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Objective: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators. Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE -ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. Results: For 193 patients (67.4% women, 53.4% APOE -ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy–Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE -ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE -ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. Conclusion: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies. [ABSTRACT FROM AUTHOR]

Background: There are two subtypes of the right Temporal Variant of Frontotemporal Dementia (rtv‐FTD). Semantic dementia (SMD) phenotype is defined by negative familiar history, word‐finding, anomia, comprehension difficulties, prosopagnosia, and topographagnosia. The behavioral frontotemporal dementia (bvFTD) phenotype is defined by personality changes, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. (1) We present a rare interesting case. Method: We describe the clinical and imaging features of a man who presented a sporadic behavioral phenotype of rtv‐FTD, showing negative genetic results. Result: A 62‐year‐old man with 8 years of progressive behavioral impairment. He showed personality changes, and compulsive‐like / ritualistic behaviors such as excessive unpurposed accumulation of items, washing hands repeatedly every five minutes, and walking and wandering repeatedly in circles. He also had hiperorality, cravings for sweet foods, social cognition impairment, associated with loss of empathy, and inappropriate social behavior (hypersexuality, verbal aggressivity to unrelated people, and talking bad words to neighbors with no reason). After years he followed with mild to moderate apathy. The neuropsychological evaluation showed impairment of executive functioning, episodic memory impairment, and MMSE 19/30. The neurological exam was unremarkable, and the familiar history was negative. Brain MRI revealed frontotemporal atrophy with a marked asymmetry in the right temporal lobe. The genetic testing was negative, illustrating and sporadic case. Conclusion: Theoretically, rtv‐FTD is considered a right variant of semantic phenotype, and the general assumption is that is also a sporadic disorder. Although the behavioral phenotype of rtv‐FTD normally has a genetic basis, showing positive family history, It can be presented as a sporadic disorder with non‐familial variants of FTD, as in this case. (2) References: 1. Josephs KA, Whitwell JL, Knopman DS, Boeve BF, Vemuri P, Senjem ML, et al. Two distinct subtypes of right temporal variant frontotemporal dementia. Neurology. 2009 Nov 3;73(18):1443‐50. 2. Ulugut Erkoyun H, van der Lee SJ, Nijmeijer B, van Spaendonk R, Nelissen A, Scarioni M, et al. The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. J Alzheimers Dis JAD. 2021;79(3):1195‐201. [ABSTRACT FROM AUTHOR]

Background: Amyloid‐β‐degrading enzymes such as the angiotensin‐converting enzyme (ACE‐1) might be surrogates of the amyloid‐β load in the brain potentially triggering tauopathy and behavioral features in dementia. Methods: Consecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset Alzheimer's dementia (AD, National Institute on Aging – Alzheimer's Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Behavioral symptoms were assessed by way of the Neuropsychiatric Inventory. APOE genotyping (rs7412&rs429358) was undertaken with TaqMan® Real‐Time PCR technology, while conventional PCR was used for the ACE insertion/deletion polymorphism. Cerebrospinal fluid (CSF) amyloid‐β42, amyloid‐β38, ACE‐1, tau and phospho‐tau Thr181 were quantified with enzyme‐linked immunosorbent assays, whereas CSF and plasma ACE‐1 activities were measured using a fluorescence method. Adjusted general linear models were used to examine relationships between log‐transformed behavioral symptoms and biomarkers of interest at p<0.05. Results: Participants with DLB (n = 27;78.48±9.0years‐old;eleven APOE‐ε4 carriers) were paired with participants with AD (n = 27;81.00±5.8years‐old;twelve APOE‐ε4 carriers) and controls (n = 27;78.48±8.7years‐old;four APOE‐ε4 carriers); two thirds were women. CSF ACE‐1 activity was associated with CSF ACE‐1 levels (p<0.0001) and with plasma ACE‐1 activity (p<0.0001), no differences among the participants. Only in DLB, the ACE deletion allele was cumulatively associated with higher plasma ACE‐1 activity (p = 0.049). Use of ACE inhibitors did not affect CSF ACE‐1 levels. For APOE‐ε4 carriers with DLB, agitation was inversely associated with amyloid‐β38, CSF and plasma ACE‐1 activities. For APOE‐ε4 non‐carriers with DLB, appetite and eating abnormalities were associated with CSF ACE‐1 levels and activity, tau and tau/phospho‐tau, and inversely associated with amyloid‐β42/amyloid‐β38. CSF ACE‐1, tau, tau/phospho‐tau, and tau/amyloid‐β42 were associated with disinhibition for APOE‐ε4 carriers with AD, and with aberrant motor behavior for APOE‐ε4 non‐carriers with AD. For APOE‐ε4 carriers with AD, irritability was associated with CSF ACE‐1 and inversely associated with amyloid‐β42. All other behavioral associations with ACE‐1 were independent of measures of amyloidosis or tauopathy. Conclusions: Biofluid activity and CSF levels of ACE‐1 may be surrogates for CSF amyloid‐β levels and tauopathy unevenly associated with behavioral symptoms across dementia syndromes. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetic effects of statins on clinical changes in Alzheimer's disease (AD) could be mediated by epistatic interactions among relevant genetic variants involved in cholesterol metabolism.Objective: To investigate associations of HMGCR (rs3846662), NR1H2 (rs2695121), or CETP (rs5882&rs708272) with cognitive and functional changes in AD, with stratification according to APOEɛ4 carrier status and lipid-lowering treatment with lipophilic statins.Methods: Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and global ratings, with prospective neurotranslational associations documented for one year.Results: Considering n = 190:142 had hypercholesterolemia, 139 used lipophilic statins; minor allele frequencies were 0.379 (rs2695121-T:46.3% heterozygotes), 0.368 (rs5882-G:49.5% heterozygotes), and 0.371 (rs708272-A:53.2% heterozygotes), all in Hardy-Weinberg equilibrium. For APOEɛ4 carriers: rs5882-GG protected from cognitive decline; rs5882-AA caused faster cognitive decline; carriers of rs2695121-CC or rs5882-AA were more susceptible to harmful cognitive effects of lipophilic statins; carriers of rs5882-GG or rs708272-AG had functional benefits when using lipophilic statins. APOEɛ4 non-carriers resisted any cognitive or functional effects of lipophilic statins, while invariability of rs3846662 (all AA) prevented the assessment of HMGCR effects. When assessing CETP haplotypes only: rs5882-GG protected from cognitive and functional decline, regardless of lipophilic statin therapy; lipophilic statins usually caused cognitive and functional harm to carriers of rs5882-A and/or rs708272-A; lipophilic statins benefitted cognition and functionality of carriers of rs5882-G and/or rs708272-G.Conclusion: Reportedly protective variants of CETP and NR1H2 also slowed cognitive and functional decline particularly for APOEɛ4 carriers, and regardless of cholesterol variations, while therapy with lipophilic statins might affect carriers of specific genetic variants. [ABSTRACT FROM AUTHOR]

Background: Midlife cerebrovascular risk, low education and copies of APOE‐ε4 are risk factors for Alzheimer's disease (AD), whereas metabolic derangements have been associated with dementia onset. This prospective study aimed to explore the impacts of variations in metabolic risk factors on progression of AD in São Paulo, Brazil. Methods: Outpatients with late‐onset AD according to National Institute on Aging – Alzheimer's Association criteria were assessed for APOE haplotypes (rs7412 & rs429358 genotyped by way of TaqMan® Real‐Time Polymerase Chain Reaction technology) and variations in one year of the following potential metabolic predictors: fasting glycemia, TSH, free T4, vitamin B12, and folic acid. Metabolic variations were assessed in accordance with concurrent variations in the Clinical Dementia Rating Sum‐of‐Boxes, the Index of Independence in Activities of Daily Living, Lawton's Scale for Instrumental Activities of Daily Living, and the Mini‐Mental State Examination in multiple linear regression models for all patients, and after stratification according to APOE‐ε4 carrier status, with the threshold of significance set at p<0.05. Results: Of 122 patients, there were 81 women (66.4%) and 41 men (33.6%), 69 APOE‐ε4 carriers (56.5%) and 53 APOE‐ε4 non‐carriers (43.5%). The mean estimated age at AD onset was 73.13±7.1 years‐old. Overall, 120 patients used a cholinesterase inhibitor (98.4%), and 90 patients used Memantine (73.8%). All test scores were significantly different at the end of one year (p<0.01), except for the Mini‐Mental State Examination (p = 0.13). None of the potential metabolic predictors varied significantly after one year (p>0.16), and no variations in metabolic risk factors were concurrently associated with variations in the Clinical Dementia Rating Sum‐of‐Boxes (p>0.17), the Index of Independence in Activities of Daily Living (p>0.09), Lawton's Scale for Instrumental Activities of Daily Living (p>0.22), or the Mini‐Mental State Examination (p>0.40), neither for APOE‐ε4 carriers (p>0.28), nor for APOE‐ε4 non‐carriers (p>0.07). Conclusions: Lifetime metabolic risk factors may affect onset of AD, but concurrent variations in metabolic parameters seem to have no associations with cognitive or functional decline in such patients, regardless of APOE‐ε4 carrier status. (Supported by FAPESP grant #2015/10109‐5) [ABSTRACT FROM AUTHOR]

Background: Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and personality changes. Findings show variation in the disease progression. Some patients show a rapid progression over a few years, and others show little or no changes over a decade (1) Mutations in the amyotrophic lateral sclerosis 2 (ALS2) gene cause autosomal recessive motor neuron diseases, including juvenile‐onset amyotrophic lateral sclerosis (JALS), and other associated disorders. (2) We present a rare case. Method: We describe the clinical and imaging features of a man who presented a rare case of Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation. Result: A 63‐year‐old man presented a 10‐year history of insidious and slowly progressive behavioral changes. He showed reduced emotional responsiveness, with no concern since his wife had received a diagnosis of a malignancy. He followed with disinhibition, and impulsive actions such as excessive shopping with no payment, overspending, and socially inappropriate behavior. He also had a compulsive/ritualized behavior with stereotyped speech, and counting repeatedly steps. His medical family history was unremarkable. The neuropsychological evaluation showed impairment of executive functioning, MMSE 27/30. Neurological examination was normal. Brain MRI frontotemporal atrophy with a marked asymmetry in the right temporal lobe in sagittal, axial, and coronal sequences. CSF biomarkers showed elevated t‐tau with no other changes, and the genetic test showed an ALS2 heterozygous mutation., also counting repeatedly steps. Conclusion: The presence of the C9ORF72 mutation has been shown in slowly progressive FTD, however, other mutations such as ALS2 have not yet been reported with the following phenotype, as in this case (3) References: 1. Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges JR. Can progressive and non‐progressive behavioural variant frontotemporal dementia be distinguished at presentation? J Neurol Neurosurg Psychiatry. 2009 Jun 1;80(6):591‐3. 2. Sheerin UM, Schneider SA, Carr L, Deuschl G, Hopfner F, Stamelou M, et al. ALS2 mutations. Neurology. 2014 Mar 25;82(12):1065‐7. 3. Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry. 2012 Apr;83(4):358‐64. [ABSTRACT FROM AUTHOR]

Background: Behavioral clusters may differ in intensity and frequency across dementia syndromes and according to genetic variants. Methods: Consecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium), Parkinson's disease dementia (PDD, Movement Disorder Society Task Force), or late‐onset Alzheimer's dementia (AD, National Institute on Aging/Alzheimer's Association, rs7412&rs429358 genotyped with TaqMan® Real‐Time PCR technology) were recruited (2010‐2018) and assessed for demographic features and scores on a 15‐item Clock Drawing Test (CDT), Mini‐Mental State Examination (MMSE), Index of Independence in Activities of Daily Living (ADL), Lawton's Scale for Instrumental Activities of Daily Living, Clinical Dementia Rating (CDR) and Zarit Caregiver Burden Interview. According to the Neuropsychiatric Inventory, affective (anxiety,apathy,dysphoria,euphoria), hyperactive (aberrant motor behavior,agitation,disinhibition,irritability), and psychotic (delusions,hallucinations) clusters were associated with cognitive, functional and caregiver burden scores, and compared according to dementia diagnoses, p<0.05. Results: All had similar education (p = 0.205): DLB (n = 38;57.9%♀), PDD (n = 14;64.3%♀), APOE‐ε4 carriers with AD (n = 117;72.6%♀), APOE‐ε4 non‐carriers with AD (n = 108;63.0%♀). Patients with AD used cholinesterase inhibitors (p = 0.004) and Memantine (p<0.0001) more often, had higher CDT (p = 0.027) and ADL (p<0.001) scores, and lower caregiver burden (p = 0.022);other score differences were non‐significant among groups. APOE‐ε4 carriers with AD had lower affective scores (p<0.0001), while APOE‐ε4 non‐carriers with AD had lower psychotic scores (p<0.0001);hyperactive scores were similar among groups (p = 0.146). Affective scores were associated with caregiver burden and inversely associated with MMSE scores only in AD, while inversely associated with functionality in DLB and AD;they were also associated with functionality and inversely associated with CDR Sum‐of‐Boxes scores in PDD. Hyperactive scores were inversely associated with functionality in all groups, while associated with cognitive scores in DLB, and inversely in PDD and AD;they were also associated with caregiver burden in DLB and AD, and inversely in PDD. Psychotic scores were associated with CDR Sum‐of‐Boxes scores in PDD and AD, while associated with caregiver burden and inversely with cognition and functionality in all groups. Conclusions: The affective and hyperactive clusters have divergent associations with clinical features across dementia syndromes, while the psychotic cluster is most consistently associated with worsened cognition, functionality and caregiver burden. APOE‐ε4 carrier status may affect cluster intensity in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is pathologically diagnosed based on abnormal amyloid and tau pathology but is also related to additional pathologic processes. (1) The cognitive symptoms are not directly associated with AD pathology but are the consequence of a complex mechanism, showing discordance between clinical symptoms and CSF biomarkers. (2) Previous evidence suggests a range from the synergistic role of white matter signal abnormality (WMSA) and CSF biomarkers on AD to no relationship between the two. (1) We aimed to analyze the CSF biomarker profiles, and brain MRI changes in AD patients with different phenotypes. Method: CSF was collected by lumbar puncture from 40 individuals with AD. We analyzed CSF levels (Aβ‐42, Aβ‐40, t‐tau, p‐tau, tau / Aβ‐42, and Aβ‐42/40) in two different samples. The clinical characteristics included: AD phenotype (amnestic or non‐amnestic), age, gender, education, and age‐onset. We used the brain MRI scales: MTA (mesial temporal lobe atrophy), and Fazekas, for white matter signal abnormality (WMSA), considering pathological changes (≥ 2). Result: Preliminary results in 16 patients showed that most of the patients with CSF typical AD pattern presented an amnestic phenotype, revealing WMSA changes. The patients with no CSF changes showed little or no WMSA changes in both clinical presentations. The amnestic phenotype showed more MTA changes in patients with typical AD CSF pattern, and no difference was found between the phenotypes in patients with no CSF changes. Conclusion: It can be a positive relation between cerebrovascular diseases, WMSA changes, and CSF pathological changes in AD, regardless of the phenotype, supporting that Aβ pathology may lead to secondary vascular damage including white matter lesions. References: 1. Lindemer ER, Greve DN, Fischl B, Salat DH, Gomez‐Isla T. White matter abnormalities and cognition in patients with conflicting diagnoses and CSF profiles. Neurology. 2018 Apr 24;90(17):e1461‐9. 2. Alexopoulos P, Roesler J, Thierjung N, Werle L, Buck D, Yakushev I, et al. Mapping CSF biomarker profiles onto NIA‐AA guidelines for Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci. 2016 Oct;266(7):587‐97. [ABSTRACT FROM AUTHOR]

Background: Neurodegeneration is a common hallmark of all dementia syndromes, whereas cerebrospinal fluid amyloid‐β may reflect amyloidosis both in Alzheimer's dementia (AD) and in dementia with Lewy bodies (DLB). It is unknown if any biomarker profiles may help discriminate DLB from AD. Methods: Consecutive outpatients with probable DLB (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset AD (National Institute on Aging – Alzheimer's Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Genotyping of rs7412 & rs429358 (APOE) was undertaken with TaqMan® Real‐Time PCR technology. Cerebrospinal fluid concentrations of amyloid‐β (Aβ42, Aβ40, Aβ38), α‐synuclein, t‐tau and p‐tau Thr181, were assessed by enzyme‐linked immunosorbent assays. The following ratios and restructured traditional regression formulas were compared among participants: Aβ42/Aβ40, Aβ42/Aβ38, t‐tau/p‐tau, t‐tau/Aβ42, p‐tau/Aβ42, α‐synuclein/Aβ42, t‐tau/α‐synuclein, (240+1.18Xt‐tau)/Aβ42, (3.694+0.0105Xt‐tau)Xp‐tau/Aβ42, (373+0.82Xt‐tau)/Aβ42, (152+8.25Xp‐tau)/Aβ42. In addition, all formulas were considered to correspond to an AD profile if >1, while t‐tau/Aβ42>0.5 and p‐tau/Aβ42>0.08 were also measured, significance at p<0.05. Results: Overall, 27 participants with DLB (78.48±9.0 years‐old, CDR sum‐of‐boxes 10.96±3.8, eleven APOE‐ε4 carriers) were paired with 27 participants with AD (81.00±5.8 years‐old, CDR sum‐of‐boxes 10.44±3.9, twelve APOE‐ε4 carriers) and 27 controls (78.48±8.7 years‐old, CDR sum‐of‐boxes 0.30±0.8, four APOE‐ε4 carriers); two thirds were women. Only for APOE‐ε4 carriers, t‐tau/Aβ42 (p = 0.065) and t‐tau/α‐synuclein (p = 0.073) were marginally significantly higher in AD. Only for APOE‐ε4 non‐carriers, Aβ42/Aβ38 was higher (p = 0.009) and α‐synuclein/Aβ42 was lower (p = 0.043) in DLB. The t‐tau/Aβ42>0.5 (p = 0.039) and p‐tau/Aβ42>0.08 (p = 0.042) ratios were able to discriminate patients with AD from controls, but not from patients with DLB, regardless of APOE‐ε4 carrier status. All formulas were able to discriminate patients with AD from controls (p<0.02), but only (152+8.25Xp‐tau)/Aβ42>1 was able to discriminate patients with AD from patients with DLB (p = 0.025), regardless of APOE‐ε4 carrier status. Conclusions: Amyloidosis and neurodegeneration are modulated by APOE‐ε4 carrier status and may differentially affect the discriminative power of cerebrospinal fluid biomarker ratios for diagnosis of dementia syndromes. The best formula to discriminate patients with AD from patients with DLB and controls was (152+8.25Xp‐tau)/Aβ42>1. (Supported by FAPESP grant #2015/10109‐5) [ABSTRACT FROM AUTHOR]

Background: Memantine antagonizes the N‐methyl‐D‐aspartate (NMDA) type of glutamate receptor leading to possible behavioral improvement and a synergistic effect with cholinesterase inhibitors on slower functional and cognitive decline in Alzheimer's dementia (AD). Some receptor genes can contribute to variable excitotoxicity and pharmacological response. NR2B is a common subunit of functional NMDA receptors, whereas the GRIN2B gene is mapped to 12p12, and rs3764028 has been associated with variable GRIN2B transcription and human susceptibility to AD. We sought to evaluate associations of promoter GRIN2B genotypes and APOE haplotypes with the age at onset of AD and cognitive and functional response to Memantine. Methods: In this prospective pharmacogenetic study, participants with late‐onset AD according to National Institute on Aging – Alzheimer's Association criteria were screened with the Clinical Dementia Rating Sum‐of‐Boxes, the Index of Independence in Activities of Daily Living, Lawton's Scale for Instrumental Activities of Daily Living, the Mini‐Mental State Examination, the Severe Mini‐Mental State Examination, and a 15‐item Clock Drawing Test, and followed for one year. Genotyping was undertaken with TaqMan® Real‐Time Polymerase Chain Reactions for rs429358 and rs7412 (APOE haplotypes), and with Polymerase Chain Reactions for rs3764028 (GRIN2B). Associations of APOE haplotypes and rs3764028 genotypes with the age at dementia onset were assessed and, after stratification according to APOE‐ε4 carrier status, the presence of each genotype of rs3764028 was linked with use of Memantine or not for test score variations, significance at p<0.05. Results: Among 190 consecutive outpatients, 141 used Memantine (74.2%); mean age at dementia onset was 73.23±6.4 years‐old, with 128 women (67.4%) and 62 men (32.6%), 101 APOE4+ carriers (53.2%) and 89 APOE4‐ carriers (46.8%). APOE‐ε4/ε4 carriers had earlier AD onset by almost five years (p = 0.004), whereas the A allele of rs3764028 had a cumulative effect on later onset of AD (p<0.0001). Memantine protected APOE4‐ carriers of the CC genotype of rs3764028 regarding Clinical Dementia Rating Sum‐of‐Boxes variations (p = 0.018), but not regarding other test score variations. Conclusions: Genotypes of rs3764028 and APOE haplotypes are associated with the age at onset of AD, as well as with variations in dementia staging according to the use of Memantine. (Supported by FAPESP grant #2015/10109‐5) [ABSTRACT FROM AUTHOR]

Introduction: The inherited risk of late-onset Alzheimer's disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, and the 10-item Neuropsychiatric Inventory, and genotyped for rs7412 and rs429358 (APOE haplotypes, Real-Time Polymerase Chain Reactions), and the ACE insertion/deletion polymorphism (Polymerase Chain Reactions). Combined genetic variants of APOE and ACE were associated with age at dementia onset, and with neuropsychiatric symptoms in each dementia stage (adjusted for sex and age at dementia onset). Results: Over two-thirds of the 238 patients were women, whereas the mean age at dementia onset was 73.82 ± 6.2 years-old. APOE-ϵ4/ϵ4 carriers had earlier dementia onset (p<.001). The ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=.37) but was not associated with age at dementia onset, regardless of APOE-ϵ4 carrier status. The only results that survived corrections for false discovery rates were higher scores of dysphoria for APOE-ϵ4 carriers (n=122) who also carried ACE deletion/deletion (p=.031). No results survived corrections for false discovery rates for APOE-ϵ4 non-carriers (n=116). Conclusions: Though only the APOE-ϵ4/ϵ4 haplotype affected AD onset, effects of the ACE insertion/deletion polymorphism over behavioural features might differ according to APOE-ϵ4 carrier status in genetic associations. [ABSTRACT FROM AUTHOR]

Background: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases.Objective: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer's disease (AD) and cognitively healthy people.Methods: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-β (Aβ)42, Aβ40, Aβ38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOEɛ4 carrier status.Results: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOEɛ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOEɛ4 carriers) and 27 controls (78.48±8.7 years old, four APOEɛ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOEɛ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis.Conclusion: Biomarker ratios were superior to Aβ and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOEɛ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB. [ABSTRACT FROM AUTHOR]

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Copyright of Arquivos de Neuro-Psiquiatria is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Anatomical studies in animals have described multiple striatal circuits and suggested that sub‐components of the striatum project to distinct cortical areas. Researchers that reconstructed tracts of the left and right putamen have shown ipsilateral projections to the primary motor area, primary somatosensory area, supplementary motor area, premotor area, cerebellum, thalamus and prefrontal cortex (specifically to the ventrolateral prefrontal cortex). The ventrolateral prefrontal cortex appears to have a specific role in spatial processing and memory retrieval. Method: Case report and analyses of MR Images (T1, T2 and Flair) of a patient presenting with vascular cognitive impairment due to dilated perivascular spaces in putamen bilaterally. Result: Male patient, 81 years‐old, right‐handed, with four years of formal education and high cerebrovascular risk. His cognitive complaints began twelve years ago, and worsened in the last two years (losing personal belongings inside his own house, sometimes forgetting names of well‐known persons, with word finding difficulties). He denied impairment in activities of daily living, was able to organize his home budget, take his medications and go to the market alone. Now, he is physically and intellectually active (walking, reading newspapers, and talking about Philosophy), and still drives cars. His CDR score is 0.5, and his MMSE score is 29 (with 3 points in evoked memory). Word List Memory Task (Immediate Recall):4/5/8 (intrusion of "vessel" in the first two lists); Evocation:6 (intrusion of "vessel"); Recognition:10; Verbal Fluency (Animals):20; Verbal Fluency (Fruits):9. MR (10/15/2018): mild supratentorial microangiopathy; encephalomalacia/gliosis in the vermis and the left cerebellar hemisphere; Fasekas = 1 / Scheltens = 1 (bilaterally); bilateral supratentorial dilated perivascular spaces, particularly in the putamen. Conclusion: Our patient does not have dementia, regardless of more than ten years of cognitive impairment. Bilateral dilated perivascular spaces in the putamen may cause deficits in memory retrieval and spatial processing. Neuropsychological evaluations must consider specific areas of brain injury. Our patient has impaired memory retrieval (with false memories verified by constant intrusions in the Word List Memory Task), and the high occurrence of losing personal belongings inside his house can be due to difficulties in spatial processing (mental map of positions of items in space). [ABSTRACT FROM AUTHOR]

Background: Klüver‐Bucy syndrome (KBS) comprises: 1) hyperorality, 2) hypermetamorphosis, 3) hypersexuality, 4) eating disorder, 5) placidity, 6) visual agnosia (psychic blindness) and 7) amnesia (at least three components are described as partial KBS). The classic description involves bilateral injuries to the anterior temporal lobes, but it has been reported that unilateral lesions can also lead to KBS. Method: Case report and analyses of MR Images (T1, Flair and Tractography) of a patient presenting partial KBS due to stroke in the left temporal lobe. Result: Male patient, 69 years‐old, with cognitive deficits that have begun after a left frontotemporal stroke in 2003, with remarkable changes in the temporal pole. In the first months after the stroke, he used to get lost when out of home and had difficulty remembering names and recognizing well known persons due to psychic blindness. During the next years, the patient developed impairment in declarative memory, but preserved visuospatial skills (many times coming to the medical appointments alone, using public transportation). Over time, he developed binge eating (once eating 1 kilogram of cheese, for instance), inability to deal with money (unnecessary loans in banks) and bizarre sexual behavior (such as excessive addiction to porn movies, public masturbation, flirting with women in his neighborhood, and an episode of inappropriate sexual behavior with his daughter‐in‐law). The patient still resists taking bath and changing clothes. Conclusion: The exact anatomic basis of KBS is still controversial. What is remarkable is the main role of the amygdala in the syndrome. However, periamygdalar lesions can cause disconnection syndromes and damage the limbic network that involves the uncus, the hippocampus, the insular cortex, orbitofrontal and cingulate gyri. Patients with KBS can mimic behavioral variant frontotemporal lobar degeneration (bvFTLD) – particularly regarding eating and sexual disorders, probably due to the connections between the amygdala and the orbitofrontal gyri. The integrity of these two regions and their connections probably play an important role in emotional continence, modulating basic desires in the human species. Lesions in the uncinate fasciculus can predispose to KBS. Our patient exhibits lack of fibers connecting temporal lobe and orbitofrontal cortex showed in the tractography. [ABSTRACT FROM AUTHOR]

Background: The study of vascular cognitive impairment and dementia (VCID) risk factors must be reproduced in every community so that disparities may be addressed. In South America, diverse levels of education, mixed ethnicity, genetic and cultural heterogeneity, and the burden of cerebrovascular risk are important features to be investigated for proper interventions. Methods: Observational and interventional VCID studies from South America will be discussed so that issues concerning potential barriers for participant recruitment and research effectiveness may be addressed. Results: Few South American institutions have studied risk factors for VCID. Older people suffer the effects of restrictions to female education that occurred a century ago. Cross‐sectional studies demonstrated that APOE‐ε4 carrier status predisposes to physical inactivity and has smaller effects over dementia onset than in studies from the Northern Hemisphere, possibly due to ethnical disparities, while the burden of combined cerebrovascular risk factors (and smoking in particular) in this regard is high. Foreigners living in Brazil had later dementia onset, unexplained by common genetic variants. While prevalent in almost half of the older population, and associated with earlier dementia onset particularly in women, depression could be a risk factor or a prodromal symptom. Late life prospective studies verified that cerebrovascular risk factors such as arterial hypertension, hypercholesterolemia and a higher coronary heart disease risk, or increased creatinine clearance for women only, may be neuroprotective against cognitive and functional decline, probably due to enhanced cerebral perfusion. Lifetime sanitary conditions and increasing late life body mass index may protect against frailty, while education is neuroprotective for women and APOE‐ε4 carriers (though associated with faster cognitive decline in some cohorts). Longitudinal pharmacogenetic studies demonstrated that potential benefits of cerebrovascular metabolism modulators such as angiotensin‐converting enzyme inhibitors and lipophilic statins depend upon epistatic interactions among specific genetic variants. Caregiver awareness of the need to control cerebrovascular risk is beneficial for patients. Conclusions: Genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes interact on mechanisms of neurodegeneration. Adherence to lifestyle and pharmacological interventions in South America is highly dependent upon proper funding, public support, harmonization efforts, institutional expertise and leadership, and caregiver education. (Supported by FAPESP grant #2015/10109‐5) [ABSTRACT FROM AUTHOR]

This study is aimed to evaluating the underlying cognitive strategies used during Semantic Verbal Fluency (SVF) performance and comparing the differences between cognitively healthy controls (CHC), amnestic and amnestic-multiple domain mild cognitive impairment (a-MCI and a-md-MCI), Alzheimer's disease (AD), Lewy body dementia (LBD), and behavioral variant frontotemporal dementia (bvFTD). The cross-sectional study comprised 236 participants involving 78 CHC individuals, 33 a-MCI and 48 a-md-MCI, 39 AD, 22 LBD, and 16 bvFTD patients. Scores differed significantly when comparing CHC with dementia groups, showing medium to large variances. The best components in distinguishing between CHC and the dementia groups were the SVF-Total score and SVF-Cluster Size variables. CHC showed different performance in the SVF-Cluster Size variable compared with a-md-MCI, AD, and bvFTD; whereas, in the SVF-Mean Cluster Size, CHC differed from MCI's, AD, and LBD. The switching component displayed smaller capacity to differentiate between the clinical groups. The effect size was large comparing AD with bvFTD (1.267) and medium comparing AD with LBD (0.689) using the SVF-Cluster Size variable, but small using the other variables for the comparisons between dementia groups. Quanti-qualitative examination of the SVF may provide a valuable clue in distinguishing CHC from MCI and different dementia subtypes. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a degenerative syndrome that impairs cognitive functioning, including speech and language. Discourse can be used to analyze language processing, which is organized into microlinguistic and macrolinguistic dimensions.Objectives: To identify the occurrence of changes in the macrolinguistic dimension of oral discourse in AD patients. Design: This was developed as a cross-sectional study. Setting: Outpatient clinic of the Behavioural Neurology Division of São Paulo Federal University.Participants: 121 elderly patients, with ≥ 4 years of education, divided into AD and comparison groups.Measurements: The subjects were asked to create a narrative based on seven figures that made up a story. The macrolinguistic aspects of the narratives were analyzed.Results: The performance of the AD group was inferior to that of the comparison group on content-related, no-content-related complete and incomplete propositions as well as macropropositions, main information units, appropriated local and global coherence, cohesive devices and all subtypes, cohesive errors and some of their subtypes. Global coherence, macropropositions and ellipsis subtype of cohesive devices were the variables that best differentiated the groups.Conclusions: Changes were observed in most aspects of the macrolinguistic dimension of oral discourse in patients with AD. [ABSTRACT FROM AUTHOR]

Background: 48 years old female, biologist researchers, with a family history of AD PSEN1 mutation, symptoms compatible with Mild Cognitive Impairment (MCI) due to probable Alzheimer's disease. As part of clinical approach Ketogenic Diet and medium‐chain triglyceride was tried combined with conventional treatment. Method: the patient had a 2 ‐year long history of amnestic symptoms with a slow worsening, when medical help was sought. She underwent neurological and neuropsychological evaluation, magnetic resonance and specific genetic tests. It was observed memory and attention deficit, executive functions impairment; left hippocampal atrophy, ApoE E2/E3 profile and a variant of uncertain significance of PSEN1. At 48, she was classified as Mild Cognitive Impairment and started a treatment with middle‐chain triglycerides and Ketogenic Diet. Before starting the treatment, she underwent another neuropsychological evaluation, PET‐FDG and cerebrospinal fluid biomarkers profile. During the treatment, she will be monitored weekly by a nutritionist expert in ketogenic diet. After three months of treatment, she will repeat tests and exams. Result: Currently, the patient is being treated, until March 2020, at the end of it she will repeat tests and exams. According to previous studies1, 6 weeks of modified ketogenic diet, is associated with an improvement of the cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake, in older adult with risk for Alzheimer Disease. Conclusion: This case is of great importance in describing a woman's history with the PSEN1 mutation, who underwent a Ketogenic Diet treatment while diagnosed with MCI. Regardless of the outcome, this case is essential to identify the effects of ketogenic diets on the biomarkers and neuropsychological tests on patients with the same profile. References: 1) Neth, B.J., Mintz, A., Whitlow, C., Jung, Y., Sai, K.S., Register, T.C. Kellar, D., Lockhart, S.N., Hoscheidt, S., Maldjian, J., Heslegrave, A.J., Blennow, K., Cunnane, S.C., Castellano, C.‐A., Zetterberg, H., Craft, S., Modified Ketogenic Diet Is Associated With Improved Cerebrospinal Fluid Biomarker Profile, Cerebral Perfusion, And Cerebral Ketone Body Uptake In Older Adults At‐Risk For Alzheimer's Disease: A Pilot Study, Neurobiology of Aging (2019). [ABSTRACT FROM AUTHOR]

Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration. [ABSTRACT FROM AUTHOR]

Background:Illiteracy, high cerebrovascular risk and copies ofAPOE-ϵ4 are risk factors for Alzheimer's disease dementia (AD). We aimed to investigate the impacts of gender, education, coronary heart disease (CHD) risk and creatinine clearance variations, body mass index (BMI) andAPOEhaplotypes over the rates of cognitive and functional decline of AD in one year. Methods:Consecutive outpatients with late-onset AD were assessed for gender, schooling, BMI andAPOEhaplotypes, variations in one year of creatinine clearance and Framingham projections of the 10-year absolute CHD risk, and prospective scores of the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Sum-of-Boxes (CDR-SOB), the Index of Independence in Activities of Daily Living (ADL) and Lawton's Scale for Instrumental Activities of Daily Living (IADL). Results:For 191 patients, mean age at AD onset was 73.26 ± 6.4 years-old, earlier forAPOE-ϵ4/ϵ4 carriers (p= 0.0039). For women, higher BMI led to improvements in CDR-SOB (β = −0.091;p= 0.037) and MMSE (β = 0.126;p= 0.017) scores, while increased creatinine clearance was associated with improvements in ADL (β = 0.028;p= 0.012) and MMSE (β = 0.043;p= 0.039) scores and higher schooling led to faster worsening of IADL (β = −0.195;p= 0.022) scores. No variables impacted cognitive or functional decline for men, whereas copies ofAPOE-ϵ4 and the CHD risk had no significant effects whatsoever. Conclusions:Higher BMI and creatinine clearance are protective regarding cognitive and functional decline for women, whereas higher cognitive reserve may lead to faster decline in instrumental functionality.APOEhaplotypes affected the age at AD onset, but not cognitive or functional decline. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease (AD) can involve changes in communication and can lead to mutism in severe cases. Oral communication may be impaired by phonetic-motor disorders, such as apraxia of speech (AOS), or by language disorders, such as aphasia. Therefore, the identification of manifestations of AOS and phonemic paraphasias in patients with AD is critical to understanding the communication changes and determining the therapeutic planning. Aims: To identify the distribution of phonetic–phonological manifestations in older patients with AD and healthy older subjects and assess whether these manifestations indicate the origin of the changes, including a predominantly phonetic-motor origin, a predominantly phonological–linguistic origin, or both. Methods & Procedures: This cross-sectional study evaluated 90 patients with AD and 30 healthy older volunteers. All of the participants underwent the same repetition task for phonetic and phonological assessments using the current classification of phonetic–phonological manifestations; this classification distinguishes characteristics that are mostly related to AOS from other signs that are mostly related to aphasia. Negative binomial regression analysis was conducted to compare the amount of each manifestation presented by the two groups. Outcomes & Results: The patients with AD showed significantly more signs of aphasia (self-correction, and vowel and consonant substitutions), AOS (prolonged intervals and extended vowel duration), and AOS or aphasia (distortion, omission, attempts at the syllable level, distorted substitutions, and additions) than the healthy older volunteers. Conclusions: Older adults with AD presented phonetic and phonological changes of aphasia and AOS and, consequently, limitations in symbolic–linguistic planning and motor planning. [ABSTRACT FROM PUBLISHER]

Background: Assigning a diagnosis to a patient with dementia is important for the present treatment of the patient and caregivers, and scientific research. Nowadays, the dementia diagnostic criteria are based on clinical information regarding medical, history, physical examination, neuropsychological tests, and supplementary exams and, therefore, subject to variability through time.Methods: A retrospective observational study to evaluate variables related to clinical diagnostic stability in dementia syndromes in at least one year follow up. From a sample of 432 patients, from a single university center, data were collected regarding sociodemographic aspects, Clinical Dementia Rating, physical examination, neuropsychological tests, and supplementary exams including a depression triage scale.Results: From this sample, 113 (26.6%) patients have their diagnosis changed, most of them adding a vascular component to initial diagnosis or depression as comorbidity or main disease. Our findings show that many factors influence the diagnostic stability including the presence of symmetric Parkinsonism, initial diagnosis of vascular dementia, presence of diabetes and hypertension, the presence of long term memory deficit in the neuropsychological evaluation, and normal neuroimaging. We discuss our findings with previous findings in the literature.Conclusion: Every step of the clinical diagnosis including history, vascular comorbidities and depression, physical examination, neuropsychological battery, and neuroimaging were relevant to diagnosis accuracy. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia and statin use have been unevenly associated with clinical change in Alzheimer's disease dementia. In this longitudinal study, 192 consecutive outpatients with late-onset Alzheimer's disease dementia were stratified according to APOE haplotypes, and followed for one year to investigate associations of lipid profile variations and lipophilic statin therapy with changes in cognition, caregiver burden, basic and instrumental functionality. Overall, 102 patients (53.1%) carried APOE4+ haplotypes and 90 (46.9%) carried APOE4- haplotypes; 189 patients (98.4%) used either a cholinesterase inhibitor, or Memantine, or both; 144 patients had dyslipidemias and 143 of them received statin therapy. Total cholesterol, LDL-cholesterol, Mini-Mental State Examination scores, and functional independence scores were significantly lower at the end of the follow-up, while Clinical Dementia Rating sum-of-boxes scores were higher. Exclusively for APOE4- carriers, rising LDL-cholesterol levels were associated with a trend toward improvements in the Index of Independence in Activities of Daily Living ( β = 0.010; ρ = 0.16), whereas rising HDL-cholesterol levels were associated with lowered scores ( β = −0.051; ρ = 0.04). Lipophilic statin therapy had non-significant protective effects over Clinical Dementia Rating sum-of-boxes score variations only for APOE4- carriers. APOE4- haplotypes might enhance lipid availability to protect neuronal membranes, thus overcoming their supposed dysfunction in cholesterol metabolism, while APOE4+ carriers have inefficient neural repair mechanisms. In conclusion, APOE haplotypes seem to influence the protective effects of lipid profile variations for patients with Alzheimer's disease dementia, but current evidence is insufficient to propose lipid-lowering drugs as specific anti-dementia therapy. [ABSTRACT FROM AUTHOR]

Background: More than 95% of right-handed individuals, as well as almost 80% of left-handed individuals, have left hemisphere dominance for language. The perisylvian networks of the dominant hemisphere tend to be the most important language systems in human brains, usually connected by bidirectional fibres originated from the superior longitudinal fascicle/arcuate fascicle system and potentially modifiable by learning. Neuroplasticity mechanisms take place to preserve neural functions after brain injuries. Language is dependent on a hierarchical interlinkage of serial and parallel processing areas in distinct brain regions considered to be elementary processing units. Whereas aphasic syndromes typically result from injuries to the dominant hemisphere, the extent of the distribution of language functions seems to be variable for each individual.Method: Review of the literatureResults: Several theories try to explain the organization of language networks in the human brain from a point of view that involves either modular or distributed processing or sometimes both. The most important evidence for each approach is discussed under the light of modern theories of organization of neural networks.Conclusions: Understanding the connectivity patterns of language networks may provide deeper insights into language functions, supporting evidence-based rehabilitation strategies that focus on the enhancement of language organization for patients with aphasic syndromes. [ABSTRACT FROM AUTHOR]

Background: Midlife hypertension followed by late life hypotension resulting from neuro-degeneration increases amyloidogenesis and tauopathy. Methods: Consecutive outpatients with late-onset Alzheimer's disease (AD) at various stages and their respective caregivers were assessed for score variations in 1 year of tests assessing caregiver burden, functionality and cognition according to blood pressure (BP) variations and APOE haplotypes, while also taking into account differential effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, diuretics, or no antihypertensive medication on score changes. The diagnosis and treatment of arterial hypertension followed the JNC 7 report. Results: Variations in systolic BP (-11.76 ± 17.1 mm Hg), diastolic BP (-4.92 ± 10.3 mm Hg) and pulse pressure (-6.84 ± 12.6 mm Hg) were significant after 1 year (n = 191; p < 0.01). For APOE4+ carriers, rises in systolic or diastolic BP improved Clinical Dementia Rating Scale Sum of Boxes scores (p < 0.04), with marginally significant improvements in Mini-Mental State Examination scores resulting from risen systolic (p = 0.069) or diastolic BP (p = 0.079), and in basic independence only regarding risen diastolic BP (p = 0.055). APOE4- carriers resisted any functional or cognitive effects of BP variations. No differences were found regarding any antihypertensive class for variations in BP or any test scores, regardless of APOE haplotypes. Conclusions: Targeting mild BP elevations brings better functional and cognitive results for APOE4+ carriers with AD. [ABSTRACT FROM AUTHOR]

Controversy over benefits of angiotensin-converting enzyme inhibitors (ACEIs) for treatment of dementia due to Alzheimer's disease (AD) led to this alternative investigational approach by the employment of pharmacogenetic methods, correlating the cognitive change of patients with late-onset AD with the presence of common ACE gene promoter polymorphisms, and stratifying the sample in groups of patients who responded or not to the brain-penetrating ACEIs Captopril or Perindopril. A trend was found for treatment with brain-penetrating ACEIs to slow cognitive decline in AD patients with the haplotype rs1800764 (CC): rs4291 (TT) (p = 0.024), and also non-significantly for independent carriers of rs1800764 or rs4291. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In view of the mild effects of pharmacological treatment for dementia due to Alzheimer's disease (AD), the search for modifiable risk factors is an important challenge. Although risk factors for AD are widely recognized, elements that influence the time of onset of the dementia syndrome have not been comprehensively reported. We aimed to investigate which risk factors might be associated with the age at onset of AD in a sample of patients with low mean schooling from Sao Paulo, Brazil. METHODS: We included 210 consecutive patients with late-onset AD to investigate whether education, gender, nationality, urban living and sanitation, occupation, cognitive and physical inactivity, head trauma, depression, systemic infections, surgical interventions, cerebrovascular risk factors, family history of neurodegenerative diseases or cardiovascular diseases and apolipoprotein E gene (APOE) haplotypes might be related to the age at AD onset. RESULTS: Each copy of APOE-4 led to onset of AD almost 2 years earlier, while depression, smoking, higher body mass index and family history of cardiovascular diseases were also highly significant. Protective factors included non-Brazilian nationality, use of a pacemaker and waist circumference. Cerebrovascular risk factors had a mild combined effect for earlier onset of AD. CONCLUSION: APOE haplotypes, depression, nationality and cerebrovascular risk factors were the most important elements to influence the age at AD onset in this sample, whereas gender, education, occupation and physical activities had no isolated effects over the age at onset of this dementia syndrome. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective In view of the mild effects of pharmacological treatment for dementia due to Alzheimer's disease (AD), the search for modifiable risk factors is an important challenge. Although risk factors for AD are widely recognized, elements that influence the time of onset of the dementia syndrome have not been comprehensively reported. We aimed to investigate which risk factors might be associated with the age at onset of AD in a sample of patients with low mean schooling from São Paulo, Brazil. Methods We included 210 consecutive patients with late-onset AD to investigate whether education, gender, nationality, urban living and sanitation, occupation, cognitive and physical inactivity, head trauma, depression, systemic infections, surgical interventions, cerebrovascular risk factors, family history of neurodegenerative diseases or cardiovascular diseases and apolipoprotein E gene (APOE) haplotypes might be related to the age at AD onset. Results Each copy of APOE- ε4 led to onset of AD almost 2 years earlier, while depression, smoking, higher body mass index and family history of cardiovascular diseases were also highly significant. Protective factors included non-Brazilian nationality, use of a pacemaker and waist circumference. Cerebrovascular risk factors had a mild combined effect for earlier onset of AD. Conclusion APOE haplotypes, depression, nationality and cerebrovascular risk factors were the most important elements to influence the age at AD onset in this sample, whereas gender, education, occupation and physical activities had no isolated effects over the age at onset of this dementia syndrome. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]