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Background Blood pressure variability (BPV) in midlife increases risk of late-life dementia, but the impact of BPV on the cognition of adults who have already reached older ages free of major cognitive deficits is unknown. We examined the risk of incident dementia and cognitive decline associated with long-term, visit-to-visit BPV in a post hoc analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Methods and Results ASPREE participants (N=19 114) were free of dementia and significant cognitive impairment at enrollment. Measurement of BP and administration of a standardized cognitive battery evaluating global cognition, delayed episodic memory, verbal fluency, and processing speed and attention occurred at baseline and follow-up visits. Time-to-event analysis using Cox proportional hazards regression models were used to calculate hazard ratios (HR) and corresponding 95% CI for incident dementia and cognitive decline, according to tertile of SD of systolic BPV. Individuals in the highest BPV tertile compared with the lowest had an increased risk of incident dementia and cognitive decline, independent of average BP and use of antihypertensive drugs. There was evidence that sex modified the association with incident dementia (interaction P =0.02), with increased risk in men (HR, 1.68; 95% CI, 1.19-2.39) but not women (HR, 1.01; 95% CI, 0.72-1.42). For cognitive decline, similar increased risks were observed for men and women (interaction P =0.15; men: HR, 1.36; 95% CI, 1.16-1.59; women: HR, 1.14; 95% CI, 0.98-1.32). Conclusions High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583; isrctn.com. Identifier: ISRCTN83772183.

Background: The neurocognitive effect of statins in older adults remain uncertain., Objectives: The aim of this study was to investigate the associations of statin use with cognitive decline and incident dementia among older adults., Methods: This analysis included 18,846 participants ≥65 years of age in a randomized trial of aspirin, who had no prior cardiovascular events, major physical disability, or dementia initially and were followed for 4.7 years. Outcome measures included incident dementia and its subclassifications (probable Alzheimer's disease, mixed presentations); mild cognitive impairment (MCI) and its subclassifications (MCI consistent with Alzheimer's disease, other MCI); and changes in domain-specific cognition, including global cognition, memory, language and executive function, psychomotor speed, and the composite of these domains. Associations of baseline statin use versus nonuse with dementia and MCI outcomes were examined using Cox proportional hazards models and with cognitive change using linear mixed-effects models, adjusting for potential confounders. The impact of statin lipophilicity on these associations was further examined, and effect modifiers were identified., Results: Statin use versus nonuse was not associated with dementia, MCI, or their subclassifications or with changes in cognitive function scores over time (p > 0.05 for all). No differences were found in any outcomes between hydrophilic and lipophilic statin users. Baseline neurocognitive ability was an effect modifier for the associations of statins with dementia (p for interaction < 0.001) and memory change (p for interaction = 0.02)., Conclusions: In adults ≥65 years of age, statin therapy was not associated with incident dementia, MCI, or declines in individual cognition domains. These findings await confirmation from ongoing randomized trials., Competing Interests: Funding Support and Author Disclosures The ASPREE trial was supported by a grant (U01AG029824) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency. Dr. Tonkin has received research support or honoraria from Merck, Pfizer, and Amgen; has received support from Bayer for materials in the ASPREE trial; and has received National Health and Medical Research Council (NHMRC) grant support for the STAREE trial. Dr. Zoungas has received NHMRC and Australian Heart Foundation research funding as the principal investigator of the STAREE trial; and has received payment to the institution (Monash University) from Eli Lilly Australia, Boehringer-Ingelheim, Merck Sharp & Dohme Australia, AstraZeneca, Novo Nordisk, Sanofi, and Servier for consultancy work outside the submitted work. Dr. Nelson has received honoraria from Sanofi and Amgen; has received support from Bayer for materials in ASPREE; and has received NHMRC grant support for STAREE. Dr. Reid is funded through a NHMRC Principal Research Fellowship. Dr. Shah serves as a noncompensated member of the board of directors of the Alzheimer’s Association, Illinois Chapter; receives research support to his institution, Rush University Medical Center, for his role as a site principal investigator or site subinvestigator for industry-initiated clinical trials and research studies of AD sponsored by Amylyx Pharmaceuticals, Eli Lilly, Genentech, Lundbeck, Merck, Navidea Biopharmaceuticals, Novartis Pharmaceuticals, Roche Holdings, and Takeda Development Center Americas; and is a member of the steering committee of the PREVENTABLE clinical trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (HRQoL) has been shown to predict adverse health outcome in the general population., Objective: We examined the cross-sectional association between HRQoL and cognitive performance at baseline. Next, we explored whether baseline HRQoL predicted 5-year incident cognitive decline and dementia and whether there were gender differences., Methods: 19,106 community-dwelling participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, aged 65-98 years, free of major cognitive impairments, and completed the HRQoL 12-item short-form (SF-12) at baseline (2010-2014), were followed until June 2017. The physical (PCS) and mental component scores (MCS) of SF-12 were calculated. The cognitive tests were assessed at baseline, year 1, 3, 5, and 7 or close-out visit. Cognitive decline was defined as > 1.5 SD drop from baseline on any of the cognitive tests. Dementia was adjudicated according to DSM-IV criteria. Linear and Cox proportional-hazards regressions were used to examine the cross-sectional and longitudinal associations respectively., Results: At baseline, higher PCS and MCS were associated with better cognition. Over a median 4.7-year follow-up, higher MCS was associated with a reduced risk of cognitive decline and dementia (12% and 15% respectively, per 10-unit increase) and a 10-unit higher PCS was associated with a 6% decreased risk of cognitive decline. PCS did not predict dementia incidence. Findings were not different by gender., Conclusion: Our study found that higher HRQoL, in particular MCS, predicted a reduced risk of cognitive decline and dementia over time in community-dwelling older people.

Unexpected cognitive lucidity and communication in patients with severe dementias, especially around the time of death, have been observed and reported anecdotally. Here, we review what is known about this phenomenon, related phenomena that provide insight into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We conclude that paradoxical lucidity, if systematically confirmed, challenges current assumptions and highlights the possibility of network-level return of cognitive function in cases of severe dementias, which can provide insight into both underlying neurobiology and future therapeutic possibilities., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that late-life depression is associated with dementia-related pathology., Method: Older participants (n = 1,965) in 3 longitudinal clinical-pathologic cohort studies who had no cognitive impairment at baseline underwent annual clinical evaluations for a mean of 8.0 years (SD = 5.0). The authors defined depression diagnostically, as major depression during the study period, and psychometrically, as elevated depressive symptoms during the study period, and established their relation to cognitive outcomes (incident dementia, rate of cognitive decline). A total of 657 participants died and underwent a uniform neuropathologic examination. The authors estimated the association of depression with 6 dementia-related markers (tau tangles, beta-amyloid plaques, Lewy bodies, hippocampal sclerosis, gross and microscopic infarcts) in logistic regression models., Results: In the full cohort, 9.4% were diagnosed with major depression and 8.6% had chronically elevated depressive symptoms, both of which were related to adverse cognitive outcomes. In the 657 persons who died and had a neuropathologic examination, higher beta-amyloid plaque burden was associated with higher likelihood of major depression (present in 11.0%; OR = 1.392, 95% CI = 1.088, 1.780) but not with elevated depressive symptoms (present in 11.3%; OR = 0.919, 95% CI = 0.726, 1.165). None of the other pathologic markers was related to either of the depression measures. Neither dementia nor antidepressant medication modified the relation of pathology to depression., Conclusion: The results do not support the hypothesis that major depression is associated with dementia-related pathology., (PsycINFO Database Record (c) 2016 APA, all rights reserved.)

Background: Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals. Methods: 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test–Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke. Results: During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants. Conclusions: These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention. [ABSTRACT FROM AUTHOR]

Study Objective: What is the association between anticholinergic burden and specific domains of cognitive function in older adults who are initially without major cognitive impairment? Design: Post‐hoc analysis of longitudinal observational data from the ASPirin in Reducing Events in the Elderly (ASPREE) study. Patients: 19,114 participants from Australia and the United States aged 70 years and older (65 years and older for US minorities) were recruited and followed for a median of 4.7 years. At enrollment, participants were free of known cardiovascular disease, major physical disability, or dementia. Measurements: Cognitive assessments administered at baseline and biennially at follow‐up visits included the Modified Mini‐Mental State examination (3MS), Hopkins Verbal Learning Test–Revised (HVLT‐R) delayed recall, Controlled Oral Word Association Test (COWAT), and Symbol Digit Modalities Test (SDMT). Anticholinergic burden was calculated at baseline using the Anticholinergic Cognitive Burden (ACB) scale and grouped as scores of 0 (no burden), 1‐2 (low to moderate), or 3+ (high). Main Results: Linear mixed effects models were used to assess the relationship between ACB score and cognition over time. After adjusting for sex, age, education, minority status, smoking status, hypertension, diabetes, depression, chronic kidney disease, country, and frailty, participants with a high ACB score had worse performance over time for 3MS (Adjusted [Adj] B=‐0.092, P=0.034), HVLT‐R delayed recall (Adj B=‐0.104, P<0.001), COWAT (Adj B=‐0.151, P<0.001), and SDMT (Adj B=‐0.129, P=0.026), than participants with an ACB score of 0. A low to moderate ACB score was also associated with worse performance over time for HVLT‐R delayed recall (Adj B=‐0.037, P=0.007) and COWAT (Adj B=‐0.065, P=0.003), compared to those with no ACB. Conclusions: Anticholinergic burden predicts worse cognitive function over time in initially dementia‐free older adults, particularly for executive function (COWAT) and episodic memory (HVLT‐R). [ABSTRACT FROM AUTHOR]

Background: Poor social health is prevalent in older adults and may be associated with worse cognition, and increased dementia risk. The aim of this study was to determine whether social isolation, social support and loneliness are independently associated with cognitive function and incident dementia over 5 years in older adults, and to investigate potential gender differences.Methods: Participants were 11,498 community-dwelling relatively healthy Australians aged 70-94, in the ASPREE Longitudinal Study of Older Persons (ALSOP). Social isolation, social support, loneliness and cognitive function were assessed through self-report. Outcomes examined were cognitive decline (>1.5 SD decline in cognitive performance since baseline) and incident dementia (adjudicated according to DSM-IV criteria).Results: Most participants self-reported good social health (92%) with very few socially isolated (2%), with low social support (2%) or lonely (5%). Among women, social isolation and low social support were consistently associated with lower cognitive function (e.g., social support and cognition β = -1.17, p < 0.001). No consistent longitudinal associations were observed between baseline social health and cognitive decline (over median 3.1 years) or incident dementia (over median 4.4 years; social isolation: HR = 1.00, p = 0.99; low social support: HR = 1.79, p = 0.11; loneliness: HR = 0.72, p = 0.34 among women and men).Conclusion: Our study provides evidence that social isolation and a low social support are associated with worse cognitive function in women, but not men. Social health did not predict incident cognitive decline or dementia, but we lacked power to stratify dementia analyses by gender. [ABSTRACT FROM AUTHOR]

The Hopkins Verbal Learning Test-Revised (HVLT-R) provides a measure of verbal learning and memory. The aim of this study was to provide normative performance data on the HVLT-R for community-dwelling older individuals according to ethno-racial group, age, gender, and years of completed education, in Australia and the U.S. The ASPirin in Reducing Events in the Elderly (ASPREE) study recruited 19,114 generally healthy community dwelling individuals aged 70 years and over (65 years and over for U.S minorities), who were without a diagnosis of dementia and scored above 77 on the modified Mini-Mental State (3MS) examination. Included in the analysis presented here were 16,251 white Australians, and in the U.S. 1,082 white, 894 African American and 314 Hispanic/Latino individuals at baseline. Performance on each of the components of the HVLT-R (trials 1–3, total, learning, delayed recall, delayed recognition, percentage retention and recognition discrimination index [RDI]) differed by demographic variables. In country and ethno-racial stratified analyses, female gender, younger age and higher education were significantly associated with better total recall, delayed recall and RDI. Among white Australians these characteristics were also associated with better retention. Age, education and gender-specific reference values across ethno-racial categories were determined. Ethno-racial, age, gender and education-stratified normative data from this large cohort of community-dwelling older individuals will serve as important reference standards in Australia and the U.S. to assess cognition in older individuals. [ABSTRACT FROM AUTHOR]

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence for all‐cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non‐APOE variants. During a median 4.5 years of follow‐up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3‐fold increased dementia risk and 1.4/1.8‐fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4‐fold dementia risk versus low (CI 1.04–1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96–1.22, p = 0.18). Incidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not. [ABSTRACT FROM AUTHOR]

Unexpected cognitive lucidity and communication in patients with severe dementias, especially around the time of death, have been observed and reported anecdotally. Here, we review what is known about this phenomenon, related phenomena that provide insight into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We conclude that paradoxical lucidity, if systematically confirmed, challenges current assumptions and highlights the possibility of network‐level return of cognitive function in cases of severe dementias, which can provide insight into both underlying neurobiology and future therapeutic possibilities. [ABSTRACT FROM AUTHOR]

Objective: To present normative performance data on the Modified Mini-Mental State (3MS) examination for healthy community-dwelling older individuals according to gender, age, education level, and ethno-racial group. Method: More than 19,000 generally healthy older men and women without a diagnosis of dementia were recruited from the general population in Australia and the U.S. for the ASPirin in Reducing Events in the Elderly (ASPREE) study. The 3MS exam was administered as part of the baseline screening and individuals scoring above 77 were eligible to participate. Results: The sample comprised 16,360 Australian whites, 1080 U.S. whites, 895 African-Americans and 316 Hispanic/Latinos. The median age of participants was 74 years (range 65–98), with an average of 12 years of education and 56% were female. Increasing age and fewer years of completed education were associated with lower scores on the 3MS. Women scored higher than men in most age and education categories. Differences across ethno-racial groups were found. With factor analysis, four factors were identified which accounted for 35% of the between-person variance in 3MS scores for white Australians. Conclusions: This large cohort of older individuals provides some of the most comprehensive 3MS normative data to be generated for whites (Australian and U.S.), Hispanic/Latinos and African-Americans, by age, gender, and educational attainment. These findings will serve as important reference standards for monitoring cognitive function in generally healthy older individuals, becoming increasingly important as this fraction of the population increases. [ABSTRACT FROM AUTHOR]

Background: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes.Objective: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm.Methods: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations.Results: In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the co-primary outcome of Souvenir I (Wechsler memory scale delayed recall). No effect was shown on cognition in patients with mild-to-moderate AD (S-Connect). The number needed to treat (6 and 21 for Souvenir I and II, respectively) and high number needed to harm values indicate a favorable harm:benefit ratio for Souvenaid versus control in patients with mild AD.Conclusions: The favorable safety profile and impact on outcome measures converge to corroborate the putative mode of action and demonstrate that Souvenaid can achieve clinically detectable effects in patients with early AD. [ABSTRACT FROM AUTHOR]

Three systematic reviews in this issue have summarized evidence on brief cognitive tests to distinguish Alzheimer dementia from mild cognitive impairment or normal cognition, biomarker testing for neuropathologic Alzheimer disease, and prescription drugs and supplements in the treatment of Alzheimer dementia. The editorialists discuss the findings and hope for more options for preventing, diagnosing, and treating Alzheimer dementia. [ABSTRACT FROM AUTHOR]