J. Wesson Ashford

ApoE genotype accounts for the vast majority of AD risk and AD pathology

In this review, evidence is provided that apolipoprotein E (apoE) genotype accounts for the majority of Alzheimers disease (AD) risk and pathology. The three major human isoforms, apoE2, apoE3, and apoE4, are encoded by different alleles (2, 3, 4) and regulate lipid metabolism and redistribution. ApoE isoforms differ in their effects on AD risk and pathology. Clinical and epidemiological data have indicated that the 4 allele may account for 50% of AD in the United States. Further, the rarity of AD among carriers of the 2 allele suggests that allelic variations in the gene encoding this protein may account for over 95% of AD cases. ApoE4 disrupts memory function in rodents. Further studies have indicated that fragments of apoE may contribute to both plaque and tangle formation. Thus, the epidemiologic and basic science evidence suggest that apoE genotype accounts for the vast majority of AD risk and pathology.

APOE Genotype Effects on Alzheimer's Disease Onset and Epidemiology

The risk of developing Alzheimer’s disease (AD) is tied most closely to age and appears to follow Gompertzian kinetics. However, specific genetic factors are also linked closely to AD, and the apolipoprotein E (APOE) genotype accounts for as much of 50% of the attributable risk for AD in many populations. This paper reviews the onset, diagnosis, and epidemiology of AD, specifically with regard to the APOE genotype and the interaction of the genotype with age.

Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease.

We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimers disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-beta (Abeta){1-40} in both brain extracts (52% reduction, p= 0.047) and serum (55% reduction, p= 0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p=0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Abeta in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-beta protein precursor, consistent with a role for beta -secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser{396} antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-alpha, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans.

Age, education, and changes in the Mini-Mental State Exam scores of older women: findings from the Nun Study.

OBJECTIVE: To describe the relationship of Mini‐Mental State Exam (MMSE) scores and changes over time in MMSE scores to age and education in a population of older women.

Non-familial Alzheimer's disease is mainly due to genetic factors.

This team takes the position that what is commonly referred to as non-familial Alzheimers disease (AD) is predominantly due to genetic factors. Population-based studies suggest that genetic factors cause the majority of cases that begin after age 60. There are several lines of evidence supporting this position: Data from the Nun Study suggest that the risk for AD is largely established by early adulthood, implying that later adult exposures likely play only a small role in causation. Family studies show that first-degree blood relatives of persons with non-familial AD have a substantially increased risk of AD relative to controls. Twin studies suggest that the heritability of AD exceeds 60%. Environmental factors, such as socioeconomic status, education, and head injury, are strong risk factors for AD only in individuals with a genetic predisposition. The APOE genotype is a powerful risk factor for AD and accounts for as much as 50%. There are numerous other candidate genes with strong associations with AD that presumably explain the remaining population risk. This paper further reviews the mechanisms associated with AD causation for APOE and other candidate genes and implications for the development of prevention strategies.

Improving dementia care: The role of screening and detection of cognitive impairment

The value of screening for cognitive impairment, including dementia and Alzheimers disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimers Foundation of America and the Alzheimers Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient‐centered management of dementia.

Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease

Adipocyte-derived leptin appears to regulate a number of features defining Alzheimers disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Anticonvulsants attenuate amyloid β-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology

Increasing evidence supports the involvement of amyloid beta-peptide (A beta) and an excitotoxic mechanism of neuronal injury in the pathogenesis of Alzheimers disease. However, approaches aimed at preventing A beta toxicity and neurofibrillary degeneration are undeveloped. We now report that anticonvulsants (carbamazepine, phenytoin, and valproic acid) can protect cultured rat hippocampal neurons against A beta- and glutamate-induced injury. Each of the anticonvulsants attenuated the elevation of intracellular free calcium levels [(Ca2+)i] elicited by A beta or glutamate suggesting that their neuroprotective mechanism of action involved stabilization of [Ca2+]i. These compounds were effective at clinically relevant concentrations (carbamazepine, 100 nM-10 microM; phenytoin, 100 nM-1 microM; valproic acid, 100 nM-100 microM). The anticonvulsants suppressed glutamate-induced alterations in tau and buiquitin immunoreactivities. Compounds that stabilize [Ca2+]i may afford protection against the kinds of insults believed to underlie neuronal injury in Alzheimers disease.

Neuroplasticity in Alzheimer's disease.

Ramon y Cajal proclaimed in 1928 that “once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers the nerve paths are something fixed, ended and immutable. Everything must die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree.” (Ramon y Cajal, 1928 ). In large part, despite the extensive knowledge gained since then, the latter directive has not yet been achieved by ‘modern’ science. Although we know now that Ramon y Cajals observation on CNS plasticity is largely true (for lower brain and primary cortical structures), there are mechanisms for recovery from CNS injury. These mechanisms, however, may contribute to the vulnerability to neurodegenerative disease. They may also be exploited therapeutically to help alleviate the suffering from neurodegenerative conditions. Published 2002 Wiley‐Liss, Inc.

Leptin reduces Alzheimer’s disease-related tau phosphorylation in neuronal cells

Leptin is a centrally acting hormone controlling metabolic pathways. Recently, it was shown that leptin can reduce amyloid beta levels both in vitro and in vivo. Herein, phosphorylation of tau was investigated following treatment of neuronal cells with leptin and insulin. Specifically, phosphorylation of tau at amino acid residues Ser(202), Ser(396) and Ser(404) was monitored in retinoic acid induced, human cell lines: SH-SY5Y and NTera-2. Both hormones induced a concentration- and time-dependent reduction of tau phosphorylation, and were synergistic at suboptimum concentrations. Importantly, leptin was 300-fold more potent than insulin (IC(50)L=46.9 nM vs. IC(50)I=13.8 microM). A central role for AMP-dependent kinase as a mediator of leptins action is demonstrated by the ability of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to decrease tau phosphorylation, and by blocking leptin in the presence of Compound C. Thus, leptin, which ameliorates both amyloid beta and tau-related pathological pathways, holds promise as a novel therapeutic for Alzheimers disease.