m...

Context: Social isolation in old age has been associated with risk of developing dementia, but the risk associated with perceived isolation, or loneliness, is not well understood.Objective: To test the hypothesis that loneliness is associated with increased risk of Alzheimer disease (AD).Design: Longitudinal clinicopathologic cohort study with up to 4 years of annual in-home follow-up.Participants: A total of 823 older persons free of dementia at enrollment were recruited from senior citizen facilities in and around Chicago, Ill. Loneliness was assessed with a 5-item scale at baseline (mean±SD, 2.3±0.6) and annually thereafter. At death, a uniform postmortem examination of the brain was conducted to quantify AD pathology in multiple brain regions and the presence of cerebral infarctions. Main Outcome Measures:Clinical diagnosis of AD and change in previously established composite measures of global cognition and specific cognitive functions.Results: During follow-up, 76 subjects developed clinical AD. Risk of AD was more than doubled in lonely persons (score 3.2, 90th percentile) compared with persons who were not lonely (score 1.4, 10th percentile), and controlling for indicators of social isolation did not affect the finding. Loneliness was associated with lower level of cognition at baseline and with more rapid cognitive decline during follow-up. There was no significant change in loneliness, and mean degree of loneliness during the study was robustly associated with cognitive decline and development of AD. In 90 participants who died and in whom autopsy of the brain was performed, loneliness was unrelated to summary measures of AD pathology or to cerebral infarction. Conclusion:Loneliness is associated with an increased risk of late-life dementia but not with its leading causes.

We developed prediction rules to guide the clinical diagnosis of Alzheimer’s disease (AD) in two community-based cohort studies (the Religious Orders Study and the Rush Memory and Aging Project). The rules were implemented without informant interviews, neuroimaging, blood work or routine case conferencing. Autopsies were performed at death and the pathologic diagnosis of AD made with a modified version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria. We compared the positive predictive value of the clinical diagnosis in the two community-based studies to the positive predictive value of the clinical diagnosis of AD made by standard clinical practice in a clinic-based cohort study using AD pathology as the gold standard. Of 306 clinic cases with probable AD, 286 (93.5%) met CERAD neuropathologic criteria for AD; the results were comparable for those with possible AD (51 of 54, 94.4%). Of 141 study subjects with probable AD, 130 (92.2%) met CERAD neuropathologic criteria for AD; the results were lower but acceptable for those with possible AD (26 of 37, 70.3%). The results were similar in secondary analyses using alternate neuropathologic criteria for AD. The clinical diagnosis of AD can be made in community-based studies without the use of informant interviews, neuroimaging, blood work or routine case conferencing. This approach holds promise for reducing the operational costs of epidemiologic studies of aging and AD.

Self-reported experiences of "everyday" discrimination have been linked to indices of cardiovascular disease and overall mortality and findings have been particularly pronounced for African-American populations. However, the biological mechanisms underlying these associations remain unclear. CReactive Protein (CRP), a marker of inflammation, is a known correlate of cardiovascular and other health outcomes and has also been linked to several psychosocial processes. To our knowledge, no studies have examined the association between experiences of discrimination and CRP. We examined the cross-sectional association between self-reported experiences of discrimination and CRP in a sample of 296 older African-American adults (70% female, Mean age= 73.1). Experiences of discrimination were assessed with the 9-item Everyday Discrimination Scale and CRP was assayed from blood samples. In linear regression models adjusted for age, sex and education, experiences of discrimination were associated with higher levels of CRP (B=.10, p=.03). This association remained significant after additional adjustments for depressive symptoms (B=.10, p=.04), smoking, and chronic health conditions (heart disease, diabetes, hypertension) that might influence inflammation (B=.11, p=.02). However, results were attenuated when Body Mass Index (BMI) was added to the model (B=.09, p=.07). In conclusion, self-reported experiences of everyday discrimination are associated with higher levels of CRP in older African-American adults, although this association is not completely independent of BMI.

Clinical and pathological data from the Rush Memory and Aging Project were used to test the hypothesis that distress proneness is associated with increased risk of Alzheimer’s disease (AD). More than 600 older persons without dementia completed a 6-item measure of neuroticism, a stable indicator of proneness to psychological distress. At annual intervals thereafter, they underwent uniform evaluations that included clinical classification of AD and administration of 18 cognitive tests. Those who died underwent brain autopsy from which composite measures of AD pathology were derived. During a mean of about 3 years of follow-up, 55 people were clinically diagnosed with AD. In analyses that controlled for age, sex, and education, persons with a high level of distress proneness (score = 24, 90th percentile) were 2.7 times more likely to develop AD than those not prone to distress (score = 6, 10th percentile). Adjustment for depressive symptomatology or frequency of cognitive, social, and physical activity did not substantially change this effect. Distress proneness was also associated with more rapid cognitive decline. Among 45 participants who died and underwent brain autopsy, distress proneness was unrelated to diverse measures of AD pathology and was inversely related to cognition after controlling for AD pathology. The results support the hypothesis that distress proneness is associated with increased risk of dementia and suggest that neurobiologic mechanisms other than AD pathology may underlie the association.

No abstract

Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A Cholinergic pathways projecting from basal forebrain regions to hippocampus and neocortex are believed to play important roles in learning and memory processes (1). In Alzheimer disease (AD) cholinergic systems are disrupted, and neurons ultimately die in several connected brain regions including hippocampus and basal forebrain (2). However, it is unclear whether deficits in cholinergic signaling occur prior to neuronal loss. Acetylcholine binding to muscarinic cholinergic receptors initiates the heterotrimeric G protein cycle, which commences with the exchange of GTP for GDP on a-subunits and the subsequent dissociation of fry subunits. The activated, GTP-bound form of the a-subunit stimulates (or inhibits) its effector, then undergoes inactivation by intrinsic GTPase activity, which converts GTP to GDP by hydrolytic cleavage of the y phosphate bond. Cholinergic agonist stimulation of M1, M3, and M5 receptors activates G proteins of the pertussis toxin-insensitive Gq/11 family. Gq/11 subunits stimulate phospholipase C, which catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate, resulting in the liberation of diacylgylcerol and inositol triphosphate (IP3). Diacylgylcerol activates protein kinase C, and IP3 induces the release of Ca2+ from endoplasmic reticulum (3).