Understanding the Amyloid Hypothesis in Alzheimer's Disease.

The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-ß (Aß) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aß peptides act as neurotoxic molecules, but only above a critical concentration [Aß]c. A threshold mechanism triggers IAD/NIAD onset only when [Aß]≥[Aß]c. In this process, APOE modifies [Aß]c threshold in an isoform-specific way. Consequently, all factors influencing Aß anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aß catabolism/clearance could contribute to exceed the threshold [Aß]c, being characteristic of each individual. In this model, AP formation does not depend on [Aß]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease.

Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.

Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

INTRODUCTION: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations. Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND. Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient's life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer's disease.

OBJECTIVE: Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer's disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. METHODS: In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. RESULTS: A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510-70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. CONCLUSION: FOXO1 may influence the clinical response to AChEIs in AD patients.

[Forkhead-box-O1 locus and metabolic markers in the elderly: an association study]. / Forkhead-box-O1 locus y marcadores metabólicos en los ancianos: estudio de asociación.

INTRODUCTION: Mutations of forkhead-box-O1 (FOXO1) gene at locus 13q14.1 cause changes in biochemical parameters leading to premature aging. Protein FoxO1 participates in the regulation of biochemical pathways, including those influencing the regulation of lipid profile and glucose metabolism. These parameters are a risk factor for all-cause mortality in the elderly population. The aim of this study was to investigate the relationship between FOXO1 locus and metabolic-nutritional markers. MATERIAL AND METHODS: Single-nucleotide polymorphisms (SNP) rs2721069, rs4943794 and rs7981045 were determined in 594 hospitalized elderly (65-99 years), patients consecutively admitted to a geriatric ward, and tested the association of FOXO1 variants with biological markers by the analyses of co-variance (ANCOVA) and by Genotype Score Model statistic. RESULTS: The ANCOVA analysis, under different genetic models, revealed significant associations. In particular, assuming a dominant genetic model, a significant association with serum levels of fasting glucose was observed for rs2721069 (P=.034) and rs4943794 (P=.012). For rs4943794 a significant association assuming a free genetic model (P=.039) and an additive one (P=.012) was also observed. No significant relationship was observed between rs7981045 and the analyzed markers. The Genotype Score Model analysis confirmed a significant association between FOXO1 SNP and fasting glucose, taking the SNP rs2721069 and rs4943794 together (P=.048; ß=3.198). CONCLUSIONS: Aging is a complex process, resulting from the interaction between several factors, including environmental and genetic ones. Our findings suggest that FOXO1 locus may influence blood glucose levels in hospitalized older patients, thus being one of the genetic factors contributing to healthy aging.