Subjective Memory Complaints Research Articles

EEG evidence of compensatory mechanisms in preclinical Alzheimer's disease.

Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer's disease and to better understand the pathophysiological processes of disease progression. Preclinical Alzheimer's disease EEG changes would be non-invasive and cheap screening tools and could also help to predict future progression to clinical Alzheimer's disease. However, the impact of amyloid-β deposition and neurodegeneration on EEG biomarkers needs to be elucidated. We included participants from the INSIGHT-preAD cohort, which is an ongoing single-centre multimodal observational study that was designed to identify risk factors and markers of progression to clinical Alzheimer's disease in 318 cognitively normal individuals aged 70-85 years with a subjective memory complaint. We divided the subjects into four groups, according to their amyloid status (based on 18F-florbetapir PET) and neurodegeneration status (evidenced by 18F-fluorodeoxyglucose PET brain metabolism in Alzheimer's disease signature regions). The first group was amyloid-positive and neurodegeneration-positive, which corresponds to stage 2 of preclinical Alzheimer's disease. The second group was amyloid-positive and neurodegeneration-negative, which corresponds to stage 1 of preclinical Alzheimer's disease. The third group was amyloid-negative and neurodegeneration-positive, which corresponds to 'suspected non-Alzheimer's pathophysiology'. The last group was the control group, defined by amyloid-negative and neurodegeneration-negative subjects. We analysed 314 baseline 256-channel high-density eyes closed 1-min resting state EEG recordings. EEG biomarkers included spectral measures, algorithmic complexity and functional connectivity assessed with a novel information-theoretic measure, weighted symbolic mutual information. The most prominent effects of neurodegeneration on EEG metrics were localized in frontocentral regions with an increase in high frequency oscillations (higher beta and gamma power) and a decrease in low frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted symbolic mutual information in theta band. Neurodegeneration was associated with a widespread increase of median spectral frequency. We found a non-linear relationship between amyloid burden and EEG metrics in neurodegeneration-positive subjects, either following a U-shape curve for delta power or an inverted U-shape curve for the other metrics, meaning that EEG patterns are modulated differently depending on the degree of amyloid burden. This finding suggests initial compensatory mechanisms that are overwhelmed for the highest amyloid load. Together, these results indicate that EEG metrics are useful biomarkers for the preclinical stage of Alzheimer's disease.

Does informant-based reporting of cognitive symptoms predict amyloid positivity on positron emission tomography?

IntroductionResearchers are searching for clinical instruments to predict amyloid positivity for disease classification. Informant-based reports could detect disease status. This study compares subjective memory complaints captured by informant-based reports between positron emission tomography (PET)–positive and PET-negative patients and hypothesizes that amyloid PET positivity associates with increased informant-based cognitive complaints. MethodsNinety-eight amnestic mild cognitive impairment or mild dementia subjects were studied. Subjective report was captured by the informant-driven Alzheimer's Questionnaire (AQ) administered before PET. Differences in demographics and AQ score by diagnostic status and amyloid status were measured, and a receiver-operating characteristic curve was calculated. ResultsSixty-five mild cognitive impairment/Alzheimer's disease amyloid PET-positive and 33 amyloid PET-negative subjects were included. AQ was significantly higher (12.51 ± 4.95) for amyloid PET-positive subjects (9.06 ± 3.65; P = .001). ConclusionsAmyloid PET-positive subjects with Alzheimer's disease or mild cognitive impairment have more informant-based reports of cognitive decline, indicating utility for a brief informant measure.

Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions

ObjectiveValproic acid (VPA)-induced hyperammonemia (VIH), is an increase in blood ammonia levels without any alteration of hepatic enzymes, which can occur during VPA treatment. We aimed to determine the prevalence rate and the risk factors for VIH and its association with cognitive functions. MethodA prospective, cross-sectional study was conducted. Patients aged between 18 and 64 who were on VPA treatment and who diagnosed with mood disorders or epilepsy were enrolled in this study (n = 107). For cognitive assessment, Serial 7's and Subjective Memory Complaints Questionnaire (SMCQ) were used. Blood samples were collected for blood VPA and ammonia levels along with other laboratory tests. Results55,3% of the sample were considered as VIH. Blood ammonia level significantly correlates with VPA blood levels, total daily dose of VPA and total number of medications concurrently used, but no significant correlation was found between blood ammonia level and cognitive test scores. Gender, body weight, blood VPA levels and the total number of medications concurrently used significantly predicted blood ammonia levels (F(4,81) = 2670, p = 0,038, R2 = 0,116). ConclusionVIH is relatively high in our sample. There is a dose-dependent association between VPA and blood ammonia level. No association was found between cognitive functions and hyperammonemia however with some limitations. Future, prospective cohort studies are needed.

Physical exercise for prevention of dementia (EPD) study: background, design and methods

BackgroundSeveral observational studies have shown that exercise reduces the risk of cognitive decline; however, evidences from long-term, well-conducted, randomized controlled trials are scanty. The principal aim of this study is to verify whether a long-term program of multimodal supervised exercise improves the cognitive function and/or reduces the rate of cognitive decline in older adults at different degrees of risk for dementia.Methods/designEPD is a parallel group, double-blind, randomized controlled trial. Community-dwelling volunteers aged 50 years or more are being recruited from different community centers and screened for eligibility. Enrolled subjects are being divided in 3 groups: a) without subjective or objective cognitive impairment, b) with subjective memory complaints, and c) with mild cognitive impairments. Participants in each group (at least 180) are being randomly assigned (1:1) to an experimental group, performing a supervised training including aerobic and resistance exercises of moderate/high intensity, or to a control group. Primary outcome will be 48-months changes in Mini Mental State Examinations. Secondary outcomes will be changes in several cognitive tests including a composite cognitive score. Time points will be at baseline, and at 6, 12, 24, 36 and 48 months. Statistical analysis will be done as intention to treat, complete case and mixed model analysis.DiscussionEPD is the first trial to examine the effects of a long exercise program (48 months) on cognitive performances. If successful, this trial may provide evidence for using long-term and multimodal exercise interventions for dementia prevention programs in the aging population.Trial registrationThe study is registered at ClinicalTrials.gov with the code NCT02236416.

Subjective working and declarative memory in dementia and normal aging.

Subjective memory complaints are common in both elderly individuals and patients with dementia. This study investigated the power of subjective memory, divided into declarative and working memory, to differentiate between patients with dementia and normal elderly individuals. Two groups of participants, patients with dementia (n=117) and normal elderly individuals (n=117), individually matched with regard to age, gender, and education. All subjects had participated in the third wave of the HUNT population health survey in Nord-Trøndelag County in Norway and completed the Meta-Memory Questionnaire (MMQ) in the HUNT study. The MMQ was subdivided into two components, one associated with declarative memory (episodic and semantic) and the other with working memory. Patients with dementia reported significantly more subjective memory concerns than normal elderly individuals. The difference between working and declarative memory components was significantly greater in patients with dementia than in normal elderly individuals. This finding made it possible to differentiate patients with dementia from the normal elderly individuals. Mental and somatic health conditions did not significantly add power to differentiating the two groups. In clinical and research applications, subjective memory components could contribute to differentiation of patients with dementia and normal elderly individuals by using self-reported impairment in working memory, rather than declarative memory.

Effect of a 24-month physical activity program on brain changes in older adults at risk of Alzheimer's disease: the AIBL active trial

White matter hyperintensities (WMHs) are a risk factor for cognitive decline. Physical activity (PA) is associated with lower WMH. Whether long-term exposure to PA programs has beneficial effects on WMH progression in older adults with memory complaints and comorbid conditions has had limited exploration. This study explored whether a 24-month moderate-intensity PA intervention can delay the progression of WMH and hippocampus loss in older adults at risk for cognitive decline. Data acquired on magnetic resonance imaging were used to measure the progression of WMH and hippocampus loss. The results of this study showed no effect of intervention on either the primary outcome measure “WMH” or the secondary outcome measure “hippocampal volume.” In addition, neither beta amyloid status nor the adherence to the intervention had any effect on the outcome. In this cohort of subjective memory complaints and mild cognitive impairment participants with vascular risk factors, there was no effect of long-term moderate-intensity PA on WMH or hippocampal loss.

Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

IntroductionBlood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. MethodsWe investigated whether plasma concentrations of the Aβ1–40/Aβ1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. ResultsThe receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ1–40/Aβ1–42 ratio. The accuracy is not affected by the apolipoprotein E (APOE) ε4 allele, sex, or age. DiscussionOur results encourage an independent validation cohort study to confirm the indication that the plasma Aβ1–40/Aβ1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

The Utility of Subset of Subjective Memory Complaint Questionnaire and Mini-Mental State Examination for Dementia Screening

Objective：Purpose of this study was to assess the potential added values of Subjective Memory Complaint Questionnaire (SMCQ) combined with Mini-Mental State Examination (MMSE) in developing a brief screening battery to improve the early detection rate of dementia in community setting. Methods：Non-depressed community-dwelling Korean elderly aged 65 years and older who 945 randomly selected and 734 voluntarily involved were recruited. Dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Diagnostic ability of 10 point SMCQ subscale for everyday memory (SMCQ-E) for dementia was eval- uated. Additive values of SMCQ-E combined with MMSE for dementia screening and the economic benefits of SMCQ-E and its combination with MMSE were also evaluated. Results：Overall area under the curve values of SMCQ-E were 0.605 (0.565-0.646) for nonrandom sample and 0.836 (0.783-0.890) for random sample. When SMCQ-E was combined with MMSE using ‘AND’ rule, accuracy, specificity, positive predictive values and positive likelihood ratio were increased than those of MMSE. While SMCQ-E was combined the MMSE using ‘OR’ rule, sensitivity and negative predictive values were increased and negative likelihood ratio were decreased than those of SMCQ-E and MMSE. When SMCQ-E and MMSE combined with AND rule, total cost for dementia screening was reduced to about 80% compared to MMSE single use model. Conclusion：Results of this study showed that brief SMCQ-E and its combination with MMSE could be used to dementia screening with cost effective manner.

Interrelationships between depression, exercise and subjective memory complaints

ObjectiveThe objective of this study was to evaluate the interrelationships between habitual engagement in exercise, subjective memory complaints (SMC) and depression symptomology. MethodsA sample (N=192) of young adults (Mage=22 y; college students) completed a survey evaluating their current exercise (Physical Activity Vital Signs questionnaire), SMC (Prospective-Retrospective Memory Questionnaire), and depression levels (PHQ-9 questionnaire). ResultsPhysical activity was not associated with prospective (β=0.87, P=0.28) or retrospective (β=0.07, P=0.92) SMC. However, those with higher depression symptomology had worse prospective (β=−0.27, P<0.001) and retrospective (β=−0.25, P<0.001) SMC. Lastly, those meeting physical activity guidelines (vs. not) had lower depression symptomology (β=−1.91, P=0.02). ConclusionThis study provides suggestive evidence that, among young adults, higher levels of depression symptomology are associated with worse SMC. Further, habitual engagement in exercise was not directly associated with SMC, but may indirectly relate to SMC via its relationship with depression.

Development and effectiveness of virtual interactive working memory training for older people with mild cognitive impairment: a single-blind randomised controlled trial.

memory training is a potential intervention for retaining memory and reducing dementia risk in older adults with mild cognitive impairment (MCI). this study examined the effect of virtual interactive working memory training (VIMT) in older adults with MCI. single-blind, two-arm parallel-group, randomised controlled design. retirement homes, institutions, and communities. a total of 66 older adults with MCI were recruited (mean age: 78.5 ± 7.6 years). participants were randomly assigned to the experimental group (VIMT, n = 33) or active control group (n = 33). The VIMT program used the CogniPlus (includes four training modules). Both groups attended 45 min sessions 3 times per week, a total of 36 sessions. The primary outcome was working memory; secondary outcomes were immediate memory, delayed memory, subjective memory complaints and global cognitive function. All variables were measured at pre-test, post-test, and 3-month follow-up. between group, the effect of working memory adjusted mean difference by 1.75 (95% CI: 0.56 to 2.94; P < 0.01) at post-test. The results were analysed by a generalised estimating equation, which indicated that VIMT group significantly improved working memory at post-test (P = 0.01) relative to the active control group. the applied VIMT program can enable older adults with MCI to maintain their working memory and reduce the rate of cognitive deterioration. This trial was registered on ClinicalTrials.gov (no.: NCT02462135).

Effects of Subjective Memory Complaints (SMCs) and Social Capital on Self-Rated Health (SRH) in a Semirural Malaysian Population.

Subjective memory complaints (SMCs) and social capital were known to be related to self-rated health (SRH). Despite this, no studies have examined the potential interaction of SMC and social capital on SRH. Using data from a cross-sectional health survey of men and women aged 56 years and above (n = 6,421), we examined how SMCs and social capital explained SRH in a population of community-dwelling older adults in a semirural area in Malaysia. We also evaluated whether SRH's relationship with SMCs is moderated by social capital. The association of SMC and social capital with poor SRH was investigated using multivariable logistic regression. Social capital (OR = 0.86, 95% CI = 0.82–0.89), mild SMC (OR = 1.70, 95% CI = 1.50–1.94), and moderate SMC (OR = 1.90, 95% CI = 1.63–2.20) were found to be associated with poor SRH after adjustment for sociodemographic factors and depression in the initial regression model. SMC was found to have partial interaction effects with social capital which was included in the subsequent regression model. Unlike individuals with no SMC and mild SMC, those who reported moderate SMC did not show decreasing probabilities of poor SRH despite increasing levels of social capital. Nevertheless, this analysis suggests that social capital and SMC are independent predictors of poor SRH. Further research needs to be targeted at improving the understanding on how social capital and SMC moderate and interact with the perception of health in older adults.

Self- and Informant-Reported Subjective Memory Complaints: Association with Depression, Cognitive Impairment, and Decline (S13.006)

Self- and Informant-Reported Subjective Memory Complaints: Association with Depression, Cognitive Impairment, and Decline (S13.006)

Subjective ratings of cognitive and emotional functioning in patients with mild cognitive impairment and patients with subjective memory complaints but normal cognitive functioning

ABSTRACTIn a retrospective chart review, 39 patients referred for a clinical neuropsychological examination were identified as showing either mild cognitive impairment of the amnestic type (MCI-A; N = 21) or subjective memory complaints but with normal memory function (SMC; N = 18). During the clinical interview, patients and informants were routinely asked to make subjective ratings regarding the patient’s cognitive and affective functioning in everyday life. The purpose of this study was to determine whether these two patient groups (and their informants) significantly differed in their subjective reports about level of cognitive and affective difficulties. It was predicted that SMC patients would report higher levels of cognitive and emotional dysfunction than MCI-A patients. It was further predicted that MCI-A patients would underreport cognitive difficulties (compared to informant reports); SMC patients would demonstrate the opposite pattern. Results supported these predictions and suggest that routine assessment of subjective experiences of patients in conjunction with informant ratings may aid clinical diagnosis, particularly when the primary complaint is a decline in memory.

Subjective memory complaints are not increased in type 2 diabetes: A matched cohort study

Type 2 diabetes is associated with several cognitive syndromes but whether this generates subjective complaints remains unclear. In an age- and sex-matched study, subjective memory complaints were neither more prevalent nor more severe in those with type 2 diabetes, despite them having lower Mini-Mental State Examination scores.

ASSOCIATION OF DEPRESSIVE SYMPTOMS AND SUBJECTIVE MEMORY COMPLAINTS WITH THE INCIDENCE OF COGNITIVE IMPAIRMENT IN OLDER ADULTS WITH HIGH BLOOD PRESSURE.

High blood pressure is a relevant risk factor for vascular damage, leading to development of depressive symptoms and dementia in older adults. Moreover, subjective memory complaints are recognized as an early marker of cognitive impairment. However, it has been established that subjective memory complaints could also be a reflection of depressive symptoms. The objective of this paper is to assess the impact of depressive symptoms and subjective memory complaints on the incidence of cognitive impairment in older adults with high blood pressure. This is a secondary analysis of the Mexican Health and Aging Study, a representative cohort composed by individuals aged ≥ 50 years. Participants with cognitive impairment in 2012 were excluded since the outcome was incident cognitive impairment in 2015. Four groups were created according to depressive symptomatology and subjective memory complaints status, analyses were stratified according to blood pressure status. The odds incident cognitive impairment was estimated through logistic regression models. A total of 6,327 participants were included, from which 6.44% developed cognitive impairment. No differences were seen regarding the development of cognitive impairment in participants without high blood pressure. However, increased risk was evident in those with both high blood pressure and depressive symptoms (OR=2.1, 95% CI 1.09 - 4.09, p =0.026) as with high blood pressure, depressive symptoms and subjective memory complaints (OR=1.91, 9% CI 1.4 - 3.2, p= 0.001). Individuals with high blood pressure have a higher risk of developing incident cognitive impairment when depressive symptoms and/or subjective memory complaints are present. Our results suggest that a sequence of events related to altered cerebral vascular dynamics is possible.

Brain structural changes after multi-strategic metamemory training in older adults with subjective memory complaints: A randomized controlled trial.

BackgroundMetamemory is the process of monitoring and controlling one's memory. Improving metamemory may reduce the memory problem in old age. We hypothesized that metamemory training (MMT) would improve cognition in older adults with subjective memory complaints and change the brain region related to metacognition.MethodWe recruited and randomized older adults to the multi‐strategic memory training of 10 weekly 90‐min sessions, based on the metamemory concept or usual care. Cognitive tests including the Elderly Verbal Learning Test, Simple Rey Figure Test, Digit Span, Spatial Span, Categorical Fluency, and the Boston Naming Test were done in 201 participants, together with magnetic resonance imaging (MRI) in 49 participants before and after training.ResultsA total of 112 in the training group and 89 in the control group participated. The training group had a significant increase in long‐term delayed free recall, categorical fluency, and the Boston Naming test. In MRI, the mean diffusivity of the bundles of axon tracts passing from the frontal lobe to the posterior end of the lateral sulcus decreased in the training group.ConclusionThese results indicate that the MMT program has a positive impact on enhancing older people’ cognitive performance. Improved white matter integrity in the anterior and posterior cerebrum and increased cortical thickness of prefrontal regions, which related to metacognition, possibly suggest that the effects of the MMT would be induced via the enhancement of cognitive control.

Vascular risk modulates the relationship between cerebral amyloid deposition and subjective memory complaints.

PurposeWe aimed to investigate the relationships of cerebral amyloid beta (Aβ) deposition and neurodegeneration (ND) with subjective memory complaints (SMCs) in cognitively normal (CN) individuals, focusing specially on the modulating effects of vascular risk (VR) on those relationships.Participants and methodsA total of 230 CN elderly individuals underwent comprehensive clinical assessments including the Subjective Memory Complaints Questionnaire (SMCQ), VR assessment, and multimodal brain imaging including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose-PET, and magnetic resonance imaging.ResultsWe found a significant overall positive association between cerebral Aβ retention and SMCQ score. In addition, we found a significant cerebral Aβ retention × VR interaction effect on the SMCQ score. Subgroup analyses showed that the Aβ–SMC association was found only in VR-negative, and not in VR-positive, individuals. We found no relationship between ND and SMCQ.ConclusionOur findings suggest that SMC in CN elderly individuals reflects early accumulation of Aβ in the brain. Given the modulating effect of VR on the Aβ–SMC relationship, SMC can be used as a meaningful marker of early Aβ deposition in individuals without VR.

Very long-term outcome in resected and non-resected patients with temporal lobe epilepsy with medial temporal lobe sclerosis: A multiple case-study

PurposeTo investigate the very long-term (i.e., ≥15 years) seizure, cognitive and psycho-social outcomes in resected patients (RP) with TLE compared to control patients not having undergone epilepsy surgery. MethodsWe applied a multiple case-study design including three non-resected patients (NRP) who were compared to a group of six RP. The latter were matched to the NRP according to clinical-demographic data. Outcome measures were various seizure, cognitive, and psycho-social variables. ResultsPatients were 56–72 years old. Seizure and AED outcome was more favourable among RP. RP reported better self-perceived overall health but higher subjective memory complaints. Upon formal neuropsychological testing, RP presented with lower verbal memory scores. Very long-term memory decline was evident in left-sided RP with good baseline memory scores, while RP with lower baseline performance, right-sided RP and NRP remained stable. Seizure-freedom had remarkable effects on the relationship between objective and subjective outcome: seizure-free patients, in general, subjectively reported the best psychosocial and cognitive outcome – irrespective of neuropsychological test results. ConclusionOur study suggests positive effects of TLE surgery in the very long-term course of ≥15 years postoperatively. Long-term seizure-freedom appears to have the strongest impact on patients’ subjectively perceived psycho-social and cognitive outcome and may even outweigh actual memory disturbances and/or decline. Overall, our data do not support the assumption of a generally accelerated cognitive decline in patients with TLE.

Normative data and validation of the Italian translation of the Working Memory Questionnaire (WMQ)

Reliable and valid measures are necessary to assess subjective working memory complaints that can be distinct from objective memory performance. The Working Memory Questionnaire (WMQ) is a self-administered scale proposed by Vallat-Azouvi. It assesses the three different working memory domains (memory storage, attention, and executive functions) in accordance with Baddeley’s working memory model. Our aim was to propose an Italian translation of the WMQ and provide normative data. We collected normative data from 697 healthy Italian participants aged between 18 and 88 years. Percentiles and cutoff scores, taking into consideration age, gender, and education, were provided for the WMQ total scores and the three separate domains. The performance on the WMQ was influenced by age and education. In particular, age and education affected self-perceived working memory efficacy. Our data demonstrate a significant correlation between the WMQ and paper-and-pencil tests assessing working memory, attention, and executive functions. This study provides normative data that have been adjusted for relevant demographics and percentile grids in an Italian population. The results are in line with a previous French study that also supported the use of the WMQ as a valid prescreening instrument for working memory deficits in clinical practice.

Discontinuation of Antihypertensive Medication, Cognitive Complaints, and Incident Dementia

ObjectivesTo evaluate whether discontinuation of antihypertensive medication in community-dwelling older people is associated with a reduction in memory complaints and/or incident dementia. DesignProspective observational cohort study within the Prevention of Dementia by Intensive Vascular Care (preDIVA) trial. Setting and ParticipantsCommunity-dwelling participants (aged 70-78 years at baseline) who underwent 2-yearly assessments during 6-8 years of follow-up. MeasuresCox regression analyses of the relation between discontinuation of antihypertensive medication during the study and change in subjective memory complaints, incident dementia, and mortality. ResultsDementia occurred more often in participants discontinuing antihypertensive treatment (13.4% vs 6.2%, P = .02); mortality was similar (16.5% vs 13.9%, P = .52). Discontinuation of antihypertensive medication was associated with a double dementia hazard [hazard ratio (HR) (95% confidence interval) = 2.15 (1.15-4.03)], which somewhat attenuated after adjustment for sex, blood pressure, number of antihypertensives and other medications [HR = 1.92 (1.01-3.65)], and additionally for stroke, cardiovascular disease, diabetes, smoking, memory complaints, and MMSE score [HR = 1.79 (0.93-3.44)]. Antihypertensive discontinuation was associated with an approximately 50% higher hazard of dementia and/or mortality combined [HR = 1.58 (1.04-2.40); model 2: HR = 1.64 (1.07-2.51); model 3: HR = 1.49 (0.96-2.30)]. Antihypertensive discontinuation was not associated with change in memory complaints [odds ratio (95% confidence interval) = 0.96 (0.55-1.67)]. Subgroup and sensitivity analyses addressing possible sources of bias and confounding gave similar results. Conclusions/ImplicationsOur results suggest that antihypertensive withdrawal in community-dwelling older people does not preserve cognition and may in fact increase dementia risk. This is not due to reduced mortality as competing risk. Additional analyses suggest results are unlikely to be explainable by confounding, reverse causality, or observational biases. Studies with person-specific reasons for antihypertensive discontinuation may be able to exclude reverse causality completely. Given the beneficial effects of antihypertensive medication on cardiovascular risk, observational data may be the best currently obtainable on the pressing issue of when withdrawal of antihypertensives in older people is acceptable and what consequences need to be weighed.