Late-onset Alzheimer's Disease Dementia Research Articles

Whole genome-wide sequence analysis of long-lived families (Long-Life Family Study) identifies MTUS2 gene associated with late-onset Alzheimer's disease.

Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N=14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N=1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels. We identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p=7.6×10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid. MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology. Long-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Diferencias neuropsicológicas en la enfermedad de Alzheimer en función de la edad de presentación

IntroductionEarly-onset Alzheimer's disease (EOAD) has been defined as a dementia due to AD presenting before the arbitrarily established age of 65 (as opposed to late-onset Alzheimer's disease or LOAD). There is still little research about other age sub-groups, the use of so-called senile dementia has been banished, usually including it within the late-onset Alzheimer's dementia. To the extent of our knowledge, there are no studies comparing the neuropsychological features of very-late-onset patients with early and late-onset ones. MethodsWe retrospectively selected 359 patients with a diagnosis of probable AD dementia. We subdivided patients into three groups attending to the age of onset of the disease: early-onset AD (EOAD; younger than 65 years old), late-onset AD (LOAD; between 65 and 80) and very-late-onset AD (VLOAD; defined here as onset age older than 80), and then we compared their neuropsychological results. ResultsAD patients with a younger age at onset scored worse on attention, executive function and visuospatial skills, while older-onset patients scored worse in memory tasks and language. Patients with a very-late-onset differed from the late-onset ones in a greater impairment of semantic fluency and naming. ConclusionAlthough the point of separation between EOAD and later-onset forms of EA at the age of 65 is an arbitrary one, our study shows that there are significant differences between these groups from a neuropsychological point of view. However, these differences do seem to follow a linear trend with age, rather than representing fundamentally distinct clinical pictures.

A Genetic Validation of the Neurodegeneration Biomarkers Tau-A and Tau-C - A Mendelian Randomization Study.

Disease modifying treatments for dementia are only just surfacing, and their development is still significantly hindered by the lack of validated tools for identification of subjects with subclinical disease. Much interest has been taken in developing accessible non-invasive serum biomarkers of neurodegeneration. Recent studies have identified caspase-3-cleaved tau (Tau-C), and ADAM-10 cleaved tau (Tau-A) as possible markers of preclinical neurodegenerative disease. To explore if serum levels of Tau-A and Tau-C change as a consequence of neurodegeneration. Cohort study with measurement of biomarkers and genome sequencing at baseline with follow-up after an average of 14 years. Postmenopausal Danish women from the Prospective Epidemiological Risk Factor (PERF) cohort (n=4968) Methods: Genotyping data was used to perform a Mendelian randomization analysis of serum levels of Tau-A and Tau-C in relation to a diagnosis of dementia at follow-up. A dementia diagnosis was defined as a composite of an all-cause dementia diagnosis derived from the Danish National Health registries, a self-reported diagnosis of dementia and/or cognitive test scores suggestive of dementia. Serum levels of Tau-A and Tau-C were measured blinded in samples from baseline in a CAP certified lab. The association with dementia was assessed using bi-directional one- and two- sample Mendelian randomization. A lead single nucleotide polymorphism (SNP) was identified for Tau-A (rs10414043) and Tau-C (rs429358), respectively were identified. Both were located in the APOE/C1 cluster on chromosome 19. APOE and EPOC1 variants were associated with lower levels of Tau-A and Tau-C levels - effect size -0.13, 95%CI [-0.17 - -0.09] log2 (ng/mL), p=7.05e-11 for rs10414043 association with Tau-A and effect size -0.12, 95%CI [-0.15 - -0.08] log2 (ng/mL), p=2e-11 for rs429358 association with Tau-C. When incorporating genetic data from a larger genetic study we found that Alzheimer's disease was marginally associated with a decreased Tau-A and Tau-C levels (Odds Ratio 0.97, 95%CI [0.93 - 1.00]. No association was found in the forward Mendelian randomization analysis. By combining genotype data with serum measurements of the novel biomarkers Tau-A and Tau-C, we conclude that Tau-A and Tau-C levels change because of neurodegeneration. We also conclude that lower serum-values of the biomarkers are associated with the presence of genetic variants commonly found in individuals suffering from late-onset Alzheimer's Dementia. These findings add to the growing data pointing towards Tau-A and Tau-C as valuable biomarkers for neurodegeneration.

Relationship of sex differences in cortical thickness and memory among cognitively healthy subjects and individuals with mild cognitive impairment and Alzheimer disease

BackgroundAn aging society has increased rates of late onset Alzheimer disease dementia (ADD), the most common form of age-related dementia. This neurodegenerative disease disproportionately affects women.MethodsWe use data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to examine sex differences in cortical thickness (CT) and memory performance. Analyses of covariance (ANCOVA) models were used to examine effects of sex and diagnosis (DX) on CT and verbal memory. For regions demonstrating significant interaction effects of sex and DX, we tested whether sex moderated cognition-thickness relationships. We used machine learning as a complementary method to explore multivariate CT differences between women and men.ResultsWomen demonstrated greater CT in many brain regions. More specifically, men showed relatively consistent CT declines in all stages, from normal control (NC) to ADD in the bilateral cingulate cortex, bilateral temporal regions, and left precuneus; women had more stable CT in these regions between NC and mild cognitive impairment (MCI) stages, but sharper declines from MCI to ADD. Similarly, for the Rey Auditory Verbal Learning Test (RAVLT), ANCOVA analyses showed that women had significantly better immediate and delayed recall scores than men, at NC and MCI stages, but greater differences, cross-sectionally, from MCI to ADD than men. We found significant sex moderation effects between RAVLT-immediate scores and CT of right isthmus-cingulate for all subjects across DX. Partial correlation analyses revealed that increased CT of right isthmus-cingulate was associated with better verbal learning in women, driven by positron emission tomography defined amyloid positive (Aβ+) subjects. Significant sex-moderation effects in cognition-thickness relationships were further found in the right middle-temporal, left precuneus, and left superior temporal regions in Aβ+ subjects. Using a machine learning approach, we investigated multivariate CT differences between women and men, showing an accuracy in classification of 75% for Aβ+ cognitively NC participants.ConclusionsSex differences in memory and CT can play a key role in the different vulnerability and progression of ADD in women compared to men. Machine learning indicates sex differences in CT are most relevant early in the ADD neurodegeneration.

Late Onset Alzheimer Dementia in Patient with Genotype E3/E4: A Case Report

ackground: Alzheimer's dementia (AD) is a neurodegenerative disorder and there is progressive cognitive impairment, functional deficits and behavioral changes. This neurodegenerative disease process is classically characterized by two pathological features: amyloid- β plaque deposition and neurofibrillary tangle of tau hyperphosphorylation. The most established genetic risk factor for late-onset Alzheimer Disease is the APOE gene allele 4. We will report a case of late-onset Alzheimer's Dementia with genotype E3/E4. Case: A 70-years-old woman patient, complained by her family that she often forgets. The Mini Mental State Examination showed disturbances in orientation, attention, calculation and recall. Non-contrast Brain Magnetic resonance imaging examination revealed decrease in hippocampal volume. Patient also performed a molecular examination of the Apolipoprotein E (APOE) genotype and the genotype E3/E4 was detected Conclusion: The APOE E4 gene has a major role in the occurrence of Late-Onset Alzheimer's Dementia. Keywords: Alzheimer Dementia, Apolipoprotein E.

The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer's disease: a randomized, triple-blind, placebo-controlled trial.

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

Cognitive consequences of COVID-19 in older adults with cognitive impairment

IntroductionCoronavirus disease 2019 (COVID-19) is due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with significant morbidity and mortality that is well documented. This includes significant central nervous system (CNS) involvement that ranges from acute delirium to meningoencephalitis. While acute symptoms and manifestations have been noted, long-term neuropsychiatric and cognitive outcomes remain unclear in convalescent COVID-19 patients. Characterizing the convalescence is particularly important since 80% recover, yet the relationship between exacerbated cognitive dysfunction and COVID-19 remains unclear. We describe 3 adults above age 65 who reported worsening cognitive symptoms in the convalescent stage of COVID-19.MethodsThree adults above the age of 65 who noted worsening cognitive difficulties after SARS-CoV-2 infection and COVID-19 were evaluated in the Memory Clinic of the Duke Neurological Disorders Clinic. Electronic medical records were retrospectively reviewed. Exam included a comprehensive neurological evaluation, formal neuropsychological evaluation, and neuroimaging. Prior history was collected for comparison with their current clinical evaluation profile data.ResultsPatient 1 is a 69 year old diabetic, hypertensive male with a history of depression and a first-order relative and a maternal aunt with late-onset Alzheimer's disease dementia who presented for evaluation of memory loss first noted about one year prior but had significantly worsened in the five months since his recovery from COVID-19. He had documented antibodies to SARS-CoV-2. The patient reported forgetting when he had eaten and now evinces navigation issues even when driving on familiar roads. Head CT without contrast obtained before COVID-19 infection showed mild bilateral hippocampal atrophy. He scored 4/8 on the AD8 Dementia Screening and 20/30 on the Montreal Cognitive Assessment (MoCA). PHQ9 was 10, GAD7 was 0, and NPI was 1. Formal neuropsychological evaluation data were collected. A diagnosis of late-onset Alzheimer's disease without behavioral disturbance was made during his clinic visit. Donezepil was started. Other comorbidities included vitamin B12 deficiency, atrial fibrillation, congestive heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea, and morbid obesity.Patient 2 is a 68 year old male with a history of anxiety, depression, and attention deficit disorder who presented for evaluation of poor memory, inability to “visually map,” and daily “senior moments” as well as a prolonged period of confusion while driving four months after recovering from COVID-19. He had documented antibodies to SARS-CoV-2. He had transient memory problems two years ago that improved after changing his bupropion dosage. He also takes fluoxetine. He now regularly misplaces objects and often stops a task midway through, thinking that he completed it. His GDS score was 5. Head CT was unremarkable. MRI of the brain demonstrated mild hippocampal and biparietal lobe atrophy as well as mild cerebral white matter disease. He scored 7/8 on the AD8 Dementia Screening and 27/30 on the MoCA. A diagnosis of dementia with behavioral disturbance was made. PHQ9 was 9, GAD7 was 6, and NPI was 7. B12 was normal. There is no family history of cognitive impairment.Patient 3 is a 76-year-old female with a history of bipolar 1, diabetes, hypothyroidism, hyperlipidemia who presented for evaluation of memory loss that started 6 months ago but worsened since she had recovered from COVID-19 diagnosed about 8 weeks earlier. After testing positive, she was hospitalized for 3 weeks due to acute encephalopathy attributed to lithium toxicity. She was also taking trazodone. Her GDS score was 7. She scored 8/8 on the AD8 Dementia Screening. MoCA could not be completed. PHQ9 was 3, GAD7 was 9, and NPI was 19. Formal neuropsychological evaluation data were collected. Head CT without contrast three weeks after COVID-19 diagnosis showed calcification in the right basal ganglia, a mild hypodense signal periventricularly, and gray-white differentiation. Brain MRI without contrast showed subtle hippocampal and perisylvian atrophy on T1, mild to moderate parietal lobe atrophy bilaterally, and mild to moderate periventricular leukoaraiosis/white matter hyperintensities on FLAIR sequence. A diagnosis of dementia without behavioral disturbance was made. There is a family history of bipolar disorder in siblings and cognitive impairment in her father but no specific diagnosis of dementia.ConclusionsThis case series describes the exacerbation of pre-existing psychiatric and cognitive conditions after COVID-19 recovery in 3 older adults with formal neuropsychological evaluation data. Longitudinal investigation of convalescent patients is warranted to better clinically characterize and provide insight into the long-term effects of COVID-19. This will allow further investigation into the pathophysiology regarding the long-term consequences of SARS-CoV-2 infection.FundingNot Applicable.

Late Onset Alzheimer Dementia in Patients with Genotype E3/E4: A Case Report

BACKGROUND: Dementia is one of the leading causes of disability and dependence in elderly worldwide. Epidemiological statistics indicate that data show that at about 60–80%, Alzheimer’s is the most common type of dementia. Alzheimer’s is also the third-most prominent cause of death in elderly.
 CASE REPORT: A 72-years-old male patient, complained by the family often forgets about things that have just been done for 3 years ago. According to the family, patient also often discussing the same things repeatedly. Patients tend not to have the initiative to start his daily activities. The family admitted that patient also became often angry and felt suspicious for the last 2 years. From the mini mental state examination showed disturbances in time orientation and recall; from Montreal Cognitive Assessment Ina found disturbances in visuospatial, fluency, abstraction, delayed memory, and time orientation; accompanied by activities of daily living (ADL) and instrumental ADL disorders. Patient also performed a molecular examination of the apolipoprotein E (APOE) genotype and the genotype E3/E4 was detected.
 CONCLUSION: The function of the APOE gene, in particular APOE4, is the most emphasized genetic relationship in late onset Alzheimer’s disease. It is proposed that blocking the action of APOE4 can delay or stop Alzheimer’s disease progression.

Exploring prior diseases associated with incident late-onset Alzheimer's disease dementia.

Studies have identified prior conditions associated with late-onset Alzheimer’s disease dementia (LOAD), but all prior diseases have rarely been screened simultaneously in the literature. Our objective in the present study was to identify prior conditions associated with LOAD and construct pathways for them. We conducted a population-based matched case-control study based on data collected in the National Health Insurance Research database of Taiwan and the Catastrophic Illness Certificate database for the years 1997–2013. Prior diseases definitions were based on the first three digits of the codes listed in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Inclusion criteria required that each ICD-code existed for at least 1 year and incurred at least 2 outpatient visits or inpatient diagnosis. The case group comprised 4,600 patients newly diagnosed with LOAD in 2007–2013. The LOAD patients were matched by sex and age to obtain 4,600 controls. Using stepwise multivariate logistic regression analysis, diseases were screened for 1, 2 …, 9 years prior to the first diagnosis of LOAD. Path analysis was used to construct pathways between prior diseases and LOAD. Our results revealed that the following conditions were positively associated with the incidence of LOAD: anxiety (ICD-code 300), functional digestive disorder (ICD code 564), psychopathology-specific symptoms (ICD-code 307), disorders of the vestibular system (ICD-code 386), concussion (ICD-code 850), disorders of the urethra and urinary tract (ICD-code 599), disorders of refraction and accommodation (ICD-code 367), and hearing loss (ICD-code 389). A number of the prior diseases have previously been described in the literature in a manner identical to that in the present study. Our study supports the assertion that mental, hearing, vestibular system, and functional digestive disorders may play an important role in the pathogenesis of LOAD.

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer's Dementia.

Nowadays, Alzheimer’s disease (AD) is a severe sociological and clinical problem. Since it was first described, there has been a constant increase in its incidence and, for now, there are no effective treatments since current approved medications have only shown short-term symptomatic benefits. Therefore, it is imperative to increase efforts in the search for molecules and non-pharmacological strategies that are capable of slowing or stopping the progress of the disease and, ideally, to reverse it. The amyloid cascade hypothesis based on the fundamental role of amyloid has been the central hypothesis in the last 30 years. However, since amyloid-directed treatments have shown no relevant beneficial results other theories have been postulated to explain the origin of the pathology. The brain is a highly metabolically active energy-consuming tissue in the human body. It has an almost complete dependence on the metabolism of glucose and uses most of its energy for synaptic transmission. Thus, alterations on the utilization or availability of glucose may be cause for the appearance of neurodegenerative pathologies like AD. In this review article, the hypothesis known as Type 3 Diabetes (T3D) will be evaluated by summarizing some of the data that has been reported in recent years. According to published research, the adherence over time to low saturated fatty acids diets in the context of the Mediterranean diet would reduce the inflammatory levels in brain, with a decrease in the pro-inflammatory glial activation and mitochondrial oxidative stress. In this situation, the insulin receptor pathway would be able to fine tune the mitochondrial biogenesis in neuronal cells, regulation the adenosine triphosphate/adenosine diphosphate intracellular balance, and becoming a key factor involved in the preservation of the synaptic connexions and neuronal plasticity. In addition, new targets and strategies for the treatment of AD will be considered in this review for their potential as new pharmacological or non-pharmacological approaches.

P2‐116: GRIN2A GENOTYPES AND APOE HAPLOTYPES AFFECT THE AGE AT ONSET OF ALZHEIMER'S DEMENTIA BUT NOT FUNCTIONAL OR COGNITIVE RESPONSE TO MEMANTINE

Earlier evidence showed that Memantine antagonizes the N-methyl-D-aspartate (NMDA) type of glutamate receptor leading to possible behavioral improvement and a synergistic effect with cholinesterase inhibitors over slower functional and cognitive decline in Alzheimer's dementia (AD). Variations in some receptor genes can contribute to AD pathogenesis and pharmacological response, particularly regarding cholinesterase inhibitors. GRIN2A is a common subunit of functional NMDA receptors, whereas the GRIN2A gene is mapped to 16p13, and rs1868291 is strongly associated with memory function and hippocampal activity in humans. We sought to evaluate associations of GRIN2A genotypes and APOE haplotypes with functional and cognitive response to Memantine and age at onset of AD. 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 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 for rs1868291 (GRIN2A). APOE haplotypes and rs1868291 genotypes were correlated with age at dementia onset and, after stratification according to APOE haplotypes, the presence of each genotype of rs1868291 was correlated with use of Memantine or not for test score variations, with the threshold of significance set at p<0.05. Among 189 consecutive outpatients, 142 used Memantine (75.1%); mean age at dementia onset was 73.44±6.3 years-old, with 130 women (68.8%) and 59 men (31.2%), 103 APOE4+ carriers (54.5%) and 86 APOE4- carriers (45.5%). APOE-ε4/ε4 carriers had earlier AD onset by almost five years (p=0.0011), whereas each T allele of rs1868291 led to almost three years later onset of AD (p=0.0046). Genotypes of rs1868291 (p>0.22) or use of Memantine (p>0.09) did not affect functional or cognitive decline in one year, regardless of APOE haplotypes. Genotypes of rs1868291 and APOE haplotypes are associated with the age at onset of AD, but not with functional or cognitive decline, nor with response to Memantine. (Supported by FAPESP grant #2015/10109-5).

The Molecular and Neuropathological Consequences of Genetic Risk for Alzheimer's Dementia.

Alzheimer's dementia commonly impacts the health of older adults and lacks any preventative therapy. While Alzheimer's dementia risk has a substantial genetic component, the specific molecular mechanisms and neuropathologies triggered by most of the known genetic variants are unclear. Resultantly, they have shown limited influence on drug development portfolios to date. To facilitate our understanding of the consequences of Alzheimer's dementia susceptibility variants, we examined their relationship to a wide range of clinical, molecular and neuropathological features. Because the effect size of individual variants is typically small, we utilized a polygenic (overall) risk approach to identify the global impact of Alzheimer's dementia susceptibility variants. Under this approach, each individual has a polygenic risk score (PRS) that we related to clinical, molecular and neuropathological phenotypes. Applying this approach to 1,272 individuals who came to autopsy from one of two longitudinal aging cohorts, we observed that an individual's PRS was associated with cognitive decline and brain pathologies including beta-amyloid, tau-tangles, hippocampal sclerosis, and TDP-43, MIR132, four proteins including VGF, IGFBP5, and STX1A, and many chromosomal regions decorated with acetylation on histone H3 lysine 9 (H3K9Ac). While excluding the APOE/TOMM40 region (containing the single largest genetic risk factor for late-onset Alzheimer's dementia) in the calculation of the PRS resulted in a slightly weaker association with the molecular signatures, results remained significant. These PRS-associated brain pathologies and molecular signatures appear to mediate genetic risk, as they attenuated the association of the PRS with cognitive decline. Notably, the PRS induced changes in H3K9Ac throughout the genome, implicating it in large-scale chromatin changes. Thus, the PRS for Alzheimer's dementia (AD-PRS) showed effects on diverse clinical, molecular, and pathological systems, ranging from the epigenome to specific proteins. These convergent targets of a large number of genetic risk factors for Alzheimer's dementia will help define the experimental systems and models needed to test therapeutic targets, which are expected to be broadly effective in the aging population that carries diverse genetic risks for Alzheimer's dementia.

Early Life Stress and Epigenetics in Late-onset Alzheimer's Dementia: A Systematic Review.

Involvement of life stress in Late-Onset Alzheimer’s Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance.For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci.Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.

Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study

IntroductionThere may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. MethodsWe analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. ResultsDuring 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants. DiscussionA cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer's dementia.

Longitudinal lipid profile variations and clinical change in Alzheimer's disease dementia

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.

Does Schizophrenia in Offspring Increase the Risk of Developing Alzheimer's Dementia

Background/Aims: Prior studies have consistently found a higher risk of dementia in individuals with schizophrenia, but whether this is due to a common etiology between the disorders remains obscure. We wanted to elucidate this association by investigating whether schizophrenia in offspring increases the risk of Alzheimer's dementia. Methods: All individuals born between 1930 and 1953 were identified through national registers and followed from their 50th birthday until the date of Alzheimer's dementia, death or end of the study. Regressions were performed to evaluate the association between offspring with schizophrenia and Alzheimer's dementia. Results: Individuals with offspring with schizophrenia did not have an increased risk of Alzheimer's dementia [incidence rate ratio (IRR), 0.97; 95% CI, 0.88-1.07] compared to individuals with offspring without psychiatric contact. This finding remained stable when evaluating early-onset (IRR, 1.10; 95% CI, 0.91-1.31) and late-onset Alzheimer's dementia (IRR, 0.92; 95% CI, 0.88-1.07). Similar findings were made for vascular and unspecified dementia. Conclusion: The finding of no familial coaggregation between schizophrenia and Alzheimer's dementia may suggest that no common etiology between the disorders exists. This may indicate that the excess risk of dementia in individuals with schizophrenia is a by-product of the higher rates of somatic comorbidity and adverse health risk factors among these individuals.

New cardiovascular targets to prevent late onset Alzheimer disease

The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care.

Chlamydophila pneumoniaeInfection and Its Role in Neurological Disorders

Chlamydophila pneumoniae is an intracellular pathogen responsible for a number of different acute and chronic infections. The recent deepening of knowledge on the biology and the use of increasingly more sensitive and specific molecular techniques has allowed demonstration of C. pneumoniae in a large number of persons suffering from different diseases including cardiovascular (atherosclerosis and stroke) and central nervous system (CNS) disorders. Despite this, many important issues remain unanswered with regard to the role that C. pneumoniae may play in initiating atheroma or in the progression of the disease. A growing body of evidence concerns the involvement of this pathogen in chronic neurological disorders and particularly in Alzheimer's disease (AD) and Multiple Sclerosis (MS). Monocytes may traffic C. pneumoniae across the blood-brain-barrier, shed the organism in the CNS and induce neuroinflammation. The demonstration of C. pneumoniae by histopathological, molecular and culture techniques in the late-onset AD dementia has suggested a relationship between CNS infection with C. pneumoniae and the AD neuropathogenesis. In particular subsets of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. The role of Chlamydia in the pathogenesis of mental or neurobehavioral disorders including schizophrenia and autism is uncertain and fragmentary and will require further confirmation.

Common variation inGRB-associated Binding Protein 2 (GAB2)and increased risk for Alzheimer dementia

GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE epsilon4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belgian AD patients (mean onset age 79.0+/-5.2 years, 70.2% females) and 601 ethnically matched control individuals (mean age 61.9+/-15.3 years, 57.1% females) were genotyped for 10 SNPs across the GAB2 locus. For 2 SNPs the most common genotype was associated with risk for AD, with the most significant result for rs4945261 [OR 1.49 (95%CI 1.04-2.15)]. After stratification by presence or absence of APOE epsilon4 these associations were present in APOE epsilon4 carriers only. When assessing the effect of APOE and rs4945261 in one model, rs4945261 did not show a main effect, but the joint risk effect of rs4945261-GG and APOE epsilon4 on AD was significant (OR 3.87, 95%CI 2.66-5.63; p=1.0E-12), with a deviation of 1.87 from the multiplicative model of interaction. Haplotype analyses showed evidence of association in the total (global p(sim) 0.04) and APOE epsilon4+ (global p(sim) 0.02) but not in the APOE epsilon4 - group (global p(sim) 0.6). The association was driven by a higher frequency of the major haplotype in patients. Our data independently replicate an association between GAB2 and late-onset AD, which appears to be limited to APOE epsilon4 carriers.

Risk Factors for Alzheimer Dementia in a Community-Based Birth Cohort at the Age of 75 Years

Background: Few prospective community-based cohort studies have so far concentrated specifically on the risk factors for Alzheimer dementia (AD) with onset after the age of 75 years. Methods: We prospectively investigated a birth cohort of 585 nondemented inhabitants in the area on the East bank of the river Danube who were born between 1925 and 1926. They were investigated at the age of 75 years and followed up after 30 months. The follow-up was possible with 488 probands; 36 died, and 61 refused to participate. Results: In multivariate analysis an elevated risk for late-onset AD could be found for (1) history of depressive episodes (OR = 2.09; 95% CI = 1.25–3.48); (2) the Ε4 allele of the APOE gene (OR = 1.86; 95% CI = 1.08–3.23); (3) lower serum level of folate (OR = 0.92; 95% CI = 0.87–0.98); (4) no chronic use of nonsteroidal anti-inflammatory drugs (OR = 0.40; 95% CI = 0.20–0.81), and (5) lower education (OR = 1.43; 95% CI = 1.03–2.00). Conclusions: Five risk factors for late-onset AD could be confirmed, which might be targets for preventive strategies.