Alzheimer's Disease In Relation Research Articles

The effects of enhancing angiotensin converting enzyme in myelomonocytes on ameliorating Alzheimer's-related disease and preserving cognition.

This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ42), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115+ myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque. We further demonstrated that introducing ACE10 myelomonocytes (microglia and peripheral monocytes) into the double transgenic APPSWE/PS1ΔE9 murine model of AD (AD+ mice), diminished neuropathology and enhanced the cognitive functions. These beneficial effects were dependent on ACE catalytic activity and vanished when ACE was pharmacologically blocked. Moreover, we revealed that the therapeutic effects in AD+ mice can be achieved by enhancing ACE expression in bone marrow (BM)-derived CD115+ monocytes alone, without targeting central nervous system (CNS) resident microglia. Following blood enrichment with CD115+ ACE10-monocytes versus wild-type (WT) monocytes, AD+ mice had reduced cerebral vascular and parenchymal Aβ burden, limited microgliosis and astrogliosis, as well as improved synaptic and cognitive preservation. CD115+ ACE10-versus WT-monocyte-derived macrophages (Mo/MΦ) were recruited in higher numbers to the brains of AD+ mice, homing to Aβ plaque lesions and exhibiting a highly Aβ-phagocytic and anti-inflammatory phenotype (reduced TNFα/iNOS and increased MMP-9/IGF-1). Moreover, BM-derived ACE10-Mo/MΦ cultures had enhanced capability to phagocytose Aβ42 fibrils, prion-rod-like, and soluble oligomeric forms that was associated with elongated cell morphology and expression of surface scavenger receptors (i.e., CD36, Scara-1). This review explores the emerging evidence behind the role of ACE in AD, the neuroprotective properties of monocytes overexpressing ACE and the therapeutic potential for exploiting this natural mechanism for ameliorating AD pathogenesis.

Editors' Note: Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment

The key to possible prevention of cognitive impairment in patients with Alzheimer disease (AD) lies in preclinical detection using serologic, radiographic, and other novel biomarkers. In the prospective observational cohort study of cognitively unimpaired adults, adults with mild cognitive impairment, and adults with probable AD dementia by Therriault and colleagues, they report that 1 in 12 cognitively unimpaired adults had biologic evidence of Alzheimer pathology using amyloid PET and tau PET imaging. In this study, 7.88% of cognitively unimpaired adults had abnormalities in both imaging modalities, which would be consistent with biologically defined AD. Dr. Garnier-Crussard and Krolak-Salmon acknowledge that Alzheimer pathology is not unusual among unimpaired adults and further suggest that additional factors (e.g., comorbid conditions and exposures) may be contributing to the clinical features of the disease. Ongoing studies exploring preclinical biomarkers may one day elucidate which mechanism (or mechanisms) are responsible for later cognitive impairment in at-risk individuals. Furthermore, such a panel of biomarkers may become useful in the personalization of disease-modifying therapy for such patients. The key to possible prevention of cognitive impairment in patients with Alzheimer disease (AD) lies in preclinical detection using serologic, radiographic, and other novel biomarkers. In the prospective observational cohort study of cognitively unimpaired adults, adults with mild cognitive impairment, and adults with probable AD dementia by Therriault and colleagues, they report that 1 in 12 cognitively unimpaired adults had biologic evidence of Alzheimer pathology using amyloid PET and tau PET imaging. In this study, 7.88% of cognitively unimpaired adults had abnormalities in both imaging modalities, which would be consistent with biologically defined AD. Dr. Garnier-Crussard and Krolak-Salmon acknowledge that Alzheimer pathology is not unusual among unimpaired adults and further suggest that additional factors (e.g., comorbid conditions and exposures) may be contributing to the clinical features of the disease. Ongoing studies exploring preclinical biomarkers may one day elucidate which mechanism (or mechanisms) are responsible for later cognitive impairment in at-risk individuals. Furthermore, such a panel of biomarkers may become useful in the personalization of disease-modifying therapy for such patients.

Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment.

ObjectiveTo assess the frequency of biologically defined Alzheimer disease (AD) in relation to age, sex, APOE ε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET.MethodsWe assessed cognitively unimpaired (CU) elderly (n = 166), patients with amnestic mild cognitive impairment (n = 77), and patients with probable AD dementia (n = 62) who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [18F]AZD4694 and tau-PET with [18F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles was assessed using logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe clinical diagnosis of probable AD dementia demonstrated good agreement with biologically defined AD (positive predictive value 85.2%). A total of 7.88% of CU were positive for both amyloid-PET and tau-PET. Frequency of biologically defined AD increased with age (OR 1.14; p < 0.0001) and frequency of APOE ε4 allele carriers (single ε4: OR 3.82; p < 0.0001; double ε4: OR 17.55, p < 0.0001).ConclusionWhereas we observed strong, but not complete, agreement between clinically defined probable AD dementia and biomarker positivity for both β-amyloid and tau, we also observed that biologically defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically defined AD and related entities.Classification of EvidenceThis study provides Class I evidence that biologically defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of CU elderly.

Sexual differences regarding Alzheimer’s disease: a narrative review

Background. Actually, there are about 5.2 million people with Alzheimer’s dementia (AD) in the USA, 3.3 million are women and 1.9 million are men. Objective. We will find out the status on the Alzheimer disease in relation to the brain structure, diagnosis, symptoms and therapy by gender. Methods. We analyzed, in this narrative review, the literature between 1989-2019 published on the Pubmed about Alzheimer disease and gender. The keywords were: Alzheimer disease and sex differences. Conclusions. Women over 80 years have a higher incidence of AD than men. Women have a faster age-related decline and are more likely to respond to donepezil and rivastigmina leading to less cognitive decline. At more advanced ages, women incurred greater costs than men of the same age. Woman gender could be a risk factor for evolution of AD. We will emphasize the importance of considering sex as a biological variable in the design of preclinical and clinical studies that investigate underlying pathologies or response to pharmacological interventions in AD.

Neprilysin and Insulin-Degrading Enzyme Levels Are Increased in Alzheimer Disease in Relation to Disease Severity

Experimental reduction of neprilysin (NEP) or insulin-degrading enzyme (IDE) in vivo exacerbates beta-amyloid accumulation in the brain. The level of these enzymes is reportedly reduced during aging and in postmortem brains of patients with sporadic Alzheimer disease (AD). To distinguish between primary decreases in NEP and IDE activity that might contribute to beta-amyloid accumulation and decreases secondary to neurodegenerative changes in AD, we measured NEP and IDE levels by indirect sandwich ELISA and enzyme activities by immunocapture-based fluorogenic assays in postmortem frontal cortex from patients of different ages and at different pathological stages of AD, as indicated by Braak tangle stage. The ELISA measurements of neuron-specific enolase were used to adjust for neuronal loss. Both unadjusted and neuron-specific enolase-adjusted NEP levels and activity were significantly increased in AD and positively correlated with Braak stage but negatively with age in AD patients. Insulin-degrading enzyme activity was higher in AD than controls; this was significant after adjustment for neuron-specific enolase level; unadjusted IDE protein level was decreased in AD but not after adjustment. Our findings suggest that reduction in NEP and IDE activity is not the primary cause of beta-amyloid accumulation in AD, but rather a late-stage phenomenon secondary to neurodegeneration.

Functional brain imaging as a looking-glass into the degraded brain: reviewing evidence from Alzheimer disease in relation to normal aging

Research on the real-time relationship between brain activity and mental performance is intense. However, relatively few studies have been devoted to patients with different diseases or lesions. Such studies may cast light on certain aspects of brain activity, such as plasticity. This review summarizes studies on Alzheimer's disease (AD) patients where the techniques to map brain activity in relation to mental performance have been utilized. Research findings suggest, that there is a spectrum of changes in AD patients that is distinct from that seen in healthy aging. These changes include: (i) loss of activated regions, (ii) reduced activation possibly due to brain degeneration typical of AD, (iii) the emergence of newly activated regions in order to compensate for minor brain deterioration (e.g., an enlargement of activated regions sometimes manifested as an increased bilaterality or a hemispheric shift of activation, and dedifferentiation), (iv) decreased level of activation, and (v) no change at all, which may occur in easy tasks or tasks that do not involve regions exposed to brain atrophy. In conclusion, the pattern of activation in AD depends on interactions between the clinical stage of patients, and the pattern of brain degeneration, as well as the task difficulty and specific networks necessary for solving the task.

Neuropeptides and Alzheimer's disease.

Numerous neuropeptides have been isolated from the human brain and postulated as neurotransmitter candidates. Their biochemical characteristics and anatomical distribution have been elucidated in some detail, but their possible physiological and pathophysiological roles, as well as their utility as diagnostic markers in brain disorders, have been more difficult to establish. The concentrations of several neuropeptides have been measured in postmortem human brain studies and in cerebrospinal fluid (CSF) of patients with Alzheimer's disease. Here we critically review these findings with focus on: (1) the relation between brain tissue and CSF neuropeptide alterations; (2) the specificity of neuropeptide alterations in Alzheimer's disease in relation to other degenerative brain diseases; (3) possible functional implications.