Efficacy of benzodiazepines and related drugs in patients over 75 years of age and impact on cognition.

BACKGROUND: In France, despite the known risks, the use of benzodiazepines and related (BZD) is excessive, particularly in older populations. Over the age of 70, 1 person in 2 uses BZD on a long-term basis (more than 3 years), whereas it is recommended not to exceed 12 weeks. To compensate for the numerous undesirable effects and to maintain a positive benefit-risk balance, these treatments must be very effective and improve significantly the quality of life. AIMS: This study aims to determine whether the efficacy of BZD outweighs their adverse effects in older population. METHODS: In a population of 109 patients with cognitive impairment and hospitalized in Saint-Quentin (France), we recorded the use of BZD and medical background. Neuropsychological and geriatric assessments allowed cognitive and thymic evaluation. RESULTS: In our cohort of 109 patients, 50% of the subjects were BZD + and 78% were women. Patients in the BZD + group were no longer anxious but had poorer cognitive and executive performance than controls. DISCUSSION: Long-term treatment of anxiety in patients aged 75 and over with BZD appears to be effective. The deleterious impact of BZD on cognition has been demonstrated. CONCLUSIONS: These results tend to consider non-medicinal therapies as serious alternatives to BZD for treating anxiety in the older population.

A Particularly Tragic Case of Possible Alzheimer's Disease, that of Marshal Pétain.

After World War I and more particularly in June 1940, the prestige of French Marshal Philippe Pétain, considered as the winning general the battle of Verdun, was very high. He became President of Council while the French army was unable to stop the German offensives. But five years later he was sentenced to death for high treason. By rereading his bibliography from a medical perspective, it is possible to find multiple suggestive events and to affirm a posteriori Pétain suffered from a neurodegenerative disorder, whose first signs appeared in the 1930s, suggestive of Alzheimer's disease, which had an impact on French politics. The modern medical knowledge of this disease casts a new light on the behavior of Petain during the last war.

Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients.

Background: Disruptions in cerebrospinal fluid (CSF) flow during aging could compromise protein clearance from the brain and contribute to the etiology of Alzheimer's Disease (AD). Objective: To determine whether CSF flow is associated with cognitive deficit in elderly patients (>70 years). Methods: We studied 92 patients admitted to our geriatric unit for non-acute reasons using phase-contrast magnetic resonance imaging (PC-MRI) to calculate their ventricular and spinal CSF flow, and assessed their global cognitive status, memory, executive functions, and praxis. Multivariable regressions with backward selection (criterion p < 0.15) were performed to determine associations between cognitive tests and ventricular and spinal CSF flow, adjusting for depression, anxiety, and cardiovascular risk factors. Results: The cohort comprised 71 women (77%) and 21 (33%) men, aged 84.1 ± 5.2 years (range, 73-96). Net ventricular CSF flow was 52 ± 40 µL/cc (range, 0-210), and net spinal CSF flow was 500 ± 295 µL/cc (range, 0-1420). Ventricular CSF flow was associated with the number of BEC96 figures recognized (ß = 0.18, CI, 0.02-0.33; p = 0.025). Spinal CSF flow was associated with the WAIS Digit Span Backward test (ß = 0.06, CI, 0.01-0.12; p = 0.034), and categoric verbal fluency (ß = 0.53, CI, 0.07-0.98; p = 0.024) and semantic verbal fluency (ß = 0.55, CI, 0.07-1.02; p = 0.024). Conclusion: Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. Alterations in CSF flow could contribute to some of the cognitive deficit observed in patients with AD. Diagnosis and treatment of CSF flow alterations in geriatric patients with neurocognitive disorders could contribute to the prevention of their cognitive decline.

Sleep Apnea Syndrome in an Elderly Population Admitted to a Geriatric Unit: Prevalence and Effect on Cognitive Function.

BACKGROUND: Sleep apnea leads to cognitive impairment in older patients, but its association with neurodegeneration remains controversial, and most studies do not distinguish between the more common obstructive form (OSAS) and the rarer central form (CSAS). OBJECTIVE: The purpose of this study was to assess the prevalence of the different forms of sleep apnea in a cohort of cognitively impaired elderly patients (>70 years) and to investigate their associations with cognitive deficit, weighted against known risk factors for neurodegeneration. METHODS: Overnight polygraphy was performed for 76 consecutive patients admitted to our geriatric unit. Their cognitive function was assessed using the Mini Mental-State Exam (MMSE), Mattis Dementia Rating Scale (MDRS) and Stroop test. Multivariable analyses were performed to determine associations between cognitive function and independent variables describing demographics, sleep apnea measures, and cardiovascular risk factors. RESULTS: The cohort comprised 58 women and 18 men aged a mean of 84 years (range, 73-96). Sleep apnea syndrome (SAS) was diagnosed in 48 patients (63%), of which 31 (41%) with OSAS and 17 (22%) with CSAS. Multivariable regression analysis revealed that MDRS was lower in patients with OSAS (ß = -10.03, p = 0.018), that Stroop Colors and Words delays increased with AHI (ß = 0.17, p = 0.030 and ß = 0.31, p = 0.047) and that that Stroop Interference delay was higher in patients with CSAS (ß = 24.45, p = 0.002). CONCLUSION: Sleep apnea is thus highly prevalent in elderly patients with cognitive impairment. OSAS was associated with lower general cognitive function, while CSAS was only associated with increased Stroop Interference delays. Elderly patients with cognitive deficit could benefit from sleep apnea screening and treatment.

Specific Effects of Anti-Hypertensive Treatment in an Older Patient with Dementia.

Dementia is one of the most common health problems in the world. Alzheimer's disease (AD) is the most common form of dementia. The presence of vascular risk factors such as hypertension (HT) may increase the risk of AD [1,2]. The relation between blood pressure (BP) and dementia has been the subject of numerous epidemiological studies, midlife HT is a risk factor for dementia and AD [3-7] but the association between HT and risk of dementia is lower in the older population [8]. A fair modulation of an antihypertensive treatment, based on the cognitive status of the elderly, can avoid multiple complications. A case of an older for whom cognitive improvement and reduced risk of falls were noticed after mild blood pressure elevation is reported.

The role of PC-MRI in neurodegenerative diseases / O papel da RM com contraste nas doenças neurodegenerativas

Introduction: Neurodegenerative diseases, a major public health problem, could have a vascular origin. Phase-contrast magnetic resonance imaging (PC-MRI) enables reliable, non-invasive, and rapid measurements of cerebrospinal fluid (CSF) and blood flows, and evaluation of the mechanical coupling between cerebral blood and CSF flows throughout the cardiac cycle (CC). Objectives: Our purpose was to evaluate the potential of PC-MRI to the study of cerebral blood and CSF flows in patients with neurodegenerative diseases such as Alzheimer's disease (AD), Mild cognitive impairment with amnesic disorders (MCIa) and Vascular Dementia (VD). Methods: The elderly population consisted of 20 AD (age: 80 ± 5 years); 12 AD patients with vascular cerebral lesions (ADvasc) (age: 81 ± 5 years), 10 MCIa patients (age: 80 ± 7 years), and 8 VD patients (age: 78 ± 7 years) were identified. They underwent the same PC-MRI protocol and were compared to 13 age-matched Healthy Elderly (HE) (age: 71± 9 years). Arterial blood pressure was analyzed to detect patients with hypertension. Results: Significantly higher cerebral blood and CSF flows were observed in HE when compared to VD, AD and ADvasc, (p<0.05), but not MCIa patients who yielded the highest cerebral arterial and venous blood flows and stroke volumes compared to the other patients, (p<0.05). The highest oscillations of CSF were also detected in MCIa patients (p<0.05). Conclusion: Our preliminary data suggests an increase in cerebral arterial blood and CSF flows in MCIa. PC-MRI provides a new hydrodynamic view, which may help evaluate a potential role of cardiovascular alterations in neurodegenerative diseases.

Introdução: As doenças neurodegenerativas, um grande problema de saúde pública, podem ser de origem vascular. A ressonância magnética (RM) com contraste de fase permite medições confiáveis, não invasivas e rápidas do líquido cefalorraquidiano (LCR) e dos fluxos sanguíneos para avaliação do acoplamento mecânico de circulação cerebral e fluxo de LCR ao longo do ciclo cardíaco (CC). Objetivos: Nosso objetivo foi avaliar o potencial da RM com contraste de fase para o estudo do fluxo sanguíneo no cérebro e LCR em pacientes com doenças neurodegenerativas, como doença de Alzheimer (DA), comprometimento cognitivo leve (CCL) com distúrbios amnésicos e demência vascular (DV). Métodos: A população foi composta por 20 sujeitos idosos com DA (idade: 80 ± 5 anos); foram identificados 12 pacientes com lesões cerebrais vasculares (idade: 81 ± 5 anos), 10 pacientes com CCL e distúrbios amnésicos (idade: 80 ± 7 anos) e 8 com DV (idade: 78 ± 7 anos). Eles foram submetidos ao mesmo protocolo de RM com contraste de fase e comparados a 13 idosos saudáveis (idade: 71 ± 9 anos). A pressão arterial foi aferida para detectar pacientes com hipertensão arterial. Resultados: Observaram-se fluxos sanguíneos cerebrais e CSF significativamente maiores em pacientes com DV, DA e com lesões cerebrais (p<0,05), mas não nos pacientes com CCL, que tiveram os maiores fluxos arteriais e venosos cerebrais em relação aos demais pacientes (p<0,05). Maiores oscilações de LCR também foram detectadas em pacientes com CCL (p<0,05). Conclusão: Nossos dados preliminares sugerem um aumento no fluxo arterial cerebral e nos fluxos de LCR na CCL. A RM com contraste e fase fornece uma nova visão hidrodinâmica, o que pode ajudar a avaliar o possível papel das alterações cardiovasculares em doenças neurodegenerativas.

Interactions between Flow Oscillations and Biochemical Parameters in the Cerebrospinal Fluid.

The equilibrium between the ventricular and lumbar cerebrospinal fluid (CSF) compartments may be disturbed (in terms of flow and biochemistry) in patients with chronic hydrocephalus (CH). Using flow magnetic resonance imaging (MRI) and CSF assays, we sought to determine whether changes in CSF were associated with biochemical alterations. Nine elderly patients with CH underwent phase-contrast MRI. An index of CSF dynamics (Idyn) was defined as the product of the lumbar and ventricular CSF flows. During surgery, samples of CSF were collected from the lumbar and ventricular compartments and assayed for chloride, glucose and total protein. The lumbar/ventricular (L/V) ratio was calculated for each analyte. The ratio between measured and expected levels (Ibioch) was calculated for each analyte and compared with Idyn. Idyn varied from 0 to 100.10(3)µl(2).s(2). In contrast to the L/V ratios for chloride and glucose, the L/V ratio for total protein varied markedly from one patient to another (mean ± standard deviation (SD): 2.63 ± 1.24). The Ibioch for total protein was strongly correlated with the corresponding Idyn (Spearman's R: 0.98; p < 5 × 10(-5)).We observed correlated alterations in CSF flow and biochemical parameters in patients with CH. Our findings also highlight the value of dynamic flow analysis in the interpretation of data on CSF biochemistry.

In geriatric patients, delirium symptoms are related to the anticholinergic burden.

AIM: Anticholinergic drugs are widely prescribed for elderly patients and could induce several neuropsychological disorders, especially delirium. The aim of the present study was to evaluate the relationship between anticholinergic burden and delirium symptoms. METHODS: A total of 102 patients aged over 75 years (86.3 ± 5.8 years, 53 women and 49 men) hospitalized in a geriatric medicine department were included in this prospective study. Anticholinergic burden was assessed by classifying drug use into three levels (low, medium or high). An overall, weighted score was established. Delirium symptoms were measured with the Confusion Assessment Method on days 1, 3, 5, 8, 15 and 21. Covariates studied were comorbidities (Charlson), health status, activities of daily living, nutrition (albumin), cognition, length of stay and mortality. RESULTS: A total of 51.6% of the patients were taking anticholinergic drugs at home (2.13 ± 1.34). Length of stay was 14.5 ± 9.9 days. Prevalence of delirium symptoms ranged on days between 34.8 and 60%. Anticholinergic burden was correlated with the appearance of delirium symptoms. Delirium symptoms were associated with greater mortality (16.1 and 3.7 % in patients with and without delirium symptoms; P = 0.049), a longer hospital stay (18.09 ± 11.34 vs 11.75 ± 7.80 days, P = 0.001), greater dependence on discharge (activities of daily living score: 1.57 ± 1.56 vs 3.41 ± 1.45, P < 0.0001) and worse health status on discharge (5.3 ± 2.7 vs 7.0 ± 1.7, P = 0.0008). CONCLUSION: Anticholinergic burden appears as a risk factor for both delirium symptoms and mortality. Prevention of delirium symptoms requires its reduction.

[Fragility assessment in primary care: which tools for predicting what?]. / Évaluation de la fragilité en soins primaires : quels outils pour quelle prédiction ?

Frailty is a geriatric syndrome associated with high risk for falls, disability, hospitalization, and mortality. The aim of this study is to assess the prevalence of frailty to the Fried's criteria in primary care and its evolution and the outcome of the patients at 1 year. Descriptive prospective study of patients over 75 years coming consult three general practitioners, evaluated initially and at 1 year. Frailty was defined by the presence of three criteria including weight loss, weakness (grip strength), self-reported exhaustion, low physical activity and slow walking speed. Of the 55 patients re-evaluated, 10.9% of patients were frail, 56.4% pre-frail and 32.7% were robust. Robust who become frail during the initial assessment, had a lower IADL score (p = 0.004) and a lower grip strength (p = 0.0311) than those who remained robust. Fried tool is difficult to implement in primary care. Grip strength and IADL are interesting for a simple screening tool in general practice to allow early treatment and delay progression to addiction.

Underuse of oral anticoagulation for individuals with atrial fibrillation in a nursing home setting in France: comparisons of resident characteristics and physician attitude.

OBJECTIVES: To describe the characteristics of nursing home residents diagnosed with atrial fibrillation (AF) and eligible for oral anticoagulants who did not receive these drugs and to detail the conditions that physicians who decide not to prescribe anticoagulants take into account. DESIGN: Cross-sectional. SETTING: Nursing home. PARTICIPANTS: Nursing home residents with a history of AF (N = 1,085). MEASUREMENTS: Data were collected on clinical characteristics, geriatric syndromes, and antithrombotic regimen. Multivariate logistic regression was used to identify factors associated with nonprescription of anticoagulants. A standardized questionnaire was submitted to physicians in charge of patients with AF, to detail conditions associated with their medical decision not to prescribe anticoagulants. RESULTS: History of AF was present in 1,085 nursing home residents (10.1%), mean age 87, with a mean CHA2DS2-VASc score of 5.1 ± 1.4. Of these residents with AF, 544 (50.1%) did not receive anticoagulants. Recurrent falls (odds ratio (OR) = 4.9, 95% confidence interval (CI) = 2.4-9.9, P < .001), past history of bleeding (OR = 3.62, 95% CI = 1.54-8.51, P = .003), paroxysmal AF (OR = 3.5, 95% CI = 1.83-6.66, P < .001), and advanced age (OR = 1.1, 95% CI = 1.01-1.17, P = .02) were significantly associated with not prescribing anticoagulants. Recurrent falls (47%), cognitive impairment (22.6%), and advanced age (16.4%) were the main reasons for not prescribing anticoagulants. CONCLUSION: The prevalence of AF in a cohort of very old nursing home residents was 10%. Anticoagulation was prescribed in fewer than 50% of eligible cases despite high individual risk of stroke. Geriatric syndromes, especially falls and cognitive disorders, were the main reported contraindications for prescribing anticoagulants. Physicians caring for those residents wrongly thought that paroxysmal AF caused fewer thromboembolic events than permanent AF, which explains lower rates of anticoagulant prescription in individuals with paroxysmal AF.

A possible role for CSF turnover and choroid plexus in the pathogenesis of late onset Alzheimer's disease.

According to the amyloid theory, the appearance of amyloid-ß (Aß) deposits represents a pivotal event in late onset Alzheimer's disease (LOAD). Physiologically, Aß42 monomers are cleaned by capillary resorption, enzymatic catabolism, and cerebrospinal fluid (CSF) transport. Factors that promote the oligomerization of Aß42 must be specified. In vitro, these monomers spontaneously form neurotoxic oligomers whose rate increases with time suggesting that the stasis of CSF favors the oligomerization. In animals, experimental hydrocephalus generates CSF stasis followed by the appearance of amyloid deposits. In normal pressure hydrocephalus, amyloid deposits are common, especially in elderly patients, and the turnover decline has the same order of magnitude as in AD. In this disease, the effects of CSF stasis are potentiated by the decline in the ability of CSF to inhibit the formation of oligomers. CSF originates from choroid plexus (CP). In LOAD, the functions of secretion, synthesis, and transport of CP are impaired and this is related to morphological modifications. These impairments favor the decrease of CSF turnover, the diminished levels of transthyretin, a sequestering protein synthesized by CP, and the oligomerization of Aß42. They are potentiated by a reduced enzymatic catabolism and a decreased capillary reabsorption of Aß42, both alterations being related to age.

Reduced CSF turnover and decreased ventricular Aß42 levels are related.

BACKGROUND: The appearance of Aß42 peptide deposits is admitted to be a key event in the pathogenesis of Alzheimer's disease, although amyloid deposits also occur in aged non-demented subjects. Aß42 is a degradation product of the amyloid protein precursor (APP). It can be catabolized by several enzymes, reabsorbed by capillaries or cleared into cerebrospinal fluid (CSF). The possible involvement of a decrease in CSF turnover in A4ß2 deposit formation is up to now poorly known. We therefore investigated a possible relationship between a reduced CSF turnover and the CSF levels of the A4ß2 peptide.To this aim, CSF of 31 patients with decreased CSF turnover were studied. These patients presented chronic hydrocephalus communicating or obstructive, which required surgery (ventriculostomy or ventriculo-peritoneal shunt). Nine subjects had idiopathic normal pressure hydrocephalus (iNPH), and the other 22 chronic hydrocephalus from other origins (oCH).The Aß42 peptide concentration was measured by an ELISA test in 31 ventricular CSF samples and in 5 lumbar CSF samples from patients with communicating hydrocephalus. RESULTS: The 5 patients with lumbar CSF analysis had similar levels of lumbar and ventricular Aß42. A significant reduction in Aß42 ventricular levels was observed in 24 / 31 patients with hydrocephalus. The values were lower than 300 pg/ml in 5 out of 9 subjects with iNPH, and in 15 out of 22 subjects with oCH. CONCLUSION: The decrease of CSF Aß42 seems to occur independently of the surgical hydrocephalus aetiology. This suggests that a CSF reduced turnover may play an important role in the decrease of CSF Aß42 concentration.

Cerebrospinal fluid and blood flow in mild cognitive impairment and Alzheimer's disease: a differential diagnosis from idiopathic normal pressure hydrocephalus.

BACKGROUND: Phase-contrast magnetic resonance imaging (PC-MRI) enables quantification of cerebrospinal fluid (CSF) flow and total cerebral blood (tCBF) flow and may be of value for the etiological diagnosis of neurodegenerative diseases. This investigation aimed to study CSF flow and intracerebral vascular flow in patients with Alzheimer's disease (AD) and patients with amnesic mild cognitive impairment (a-MCI) and to compare the results with patients with idiopathic normal pressure hydrocephalus (NPH) and with healthy elderly volunteers (HEV). METHODS: Ten a-MCI and 9 mild AD patients were identified in a comprehensive neurological and neuropsychological assessment. They underwent brain MRI; PC-MRI pulse sequence was performed with the following parameters: two views per segment; flip angle: 25° for vascular flow and 20° for CSF flow; field-of-view (FOV): 14 × 14 mm²; matrix: 256 × 128; slice thickness: 5 mm; with one excitation for exams on the 3 T machine, and 2 excitations for the 1.5 T machine exams. Velocity (encoding) sensitization was set to 80 cm/s for the vessels at the cervical level, 10 or 20 cm/s for the aqueduct and 5 cm/s for the cervical subarachnoid space (SAS). Dynamic flow images were analyzed with in-house processing software. The patients' results were compared with those obtained for HEVs (n = 12), and for NPH patients (n = 13), using multivariate analysis. RESULTS: Arterial tCBF and the calculated pulsatility index were significantly greater in a-MCI patients than in HEVs. In contrast, vascular parameters were lower in NPH patients. Cervical CSF flow analysis yielded similar values for all four populations. Aqueductal CSF stroke volumes (in µl per cardiac cycle) were similar in HEVs (34 ± 17) and AD patients (39 ± 18). In contrast, the aqueductal CSF was hyperdynamic in a-MCI patients (73 ± 33) and even more so in NPH patients (167 ± 89). CONCLUSION: Our preliminary data show that a-MCI patients present with high systolic arterial peak flows, which are associated with higher mean total cerebral arterial flows. Aqueductal CSF oscillations are within normal range in AD and higher than normal in NPH. This study provides an original dynamic vision of cerebral neurodegenerative diseases, consistent with the vascular theory for AD, and supporting primary flow disturbances different from those observed in NPH.

Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?

First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia. Third, we review most of the large primary and secondary stroke prevention trials as well as the ACCESS acute stroke trial in which antihypertensive drugs were evaluated. With the exception of the secondary stroke prevention trial PRoFESS, most trials support the hypothesis that angiotensin II-increasing drugs confer specific blood pressure-independent brain ischemia protection when compared with angiotensin II-decreasing drugs or placebo. A careful analysis of the PRoFESS trial, however, reveals study design limitations, the main one being that diastolic BP (<80 mmHg) in the first month post-stroke may have been too low in at least one third of the population with baseline systolic blood pressure less than 130 mmHg, because a high dose of telmisartan was given after a very short post-stroke delay (median 15 days) without discontinuation of the baseline antihypertensive treatment.

Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors.

Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer's disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. beta-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating beta-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Abeta(42) into less toxic Abeta(40). Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Abeta(42) brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on beta-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.