Altered Extracellular Vesicle miRNA Profile in Prodromal Alzheimer's Disease.

Extracellular vesicles (EVs) are nanosized vesicles released by almost all body tissues, representing important mediators of cellular communication, and are thus promising candidate biomarkers for neurodegenerative diseases like Alzheimer's disease (AD). The aim of the present study was to isolate total EVs from plasma and characterize their microRNA (miRNA) contents in AD patients. We isolated total EVs from the plasma of all recruited subjects using ExoQuickULTRA exosome precipitation solution (SBI). Subsequently, circulating total EVs were characterized using Nanosight nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blotting. A panel of 754 miRNAs was determined with RT-qPCR using TaqMan OpenArray technology in a QuantStudio 12K System (Thermo Fisher Scientific). The results demonstrated that plasma EVs showed widespread deregulation of specific miRNAs (miR-106a-5p, miR-16-5p, miR-17-5p, miR-195-5p, miR-19b-3p, miR-20a-5p, miR-223-3p, miR-25-3p, miR-296-5p, miR-30b-5p, miR-532-3p, miR-92a-3p, and miR-451a), some of which were already known to be associated with neurological pathologies. A further validation analysis also confirmed a significant upregulation of miR-16-5p, miR-25-3p, miR-92a-3p, and miR-451a in prodromal AD patients, suggesting these dysregulated miRNAs are involved in the early progression of AD.

The influence of inflammation and frailty in the aging continuum.

Inflammaging is a low-grade inflammatory state that can be considered an adaptive process aimed at stimulating appropriate anti-inflammatory response. Frailty is determined by the accumulation of molecular and cellular defects accumulated throughout life; therefore, an appropriate frailty computation could be a valuable tool for measuring biological age. This study aims to analyse the association between inflammatory markers and both chronological age "per se" and frailty. We studied 452 persons aged 43-114 years. A Frailty Index (FI) was computed considering a wide range of age-related signs, symptoms, disabilities, and diseases. Plasma concentrations of inflammatory cytokines and peripheral markers of neuroinflammation were analysed by next-generation ELISA. The mean age of the cohort was 79.7 (from 43 to 114) years and the median FI was 0.19 (from 0.00 to 0.75). The concentrations of most inflammatory markers increased significantly with chronological age, after adjustment for sex and FI. Interferon-γ was significantly affected only by FI, while interleukin (IL)-10 and IL-1ß were associated only with chronological age. In conclusion, we described different associations between inflammatory components and chronological vs. biological age. A better characterization of the molecular signature of aging could help to understand the complexity of this process.

Klotho Gene Expression Is Decreased in Peripheral Blood Mononuclear Cells in Patients with Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far. OBJECTIVE: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene. METHODS: A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software. RESULTS: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation - 4.286 and - 6.561 versus controls in AD and FTD, respectively, p = 0.0037). CONCLUSION: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.

Sarcopenia and Cognitive Decline in Older Adults: Targeting the Muscle-Brain Axis.

Declines in physical performance and cognition are commonly observed in older adults. The geroscience paradigm posits that a set of processes and pathways shared among age-associated conditions may also serve as a molecular explanation for the complex pathophysiology of physical frailty, sarcopenia, and cognitive decline. Mitochondrial dysfunction, inflammation, metabolic alterations, declines in cellular stemness, and altered intracellular signaling have been observed in muscle aging. Neurological factors have also been included among the determinants of sarcopenia. Neuromuscular junctions (NMJs) are synapses bridging nervous and skeletal muscle systems with a relevant role in age-related musculoskeletal derangement. Patterns of circulating metabolic and neurotrophic factors have been associated with physical frailty and sarcopenia. These factors are mostly related to disarrangements in protein-to-energy conversion as well as reduced calorie and protein intake to sustain muscle mass. A link between sarcopenia and cognitive decline in older adults has also been described with a possible role for muscle-derived mediators (i.e., myokines) in mediating muscle-brain crosstalk. Herein, we discuss the main molecular mechanisms and factors involved in the muscle-brain axis and their possible implication in cognitive decline in older adults. An overview of current behavioral strategies that allegedly act on the muscle-brain axis is also provided.

Liver Enzymes in a Cohort of Community-Dwelling Older Persons: Focus on Sex Contribution.

Dysfunctions in liver metabolic activities may increase the risk of cognitive impairment and dementia. In a cohort of community-dwelling older persons investigated for a suspected cognitive decline, we studied the association between liver status and dementia, considering sex and frailty contribution. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, and the AST/ALT ratio were used to assess liver function in 419 older adults (248 persons with dementia and 171 age- and sex-matched subjects without cognitive decline). Although the serum concentrations of the liver enzymes were in the physiologic range, patients with dementia showed lower ALT concentrations (p = 0.005) and higher AST/ALT ratios (p = 0.003) compared to controls. The same differences were found when comparing men with and without dementia (ALT, p = 0.009; AST/ALT ratio, p = 0.003) but disappeared in women. Curiously, comparing women and men with the same diagnosis, the ALT concentrations were lower (p = 0.008), and the AST/ALT ratio was higher (p = 0.001) in control women than men, whereas no significant difference was found between persons with dementia. In conclusion, in our cohort of older people living in the community, the association between serum aminotransferases and dementia was remarked. Moreover, our results support attention to sex difference in liver function, suggesting a role in the pathogenesis of dementia.

Age-Associated Glia Remodeling and Mitochondrial Dysfunction in Neurodegeneration: Antioxidant Supplementation as a Possible Intervention.

Aging induces substantial remodeling of glia, including density, morphology, cytokine expression, and phagocytic capacity. Alterations of glial cells, such as hypertrophy of lysosomes, endosomes and peroxisomes, and the progressive accumulation of lipofuscin, lipid droplets, and other debris have also been reported. These abnormalities have been associated with significant declines of microglial processes and reduced ability to survey the surrounding tissue, maintain synapses, and recover from injury. Similarly, aged astrocytes show reduced capacity to support metabolite transportation to neurons. In the setting of reduced glial activity, stressors and/or injury signals can trigger a coordinated action of microglia and astrocytes that may amplify neuroinflammation and contribute to the release of neurotoxic factors. Oxidative stress and proteotoxic aggregates may burst astrocyte-mediated secretion of pro-inflammatory cytokines, thus activating microglia, favoring microgliosis, and ultimately making the brain more susceptible to injury and/or neurodegeneration. Here, we discuss the contribution of microglia and astrocyte oxidative stress to neuroinflammation and neurodegeneration, highlight the pathways that may help gain insights into their molecular mechanisms, and describe the benefits of antioxidant supplementation-based strategies.

VAMP2 Expression and Genotype Are Possible Discriminators in Different Forms of Dementia.

Vascular alterations often overlap with neurodegeneration, resulting in mixed forms of dementia (MD) that are hard to differentiate from Alzheimer's Disease (AD). The 26 bp intergenic polymorphism of VAMP2, a key component of SNARE complex, as well as its mRNA and protein levels are associated with neurological diseases. We evaluated ApoE4 and VAMP2 26 bp Ins/Del genotype distribution in 177 AD, 132 MD, 115 Mild Cognitive Impairment (MCI) and 250 individuals without cognitive decline (CT), as well as VAMP2 gene expression in a subset of 73 AD, 122 MD, 103 MCI and 140 CT. Forty-two MCI evolved to AD (22 MCI-AD) or MD (20 MCI-MD) over time. VAMP2 mRNA was higher in MD compared to AD (p = 0.0013) and CT (p = 0.0017), and in MCI-MD compared to MCI-AD (p < 0.001) after correcting for age, gender, MMSE and ApoE4 +/- covariates (p c = 0.004). A higher VAMP2 expression was observed in subjects carrying the minor allele Del compared to those carrying the Ins/Ins genotype (p = 0.012). Finally, Del/Del genotype was more frequently carried by MD/MCI-MD compared to CT (p c = 0.036). These results suggest that VAMP2 mRNA expression can discriminate mixed form of dementia from AD, possibly being a biomarker of AD evolution in MCI patients.

Characterization of Vitamin D Status in Older Persons with Cognitive Impairment.

Vitamin D exerts a role in the maintenance of cognitive abilities and in frailty. Although several studies evaluated the interactions between vitamin D and cognitive impairment, results were conflicting. In a cohort of community-dwelling older persons, we described the association between vitamin D levels and cognitive decline and all-cause dementia evaluating frailty's contribution. Our cohort included 509 adults, aged 64-92 years: 176 patients with mild cognitive impairment (MCI), 59 with Alzheimer's Disease (AD), 26 with idiopathic Normal Pressure Hydrocephalus (iNPH), 133 with mixed dementia (MD) and 115 without cognitive decline. Frailty was measured by frailty index, and serum 25-hydroxyvitamin D concentrations through electrochemiluminescence immunoassays. We found a significant association between vitamin D levels and Mini Mental State Examination independently of cognitive impairment, age, sex and frailty. The patients with dementia (AD and MD) showed the lowest vitamin D levels, while MCI patients showed higher levels than the other groups. The most severe deficiency was observed in MD patients, the most aged as well as cognitively and functionally impaired. In conclusion, in our community-dwelling older persons investigated for a suspected cognitive impairment, we observed an association between vitamin D levels and cognitive decline, regardless of the frailty status.

Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity.

Sphingolipids (SLs) are structural components of the lipid bilayer regulating cell functions. In biological fluids, their distribution is sex-specific and is at variance in aging and many disorders. The aim of this study is to identify SL species associated with the decelerated aging of centenarians. SLs, extracted from serum of adults (Ad, 35-37 years old), aged (Ag, 75-77 years old) and centenarian (C, 105-107 years old) women were analyzed by LC-MS/MS in combination with mRNA levels in peripheral blood mononuclear cells (PBMCs) of SL biosynthetic enzymes. Results indicated in Ag and C vs. Ad a comparable ceramides (Cers) increase, whereas dihydroceramide (dhCer) decreased in C vs. Ad. Hexosylceramides (HexCer) species, specifically HexCer 16:0, 22:0 and 24:1 acyl chains, increased in C vs. Ag representing a specific trait of C. Sphingosine (Sph), dihydrosphingosine (dhSph), sphingosine-1-phosphate (S1P) and dihydrosphingosine-1-phosphate (dhS1P), increased both in Ag and C vs. Ad, with higher levels in Ag, indicating a SL fine-tuning associated with a reduced physiological decline in C. mRNA levels of enzymes involved in ceramide de novo biosynthesis increased in Ag whereas enzymes involved in sphingomyelin (SM) degradation increased in C. Collectively, results suggest that Ag produce Cers by de novo synthesis whereas C activate a protective mechanism degrading SMs to Cers converting it into glycosphingolipids.

Biological Frailty Index in centenarians.

This study measured the subclinical frailty of centenarians by looking at the accumulation of their biological abnormalities. For this aim, a biological Frailty Index (FI) was computed in centenarians living in Northern Italy. The median value of the biological FI was 0.33 (interquartile range, IQR 0.28-0.41). The biological FI did not significantly differ between women (0.34, IQR 0.31-0.39) and men (0.32, IQR 0.26-0.43). The biological FI seems to have a narrower distribution compared to clinical FI we previously computed in the same cohort. In conclusion, our study suggests that centenarians benefit from exceptional biological reserves that might be underestimated by clinical appearances.

Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition.

BACKGROUND: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-ß 1-42 (Aß) deposition and to correlate genetic data with clinical phenotypes. METHODS: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aß levels or positive PET with Aß tracer and 200 non-demented geriatric subjects. RESULTS: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p > 0.05). CONCLUSION: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aß deposition is higher than in the general population.

Sarcopenia and Menopause: The Role of Estradiol.

During aging and menopausal transition in women, a progressive muscle degeneration (i.e. decrease in quality and muscle function) occurs. This muscle dysfunction, caused by decreased proliferation of muscle satellite cells, increased levels of inflammatory markers, and altered levels of sex hormones, exposes women to a raised incidence of sarcopenia. In this regard, hormonal balance and, in particular, estradiol, seems to be essential in skeletal muscle function. The role of the estradiol on satellite cells and the release of inflammatory cytokines in menopausal women are reviewed. In particular, estradiol has a beneficial effect on the skeletal muscle by stimulating satellite cell proliferation. Skeletal muscle can respond to estrogenic hormonal control due to the presence of specific receptors for estradiol at the level of muscle fibers. Additionally, estradiol can limit inflammatory stress damage on skeletal muscle. In this review, we primarily focused on the role of estradiol in sarcopenia and on the possibility of using Estradiol Replacement Therapy, which combined with nutritional and physical activity programs, can counteract this condition representing a valid tool to treat sarcopenia in women.

Whole-genome sequencing analysis of semi-supercentenarians.

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

Corrigendum to "Peripheral Blood Mononuclear Cells as a Laboratory to Study Dementia in the Elderly".

[This corrects the article DOI: 10.1155/2014/169203.].

Vitamin D Receptor Polymorphisms in Sex-Frailty Paradox.

The "male-female health-survival paradox" evidences that the survival advantage observed in women is linked to higher rates of disability and poor health status compared to men, a phenomenon also called the "sex-frailty paradox". The depletion of vitamin D seems to play a role in the fragilization of old persons, and genetic polymorphisms of the vitamin D receptor (VDR) gene seem to be involved in regulating the vitamin D pathway. This study correlated the VDR gene polymorphisms (FokI, ApaI, BsmiI, and TaqI) with frailty, computed by frailty index (FI), in 202 persons (127 women and 75 men, aged from 60 to 116 years), aiming to capture the involvement of vitamin D in the sex-frailty paradox. The results showed slightly higher FI (p = 0.05), lower levels of 25(OH)D (p = 0.04), and higher levels of parathyroid hormone PTH (p = 0.002) and phosphorus (p < 0.001) in women than in men. Interestingly, the ApaI minor allele (Aa + aa) showed a significant positive association with FI (p = 0.03) and a negative association with inorganic phosphorus values (p = 0.04) compared to AA genotype only in women, regardless of age. The exact mechanism and the causal role that, in old women, links ApaI polymorphism with frailty are still unclear. However, we could speculate that a specific genetic profiling, other than 25(OH)D levels, play a role in the sex-frailty paradox.

Role of Age-Related Mitochondrial Dysfunction in Sarcopenia.

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

Thyroid hormones and frailty in persons experiencing extreme longevity.

CONTEXT: The aging phenotype is quite heterogeneous, being the result of the capability of each individual to successfully or unsuccessfully response to stressors. The reduction of homeostatic reserve characterizing aging is accompanied by a remodeling of the endocrine system. Frailty has been indicated as a promising way for capturing the physiological decline as well as the biological aging of the individuals. In particular, the Frailty Index (FI), based on the assumption that health deficits tend to accumulate with aging, represents a quantitative measure of extreme interest. OBJECTIVE: The study aims to correlate the thyroid hormone levels with FI in a population of centenarians and their offspring to capture the effects of thyroid remodeling in extreme longevity. STUDY DESIGN: The study described 593 well-characterized Italian subjects, including 180 centenarians, as well as 276 centenarian's offspring and 137 age-matched controls. RESULTS: FT3 levels and FT3/FT4 ratio were significantly lower (p < 0.001) and TSH levels higher (p < 0.001) in centenarians compared to the other groups, analysing both overall subjects and excluding subjects with hormone levels out of the normal ranges. In overall centenarians, we observed a negative correlation between FI and FT3 (ρ: -0.281, p < 0.001), FT3/FT4 (ρ: -0.344, p < 0.001) and TSH (ρ: -0.223, p 0.003) and a positive association between FI and FT4 (ρ: 0.189, p = 0.001). In centenarians with hormone levels within the normal ranges, similar negative correlations were observed between FI and FT3 (ρ: -0.201, p = 0.02) and FT3/FT4 (ρ: -0.264, p = 0.002). In this sub-analysis, FI positively correlated with FT4 and age (ρ: 0.167, p = 0.05; ρ: 0.219, p = 0.005, respectively). Conversely, no significant correlations were observed between hormone levels and FI in offspring and controls. CONCLUSIONS: We found an association between thyroid hormone levels and frailty in centenarians, underlying the significant role of thyroid in the aging process and longevity.

The sTREM2 Concentrations in the Blood: A Marker of Neurodegeneration?

Microglia performs a variety of functions during brain development designed to maintain brain homeostasis. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in microglial cells modulating phagocytosis, cytokine production, cell proliferation, and cell survival. Interestingly, the levels of soluble TREM2 (the secreted ectodomain of TREM2, sTREM2) were higher in cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients than subjects without cognitive decline. It is noteworthy that, while CSF sTREM2 levels have been extensively studied, few studies have investigated sTREM2 in blood producing conflicting results. We aimed to investigate the levels of sTREM2 in CSF and blood from a cohort of well-characterized AD comparing the results to those obtained in patients suffering from idiopathic normal pressure hydrocephalus (iNPH), a potentially reversible cognitive impairment. Our findings underlined a significantly lower plasma sTREM2 concentration in AD patients compared to iNPH subjects [39.1 ng/mL (standard deviation (SD), 15.0) and 47.2 ng/mL (SD, 19.5), respectively; p = 0.01], whereas no difference was revealed between the two groups in the CSF sTREM2 levels. The adjusted regression analyses evidenced in AD patients an association between plasma and CSF sTREM2 levels [B = 0.411; 95% confidence interval (CI), 0.137-0.685, p = 0.004], as well as ß-amyloid concentrations (B = 0.035; 95% CI, 0.007-0.063, p = 0.01) and an association between CSF sTREM2 and phospho-Tau concentrations (B = 0.248; 95% CI, 0.053-0.443; p = 0.01). No significant relation was found in iNPH patients. In conclusion, these differences in sTREM2 profiles between AD and iNPH reinforce the notion that this receptor has a role in neurodegeneration.

Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects.

PURPOSE: Advancing age represents the strongest risk factor for Alzheimer's disease (AD), and the identification of biomarkers able to define what characterizes physiological aging from AD may represent a potential starting point for novel preventive strategies. Among these biomarkers, telomeres seem to be a promising target. Interestingly, high intake of carotenoid-rich food may play a role in protecting telomeres by oxidative stress reduction. Accordingly, low plasma ß-carotene concentrations have been found in AD subjects when compared with cognitively healthy subjects. In this study, we aim at investigating the hypothesis that low ß-carotene might be associated with markers of accelerated cellular aging, including leucocyte telomere length (LTL) and peripheral mononuclear cell (PBMC) telomerase activity in a cohort of old age subjects. METHODS: The study was conducted in 68 old age subjects, 37 AD, and 31 age-matched healthy controls. In all subjects, ß-carotene plasma level, LTL and peripheral telomerase activity were measured. RESULTS: In all populations, ß-carotene significantly and positively (r = 0.320, p = 0.008) correlated with telomerase activity, independent of gender. A model having telomerase activity levels as the dependent variable, and age, gender, smoking habit, and ß-carotene as independent variables, confirmed that ß-carotene was independently associated with telomerase activity (ß = 0.319, p = 0.012). Subjects affected by AD had significantly lower plasmatic levels of ß-carotene (448 ± 66 mg/ml vs 497 ± 59 mg/ml, p = 0.001) and LTL (0.53 ± 0.25 vs 0.69 ± 0.29; p = 0.009) as compared with healthy controls. Β-carotene plasma level was associated with AD diagnosis (OR 0.988; IC95% 0.978-0.997; p = 0.013) independently of age, gender, smoking habit, ApoE genotype, and LTL. CONCLUSION: Our data show that ß-carotene may modulate telomerase activity in old age. Moreover, lower plasma ß-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates.

Vitamin E and Alzheimer's disease: the mediating role of cellular aging.

BACKGROUND: Vitamin E represents a potent antioxidant and anti-inflammatory system, playing a role in Alzheimer's disease (AD). Different plasma concentrations of the forms of vitamin E are observed in AD compared to cognitively healthy subjects. AIM: Since these modifications may modulate the markers of oxidative stress and cellular aging, we aim to explore the relationship between vitamin E forms and leukocyte telomere length (LTL) in AD. METHODS: 53 AD subjects and 40 cognitively healthy controls (CTs) were enrolled. The vitamin E forms (α-, ß-, γ- and δ-tocopherol, α-, ß-, γ- and δ-tocotrienol), the ratio of α-tocopherylquinone/α-tocopherol and 5-nitro-γ-tocopherol/γ-tocopherol (markers of oxidative/nitrosative damage) and LTL were measured. RESULTS AND DISCUSSION: Regression model was used to explore the associations of vitamin E forms and LTL with AD. The interaction of LTL in the association between vitamin E forms and AD was tested. AD subjects showed significantly lower concentrations of α-, ß-, γ- and δ-tocopherol, α- and δ-tocotrienol, total tocopherols, total tocotrienols and total vitamin E compared to CTs. AD subjects showed higher values of nitrosative/oxidative damage. The adjusted analyses confirmed a significant relationship of AD with plasma concentrations of α- and ß-tocopherols, δ-tocotrienol, total tocopherols, total tocotrienol, total vitamin E and oxidative/nitrosative damage. However, nitrosative damage was significantly associated with AD only in subjects with higher LTL and not in those expressing marked cellular aging. CONCLUSIONS: Our study confirms the role of vitamin E in AD pathology and indicates that nitrosative damage influences the association with AD only in subjects characterized by longer LTL.