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Background: Amyloid-associated depression is associated with cognitive impairment cross sectionally. This follow-up study was to determine the relationship between amyloid-associated depression and the development of Alzheimer's disease (AD).Methods: Two hundred and twenty three subjects who did not have dementia at baseline were given a repeat cognitive evaluation for incident AD. Depression was defined by having a Center for Epidemiological Studies Depression (CES-D) score ≥ 16, and non-amyloid vs. amyloid-associated depression by having a low vs. high plasma amyloid-β peptide 40 (Aβ40)/Aβ42 ratio. Apolipoprotein E (ApoE) genotype was determined, and antidepressant usage was documented.Results: Fifteen subjects developed AD (7%) after an average follow-up time of 6.2 years. While none of those with non-amyloid depression developed AD, 9% of those with amyloid-associated depression developed AD. Further, among those with amyloid-associated depression, ApoE4 carriers tended to have a higher risk of AD than ApoE4 non-carriers (40% vs. 4%, p = 0.06). In contrast, 8% of those who did not have depression at baseline developed AD, but ApoE4 carriers and non-carriers did not show a difference in the AD risk. After adjusting for age, the interaction between ApoE4 and amyloid-associated depression (β = +0.113, SE = 0.047, P = 0.02) and the interaction between ApoE4 and antidepressant use (β = +0.174, SE = 0.064, P = 0.007) were associated with the AD risk.Conclusions: Amyloid-associated depression may be prodromal depression of AD especially in the presence of ApoE4. Future studies with a larger cohort and a longer follow-up are warranted to further confirm this conclusion. [ABSTRACT FROM AUTHOR]

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD. [ABSTRACT FROM AUTHOR]

Background: The ratio of high amyloid-β peptide40 (Aβ40) and low Aβ42 in plasma predicts the risk of Alzheimer's disease (AD) and is associated with episodic recall in depression. We thus examined the relationship between plasma Aβ levels and brain volumes.Methods: Homebound elders (N = 352) who had undergone brain MRI were used. Plasma Aβ1-40 and Aβ1-42 were measured by ELISA. Volumes of medial temporal regions, including the amygdala and hippocampus, were manually measured.Results: Amygdala volume was associated with log(10) of plasma Aβ1-42 (β = +0.19, SE = 0.07, p = 0.005) after adjusting for AD, infarcts, white matter hyperintensities and demographics. In the absence of dementia, decreasing quartiles of plasma Aβ1-42 (Mean + SD ml: Q4 = 4.1 ± 0.8; Q3 = 3.9 ± 0.7; Q2 = 3.6 ± 0.8 and Q1 = 3.7 ± 0.8, p = 0.01) and increasing quartiles of plasma Aβ1-40/1-42 ratio were associated with smaller amygdala volume. Those depressed subjects with a high plasma Aβ1-40/1-42 ratio had smaller amygdala (Mean + SD ml: 3.3 ± 0.8 vs. 3.6 ± 0.8, p = 0.04) and total brain volume (Mean + SD liter: 0.95 ± 0.07 vs. 1.04 ± 0.12, p = 0.005), and had a higher rate of MCI (67 vs. 36%, p = 0.02) than those with a low plasma Aβ1-40/1-42 ratio.Conclusions: The combination of low plasma Aβ1-42 concentration and atrophy of the medial temporal lobe structures, which regulates mood and cognition, may represent a biomarker for a prodromal stage of AD. [ABSTRACT FROM AUTHOR]

Introduction: Brain magnetic resonance imaging (MRI) and inflammatory biomarkers are crucial for investigating preclinical neurocognitive disorders. Current investigations focus on a few inflammatory markers. The study aims to investigate the associations between inflammatory biomarkers and MRI measures and to examine sex differences among the associations in the Framingham Heart Study., Methods: Dementia and stroke-free participants underwent OLINK Proteomics profiling and MRI measurements within 5 years. Pairwise cross-sectional analysis assessed 68 biomarkers with 13 brain MRI volumes, adjusting for covariates and familial correlations., Results: Elevated CDCP1, IL6, OPG, and 4E.BP1 were related to smaller total cerebral brain volume (TCBV), whereas higher HGF, IL8, and MMP10 were associated with smaller TCBV, total and frontal white matter volumes. Higher SCF and TWEAK were associated with larger TCBV. In sex-stratified analyses, associations were observed exclusively among males., Discussion: We report several associations between inflammatory biomarkers and brain volumes, highlighting different associations within sex subgroups., Highlights: Higher CDCP1, IL6, OPG, and 4E.BP1 levels were associated with smaller TCBV. Higher levels of HGF, IL8 and MMP10 were associated with smaller TCBV, CWV and FWV. Higher levels of SCF and TWEAK, were associated with larger TCBV. Significance diminished in models adjusting for CVD risk factors. Associations were observed exclusively in males., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau) 181+231 ., Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes., Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia., Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD., Competing Interests: The authors MA, MAS, TKK, HJA, BF, YT, BM, JNP, EGS, IS, LAF, GRJ, KWT, AEB, MKO, LEG, NWK, RK, TDS, ACM, WQ, and JM have no competing interests to declare. HZ has served on scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. NJA has given lectures in symposia sponsored by Eli‐Lily. AEB has served as a consultant or on advisory boards for Eli Lilly and Roche Pharmaceuticals and has received grant monies from Cumulus Neuroscience, VoxNeuro, Bristol Myers Squibb, and Cyclerion. He receives publishing royalties from Elsevier and Oxford University Press. RA serves on the scientific advisory board of Signant Health, as consultant to Biogen, and has given a lecture in a symposium sponsored by Eisai. RAS has served as a consultant to Biogen and Lundbeck. He receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. MLA has received honorarium from the Michael J. Fox Foundation for services unrelated to this study. He receives royalties from Oxford University Press., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Previous study shows that monocyte chemoattractant protein-1 (MCP-1), which is implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption, modulates the genetic risks of AD in established AD loci., Methods: In this study, we hypothesized that blood MCP-1 impacts the AD risk of genetic variants beyond known AD loci. We thus performed a genome-wide association study (GWAS) using the logistic regression via generalized estimating equations (GEE) and the Cox proportional-hazards models to examine the interactive effects between single nucleotide polymorphisms (SNPs) and blood MCP-1 level on AD in three cohorts: the Framingham Heart Study (FHS), Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study/Memory and Aging Project (ROSMAP)., Results: We identified SNPs in two genes, neuron navigator 3 ( NAV3 , also named Unc-53 Homolog 3, rs696468) (p < 7.55×10 - 9 ) and Unc-5 Netrin Receptor C ( UNC5C rs72659964) (p < 1.07×10 - 8 ) that showed an association between increasing levels of blood MCP-1 and AD. Elevating blood MCP-1 concentrations increased AD risk and AD pathology in genotypes of NAV3 (rs696468-CC) and UNC5C (rs72659964-AT + TT), but did not influence the other counterpart genotypes of these variants., Conclusions: NAV3 and UNC5C are homologs and may increase AD risk through dysregulating the functions of neurite outgrowth and guidance. Overall, the association of risk alleles of NAV3 and UNC5C with AD is enhanced by peripheral MCP-1 level, suggesting that lowering the level of blood MCP-1 may reduce the risk of developing AD for people with these genotypes., Competing Interests: Competing interests The authors declare that they have no competing interests.

Introduction: C-Reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) are both implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP-1 level exerts different effects on the AD risk depending on the genotypes., Methods: Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed., Results: An elevated blood MCP-1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA-DRB1) rs9271192-AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50-6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59-6.53, p = 0.001). In contrast, among HLA-DRB1 rs9271192-AA and APOE ε4 noncarriers, blood MCP-1 levels were not associated with these phenotypes., Discussion: Since HLA-DRB1 and APOE are expressed in the BBB, blood MCP-1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA-DRB1 rs9271192-AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways., (© 2022 the Alzheimer's Association.)

Background: Blood-brain barrier (BBB) breakdown is a component of the progression and pathology of Alzheimer's disease (AD). BBB dysfunction is primarily caused by reduced or disorganized tight junction or adherens junction proteins of brain microvascular endothelial cell (BMEC). While there is growing evidence of tight junction disruption in BMECs in AD, the functional role of adherens junctions during BBB dysfunction in AD remains unknown. Exosomes secreted from senescent cells have unique characteristics and contribute to modulating the phenotype of recipient cells. However, it remains unknown if and how these exosomes cause BMEC dysfunction in AD., Objectives: This study aimed to investigate the potential roles of AD circulating exosomes and their RNA cargos in brain endothelial dysfunction in AD., Methods: We isolated exosomes from sera of five cases of AD compared with age- and sex-matched cognitively normal controls using size-exclusion chromatography technology. We validated the qualities and particle sizes of isolated exosomes with nanoparticle tracking analysis and atomic force microscopy. We measured the biomechanical natures of the endothelial barrier of BMECs, the lateral binding forces between live BMECs, using fluidic force miscopy. We visualized the paracellular expressions of the key adherens junction protein VE-cadherin in BMEC cultures and a 3D BBB model that employs primary human BMECs and pericytes with immunostaining and evaluated them using confocal microscopy. We also examined the VE-cadherin signal in brain tissues from five cases of AD and five age- and sex-matched cognitively normal controls., Results: We found that circulating exosomes from AD patients suppress the paracellular expression levels of VE-cadherin and impair the barrier function of recipient BMECs. Immunostaining analysis showed that AD circulating exosomes damage VE-cadherin integrity in a 3D model of microvascular tubule formation. We found that circulating exosomes in AD weaken the BBB depending on the RNA cargos. In parallel, we observed that microvascular VE-cadherin expression is diminished in AD brains compared to normal controls., Conclusion: Using in vitro and ex vivo models, our study illustrates that circulating exosomes from AD patients play a significant role in mediating the damage effect on adherens junction of recipient BMEC of the BBB in an exosomal RNA-dependent manner. This suggests a novel mechanism of peripheral senescent exosomes for AD risk.

Cerebrovascular damage coexists with Alzheimer's disease (AD) pathology and increases AD risk. However, it is unclear whether endothelial progenitor cells reduce AD risk via cerebrovascular repair. By using the Framingham Heart Study (FHS) offspring cohort, which includes data on different progenitor cells, the incidence of AD dementia, peripheral and cerebrovascular pathologies, and genetic data (n = 1,566), we found that elevated numbers of circulating endothelial progenitor cells with CD34+CD133+ co-expressions had a dose-dependent association with decreased AD risk (HR = 0.67, 95% CI: 0.46-0.96, p = 0.03) after adjusting for age, sex, years of education, and APOE ε4. With stratification, this relationship was only significant among those individuals who had vascular pathologies, especially hypertension (HTN) and cerebral microbleeds (CMB), but not among those individuals who had neither peripheral nor central vascular pathologies. We applied a genome-wide association study (GWAS) and found that the number of CD34+CD133+ cells impacted AD risk depending on the homozygous genotypes of two genes: KIRREL3 rs580382 CC carriers (HR = 0.31, 95% CI: 0.17-0.57, p<0.001), KIRREL3 rs4144611 TT carriers (HR = 0.29, 95% CI: 0.15-0.57, p<0.001), and EXOC6B rs61619102 CC carriers (HR = 0.49, 95% CI: 0.31-0.75, p<0.001) after adjusting for confounders. In contrast, the relationship did not exist in their counterpart genotypes, e.g. KIRREL3 TT/CT or GG/GT carriers and EXOC6B GG/GC carriers. Our findings suggest that circulating CD34+CD133+ endothelial progenitor cells can be therapeutic in reducing AD risk in the presence of cerebrovascular pathology, especially in KIRREL3 and EXOC6B genotype carriers.

Introduction: It is unknown whether vascular and metabolic diseases assessed in early adulthood are associated with Alzheimer's disease (AD) later in life., Methods: Association of AD with lipid fractions, glucose, blood pressure, body mass index (BMI), and smoking obtained prospectively from 4932 Framingham Heart Study (FHS) participants across nine quadrennial examinations was evaluated using Cox proportional hazard and Kaplan-Meier models. Age-, sex-, and education-adjusted models were tested for each factor measured at each exam and within three adult age groups (early = 35-50, middle = 51-60, and late = 61-70)., Results: A 15 mg/dL increase in high density lipoprotein (HDL) cholesterol was associated with decreased AD risk during early (15.4%, P = 0.041) and middle (17.9%, P = 0.014) adulthood. A 15 mg/dL increase in glucose measured during middle adulthood was associated with 14.5% increased AD risk (P = 0.00029). These findings remained significant after adjusting for treatment., Discussion: Our findings suggest that careful management of cholesterol and glucose beginning in early adulthood can lower AD risk., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We examined the ability of plasma hyperphosphorylated tau (p-tau) 181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL)., Methods: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables., Results: Plasma p-tau 181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau 181 had a direct association with cognitive diagnosis in a bootstrapped GGM., Discussion: These results support plasma p-tau 181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection., (© 2021 the Alzheimer's Association.)

Introduction: Human study shows that elevated C-reactive protein (CRP) in blood impacts apolipoprotein E ( APOE ) ε4, but not APOE ε3 or APOE ε2, genotype to increase the risk of Alzheimer's disease (AD). However, whether CRP is directly involved in cellular AD pathogenesis and in which type of neuronal cells of APOE ε4 carriers are unknown., Methods: We aimed to use different primary neuronal cells and investigate if CRP induces cellular AD pathology depending on APOE genotypes. Here the different primary neuronal cells from the different APOE genotype knock-in mice cortex were isolated and used., Results: Monomeric CRP (mCRP) increased amyloid beta production and, in parallel, induced tau phosphorylation in addition to their related proteins in the primary neurons in a pattern of APOE ε4 >  APOE ε3 >  APOE ε2 in a dose- and time-dependent manner. Consistently, mCRP induced the staining of other neurodegenerative biomarkers, including Fluoro-Jade B stain (FjB), TUNEL and Cleaved Caspase-3, in primary neurons in a similar pattern of APOE ε4 >  APOE ε3 >  APOE ε2. In contrast, pentameric CRP (pCRP) had a tendency to induce cellular AD pathology but did not reach statistical significance. On the other hand, it is intriguing that regardless of APOE genotype, mCRP did not influence the expressions of Iba-1 and CD68 in primary microglia or the expression of glial fibrillary acidic protein in primary astrocytes, and additionally mCRP did not affect the secretions of interleukin (IL)-1α, IL-1β, and tumor necrosis factor α from these cells., Discussion: This is the first report to demonstrate that mCRP directly induces cellular AD pathogenesis in neurons in an APOE genotype-dependent pattern, suggesting that mCRP plays a role as a mediator involved in the APOE ε4-related pathway for AD during chronic inflammation., Highlights: Pentameric C-reactive protein (pCRP) can be dissociated irreversibly to form free subunits or monomeric CRP (mCRP) during and after the acute phase.mCRP increased amyloid beta production in the primary neurons in a pattern of apolipoprotein E ( APOE ) ε4 >  APOE ε3 >  APOE ε2 in a dose-dependent manner.mCRP induced the expression of phosphorylated tau in the primary neurons in a pattern of APOE ε4 >  APOE ε3 >  APOE ε2 in a dose- and time-dependent manner.mCRP plays an important mediator role in the APOE ε4-related pathway of Alzheimer's disease risk., Competing Interests: The authors declare no biomedical financial interests or potential conflicts of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long-term effects on the dementia/AD risk remain unknown., Methods: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health-care system from 2000 to 2020., Results: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52-0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long-term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39-0.83) during the 20 years of follow-up., Conclusion: TNF inhibitor use is associated with lower long-term risk of dementia/AD among US veterans with RA., (© 2021 the Alzheimer's Association.)

Background and Objectives: Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer disease (AD) risk only in APOE ε4 allele carriers; the objective of this study was to examine the interactive effects of plasma CRP and APOE genotype on cognition and AD biomarkers., Methods: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., mild cognitive impairment and dementia due to AD); Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Dementia Staging Instrument scores; CSF concentrations of β-amyloid peptide (Aβ 42 ), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes., Results: Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had 1, and 70 (12.4%) had 2 APOE ε 4 alleles. Among only participants who had 2 APOE ε4 alleles, elevated CRP was associated with lower MMSE score at baseline ( β [95% confidence interval] -0.52 [-1.01, -0.12]) and 12-month follow-up (β -1.09 [-1.88, -0.17]) after adjustment for sex, age, and education. The interaction of 2 APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (β = 11.21, SE 3.37, p < 0.001) and p-Tau (β = +2.74, SE 1.14, p < 0.01). Among those who had no APOE ε4 alleles, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at the 12-month follow-up., Discussion: CRP released during peripheral inflammation could be a mediator in APOE ε4-related AD neurodegeneration and serve as a drug target for AD., (© 2021 American Academy of Neurology.)

Introduction: Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimer's disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans., Methods: We administered a single subcutaneous injection of 60 μg of pramlintide to nondiabetic subjects under fasting conditions., Results: None of the participants developed hypoglycemia after the injection of pramlintide. The pramlintide challenge induced a significant surge of amyloid-β peptide and a decrease in total tau in the plasma of AD subjects but not in control participants. The pramlintide injection provoked an increase in interleukin 1 receptor antagonist and a decrease in retinol-binding protein 4, which separates AD subjects from control subjects., Discussion: Pramlintide use appeared to be safe in the absence of diabetes. The biomarker changes as a result of the pramlintide challenge, which distinguished AD from control subjects and mild cognitive impairment.

Background: The 776C→G polymorphism of the vitamin B-12 transport protein transcobalamin gene (TCN2) (rs1801198; Pro259Arg) is associated with a lower holotranscobalamin concentration in plasma. This effect may reduce the availability of vitamin B-12 to tissues even when vitamin B-12 intake is adequate. Clinical outcomes associated with vitamin B-12 insufficiency could potentially be worsened by high folate intake., Objective: We determined the association of the TCN2 776C→G polymorphism and folate intake with peripheral neuropathy in elders with normal plasma concentrations of vitamin B-12., Design: Participants in this cross-sectional study (n = 171) were from a cohort of community-based, home-bound elderly individuals aged ≥60 y who underwent an evaluation by physicians including an assessment for peripheral neuropathy. Participants were administered food-frequency and general health status questionnaires, anthropometric measurements were taken, and a fasting blood sample from each subject was collected., Results: Odds of neuropathy were 3-fold higher for GG genotypes than for CC genotypes (OR: 3.33; 95% CI: 1.15, 9.64). When folate intake was >2 times the Recommended Dietary Allowance (800 μg), GG genotypes had 6.9-fold higher odds of neuropathy than CC genotypes (OR: 6.9; 95% CI: 1.31, 36.36). There was no difference between the genotypes in the odds of peripheral neuropathy when folate intake was ≤800 μg (OR: 1.5; 95% CI: 0.18, 12.33)., Conclusion: The TCN2 776C→G polymorphism is associated with increased odds of peripheral neuropathy in the elderly, even with a normal vitamin B-12 status, especially if their folate intake is >2 times the Recommended Dietary Allowance., (© 2016 American Society for Nutrition.)

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD.

Premorbid intelligence does not decline through life even at the early stages of Alzheimer's disease (AD). However, other cognitive measures such as Mini Mental State Examination (MMSE) decline with aging and severely with dementia. In this study, we examine the associations of premorbid intelligence vs. current cognition with body mass index (BMI), insulin and diabetes in elderly adults. Using a cross-sectional, population-based study, we assessed BMI, plasma insulin and the evidence of diabetes in homebound elders. The North American Adult Reading Test (NAART) and MMSE were conducted. Associations were assessed by T-test, linear correlation and multivariate regression analysis. Subjects were divided into four subgroups: 1) BMI <25; 2) 25 < BMI <30; 3) 30 < BMI <35 and 4) BMI >35. Lower verbal IQ, assessed by NAART, was associated with higher BMI (β=-0.28; P<0.01), elevated insulin (β= -0.02, P=0.02), and diabetes (β=- 3.18, P<0.01). Multivariate regression analyses showed that all three clinical conditions - obesity, hyperinsulinaemia and diabetes - were associated with lower premorbid intelligence assessed by verbal IQ, but only diabetes was associated with current cognitive impairment assessed by MMSE. These relationships persisted after adjustment for education. Premorbid intelligence is associated with diabetes precursors - obesity and high insulin - and diabetes itself, but cognitive impairment is related to diabetes only. Understanding the mechanisms that link verbal IQ to diabetes precursors might suggest targeted interventions for the prevention of diabetes and cognitive decline caused by diabetes.

Background: Plasma amylin is positively associated with cognitive function in humans. Amylin treatment improves memory in Alzheimer's mouse models. However, the relationship between plasma amylin, diabetes and cognition is not clear., Objectives: In this study we examined the concentration of plasma amylin, its relationship with diabetes and cognition., Material and Method: A cross-sectional, homebound elderly population with data of plasma amylin under fasting condition and cognitive measurements was used., Results: We found that subjects with a long and chronic duration of diabetes were more likely to take insulin treatment and have reduced secretion of amylin. Compared to non-diabetics, diabetic subjects without insulin treatment had a higher concentration, but those with insulin treatment had a lower concentration, of plasma amylin [median (Q1, Q3): 20 (11.0, 36.2) vs. 25.2 (13.2, 50.6) vs. 15.0 (4.9, 33.8), p<0.0001]. In the whole sample vs. in the absence of diabetes, plasma amylin was positively associated with logical memory delayed recall (β= +0.61, SE=0.25, p=0.02 vs. β=+0.80, SE=0.33, p=0.02) and block design (β=+0.62, SE=0.24, p=0.009 vs. β=+0.93, SE=0.31, p=0.003), and negatively associated with Trailmaking A scores (β= -6.21, SE=1.55, p<0.0001 vs. β=-7.51, SE=1.95, p=0.0001) and Trailmaking B (β= -4.32, SE=2.13, p=0.04 vs. β= -5.86, SE=2.73, p=0.04). All these relationships disappeared in the presence of diabetes regardless the treatment., Conclusion: This study suggests that secretion of amylin by pancreas compensates and then deteriorates depending on the duration of diabetes. Amylin's activities for cognition are impaired in the presence of diabetes.

Brain-derived neurotrophic factor (BDNF) has been associated with regulation of body weight and appetite. The goal of this study was to examine the interactions of a functional variant (rs6265) in the BDNF gene with dietary intake for obesity traits in the Boston Puerto Rican Health Study. BDNF rs6265 was genotyped in 1147 Puerto Rican adults and examined for association with obesity-related traits. Men (n = 242) with the GG genotype had higher BMI (P = 0.009), waist circumference (P = 0.002), hip (P = 0.002), and weight (P = 0.03) than GA or AA carriers (n = 94). They had twice the risk of being overweight (BMI ≥ 25) relative to GA or AA carriers (OR = 2.08, CI = 1.02-4.23, and P = 0.043). Interactions between rs6265 and polyunsaturated fatty acids (PUFA) intake were associated with BMI, hip, and weight, and n-3 : n-6 PUFA ratio with waist circumference in men. In contrast, women (n = 595) with the GG genotype had significantly lower BMI (P = 0.009), hip (P = 0.029), and weight (P = 0.027) than GA or AA carriers (n = 216). Women with the GG genotype were 50% less likely to be overweight compared to GA or AA carriers (OR = 0.05, CI = 0.27-0.91, and P = 0.024). In summary, BDNF rs6265 is differentially associated with obesity risk by sex and interacts with PUFA intake influencing obesity traits in Boston Puerto Rican men.

Objectives: Both plasma amyloid-β peptide 40 (Aβ40) and homocysteine (tHcy) are linked to vascular disease, which is related to depression in the elderly. We sought to study whether the relationship between tHcy and plasma Aβ40 differs in those with and without depression., Study Design and Methods: In a cross-sectional study of 1058 homebound elders, vascular depression was defined as a score ≥ 16 on the Center for Epidemiological Studies Depression scale (CES-D) along with self-reported cardiovascular disease (CVD). Plasma Aβ40 and Aβ42, and serum tHcy and creatinine were measured., Results: Elders with high tHcy had higher concentrations of plasma Aβ40 (median: 147.5 vs. 123.1 pg/ml, P < 0.0001) and Aβ42 (median: 20.2 vs. 16.6 pg/ml, P < 0.0001) than those with low tHcy. In elders with depression, the relationship between logarithm of plasma Aβ40 (LogAβ40), but not LogAβ42, and tHcy was significant (β = +0.010, SE = 0.004, P = 0.007); in contrast, this relationship was not observed in those without depression. Subjects with vascular depression had the highest concentration of tHcy (mean ± SD: 12.8 ± 4.6 vs. 11.7 ± 4.5 vs. 11.9 + 5.5, P = 0.008) compared to those without CVD and those without depression. Depressed subjects without CVD had the lowest concentration of plasma Aβ42 (median: 15.5 vs. 19.1 vs. 18.7, P = 0.01) compared to those with CVD and those without depression., Conclusions: Vascular depression, which is associated with tHcy and Aβ40 in blood, appears to be different from depression that is associated with low plasma Aβ42. This suggests that reducing tHcy and Aβ40 may be an adjunct treatment for vascular depression.

Depression associated with low plasma amyloid-beta peptide 42 (Abeta42) leading to a high ratio of Abeta40/Abeta42, a biomarker of Alzheimer disease (AD), may represent a unique depression subtype. The relationship between low plasma Abeta42 in depression and the major risk factor of AD, apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Abeta40 and Abeta42 were measured, and cognition were evaluated. In the absence of the ApoE4 allele, depressed subjects had lower plasma Abeta42 [median (Q1, Q3): 17.1 (11.6, 27.8) vs. 20.2 (12.9, 32.9) pg/mL, P=0.006], a higher Abeta40/Abeta42 ratio [median (Q1, Q3): 7.1 (4.6, 11.3) vs. 6.9 (3.4, 9.7), P=0.03], and lower cognitive function (mean+/-SD of Mini-Mental State Examination: 24.5+/-3.1 vs. 25.5+/-3.3, P<0.0001) than those without depression. In contrast, these relationships were not observed in the presence of ApoE4. Instead, regardless the depression status ApoE4 carriers had lower plasma Abeta42 and a higher Abeta40/Abeta42 ratio than non-ApoE4 carriers. Using multivariate logistic regression, it was found that depression was not associated with ApoE4 allele, but with the interaction between plasma Abeta42 and ApoE4 (odds ratio=3.94, 95% confidence interval=1.50, 10.33, P=0.005), denoting low plasma Abeta42 in the absence of ApoE4. Both ApoE4 carriers and non-ApoE4 carriers with depression had lower Abeta42 and a higher Abeta40/Abeta42 ratio in plasma compared with non-ApoE4 carriers without depression in the homebound elderly. As a combination of low plasma Abeta42 and high plasma Abeta40 has been shown to increase the risk of AD in 2 large cohort studies, amyloid-associated depression shown in this study may suggest a risk factor of AD in the absence of ApoE4.