Reviewing the research presented in this article, it is evident that from an epidemiological perspective, it is important to evaluate the extent to which findings of sex and gender differences in ...Alzheimer's dementia (AD) are due to differences in longevity, survival bias, and comorbidities. Medical, genetic, psychosocial, and behavioral factors, in addition to hormonal factors, can differentially affect the risk and progression of AD in women versus men. Further, evaluation of sex differences in AD progression and the trajectory of change in cognitive function, neuroimaging, cerebrospinal fluid (CSF), and blood-based biomarkers of AD is needed. Finally, identifying sex differences in AD biomarkers and change across the lifespan is critical for the planning of prevention trials to reduce the risk of developing AD.
OBJECTIVEWe investigated different dimensions of subjective cognitive decline (SCD) to determine which was the best prognostic risk factor for incident mild cognitive impairment (MCI) among ...cognitively unimpaired participants.
METHODSWe included 1,167 cognitively unimpaired participants, aged 70 to 95 years, from the Mayo Clinic Study of Aging based on 2 concurrent SCD scales (part of the Blessed memory test and the 39-item Everyday Cognition ECog scale, which included a validated 12-item derivative) and a single question assessing worry about cognitive decline. We evaluated multiple ways to dichotomize scores. In continuous models, we compared average scores on 4 ECog domains and multidomain (39- and 12-item) ECog scores. Cox proportional hazards models were used to assess the association between each measure and risk of MCI in models adjusted for objective memory performance, depression, anxiety, sex, APOE ε4 carriership, and medical comorbidities.
RESULTSIt was possible to select a substantial group of participants (14%) at increased risk of incident MCI based on combined baseline endorsement of any consistent SCD on the ECog (any item scored ≥3; 12-item ECog hazard ratio HR 2.17 95% confidence interval 1.51–3.13) and worry (HR 1.79 1.24–2.58) in an adjusted model combining these dimensions. In continuous models, all ECog domains and the multidomain scores were associated with risk of MCI with a small advantage for multidomain SCD (12-item ECog HR 2.13 1.36–3.35 per point increase in average score). Information provided by the informant performed comparable to self-perceived SCD.
CONCLUSIONPrognostic value of SCD for incident MCI improves when both consistency of SCD and associated worry are evaluated.
To conduct a systematic review of all studies to determine whether there is an association between the Mediterranean diet (MeDi) and cognitive impairment.
We conducted a comprehensive search of the ...major databases and hand-searched proceedings of major neurology, psychiatry, and dementia conferences through November 2012. Prospective cohort studies examining the MeDi with longitudinal follow-up of at least 1 year and reporting cognitive outcomes (mild cognitive impairment MCI or Alzheimer's disease AD) were included. The effect size was estimated as hazard-ratio (HR) with 95% confidence intervals (CIs) using the random-effects model. Heterogeneity was assessed using Cochran's Q-test and I2-statistic.
Out of the 664 studies screened, five studies met eligibility criteria. Higher adherence to the MeDi was associated with reduced risk of MCI and AD. The subjects in the highest MeDi tertile had 33% less risk (adjusted HR = 0.67; 95% CI, 0.55-0.81; p < 0.0001) of cognitive impairment (MCI or AD) as compared to the lowest MeDi score tertile. Among cognitively normal individuals, higher adherence to the MeDi was associated with a reduced risk of MCI (HR = 0.73; 95% CI, 0.56-0.96; p = 0.02) and AD (HR = 0.64; 95% CI, 0.46-0.89; p = 0.007). There was no significant heterogeneity in the analyses.
While the overall number of studies is small, pooled results suggest that a higher adherence to the MeDi is associated with a reduced risk of developing MCI and AD, and a reduced risk of progressing from MCI to AD. Further prospective-cohort studies with longer follow-up and randomized controlled trials are warranted to consolidate the evidence. Systematic review registration number: PROSPERO 2013: CRD42013003868.
Abstract The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have ...significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.
We examined and compared plasma phospho-tau181 (pTau181) and total tau: (1) across the Alzheimer's disease (AD) clinical spectrum; (2) in relation to brain amyloid β (Aβ) positron emission tomography ...(PET), tau PET, and cortical thickness; and (3) as a screening tool for elevated brain Aβ.
Participants included 172 cognitively unimpaired, 57 mild cognitively impaired, and 40 AD dementia patients with concurrent Aβ PET (Pittsburgh compound B), tau PET (AV1451), magnetic resonance imaging, plasma total tau, and pTau181.
Plasma total tau and pTau181 levels were higher in AD dementia patients than those in cognitively unimpaired. Plasma pTau181 was more strongly associated with both Aβ and tau PET. Plasma pTau181 was a more sensitive and specific predictor of elevated brain Aβ than total tau and was as good as, or better than, the combination of age and apolipoprotein E (APOE).
Plasma pTau181 may have utility as a biomarker of AD pathophysiology and as a noninvasive screener for elevated brain Aβ.
•Plasma total tau and phosphorylated tau 181 (pTau181) increased with Alzheimer's disease severity.•Plasma pTau181, but not total tau, was higher among those with elevated brain amyloid β (Aβ).•Plasma pTau181 was associated with both Aβ and tau PET.•Plasma pTau181 was a sensitive and specific predictor of elevated brain Aβ.
Multimorbidity and Risk of Mild Cognitive Impairment Vassilaki, Maria; Aakre, Jeremiah A.; Cha, Ruth H. ...
Journal of the American Geriatrics Society (JAGS),
September 2015, Letnik:
63, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Objectives
To determine the association between multiple chronic conditions and risk of incident mild cognitive impairment (MCI) and dementia.
Design
Prospective cohort study.
Setting
Olmsted County, ...Minnesota.
Participants
Cognitively normal individuals (N = 2,176) enrolled in the Mayo Clinic Study of Aging (MCSA).
Measurements
Participants were randomly selected from the community, evaluated by a physician, and underwent neuropsychometric testing at baseline and at 15‐month intervals to assess diagnoses of MCI and dementia. Information on International Classification of Diseases, Ninth Revision codes for chronic conditions in the 5 years before enrollment was electronically captured using the Rochester Epidemiology Project medical records linkage system. Multimorbidity was defined as having two or more chronic conditions, and the association between multimorbidity and MCI and dementia was examined using Cox proportional hazards models.
Results
Of 2,176 cognitively normal participants (mean age ± standard deviation 78.5 ± 5.2; 50.6% male), 1,884 (86.6%) had multimorbidity. The risk of MCI or dementia was higher in persons with multimorbidity (hazard ratio (HR) = 1.38, 95% confidence interval (CI) = 1.05–1.82) than in those with one or no chronic condition. The HR was of greater magnitude in persons with four or more conditions (HR = 1.61, 95% CI = 1.21–2.13) than in those with two or three conditions (HR = 1.03, 95% CI = 0.76–1.39) and for men with multimorbidity(HR = 1.53, 95% CI = 1.01–2.31) than for women with multimorbidity (HR = 1.20, 95% CI = 0.83–1.74), compared to those with one or no chronic condition.
Conclusion
In older adults, having multiple chronic conditions is associated with greater risk of MCI and dementia. This is consistent with the hypothesis that multiple etiologies may contribute to MCI and late‐life dementia. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia.
See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.
Where should measurements be taken to best capture tau accumulation in ageing and Alzheimer's disease? ...Jack et al. report that in clinically symptomatic stages of Alzheimer's disease, tau accumulation occurs throughout the brain, rather than only in specific areas. Rate measurements from simple meta-regions of interest may be sufficient to capture progressive within-person tau accumulation.
Abstract
See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.
Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low 0.006 standardized uptake value ratio (SUVR), 0.5%, per year but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.
Abstract This is a narrative review of new ideas and concepts related to differences between men and women in their risk of developing dementia or Alzheimer's disease (AD). We introduce the concept ...of dimorphic neurology and the distinction between sex and gender. We then provide three examples of risk factors related to sex and gender from the literature. Apolipoprotein E genotype is equally common in men and women but has a stronger effect in women. Apolipoprotein E genotype is a biological factor that cannot be modified but interacts with sex or gender related factors that can be modified. Low education has a similar harmful effect in men and women but has been historically more common in women. Education is a social factor related to gender that can be modified. Finally, bilateral oophorectomy is a factor restricted to women. Bilateral oophorectomy is a surgical practice related to sex that can be modified. Consideration of risk and protective factors in men and women separately may accelerate etiologic research for neurological diseases in general, and for dementia and AD in particular. Similarly, future preventive interventions for dementia should be tailored to men and women separately.
IMPORTANCE: A National Institute on Aging and Alzheimer’s Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is ...labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers. OBJECTIVE: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018. EXPOSURES: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (−), resulting in 8 AT(N) profiles. MAIN OUTCOMES AND MEASURES: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only. RESULTS: Participants were followed up for a median of 4.8 years (interquartile range IQR, 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A−T−(N)− group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)−, and A+T−(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were −0.13 (95% CI, −0.17 to −0.09), −0.10 (95% CI, −0.16 to −0.05), and −0.10 (95% CI, −0.13 to −0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier. CONCLUSIONS AND RELEVANCE: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.
IMPORTANCE: A National Institute on Aging–Alzheimer’s Association (NIA-AA) workgroup recently published a research framework in which Alzheimer disease is defined by neuropathologic or biomarker ...evidence of β-amyloid plaques and tau tangles and not by clinical symptoms. OBJECTIVES: To estimate the sex- and age-specific prevalence of 3 imaging biomarker–based definitions of the Alzheimer disease spectrum from the NIA-AA research framework and to compare these entities with clinically defined diagnostic entities commonly linked with Alzheimer disease. DESIGN, SETTING, AND PARTICIPANTS: The Mayo Clinic Study of Aging (MCSA) is a population-based cohort study of cognitive aging in Olmsted County, Minnesota. The MCSA in-person participants (n = 4660) and passively ascertained (ie, through the medical record rather than in-person) individuals with dementia (n = 553) aged 60 to 89 years were included. Subsets underwent amyloid positron emission tomography (PET) (n = 1524) or both amyloid and tau PET (n = 576). Therefore, this study included 3 nested cohorts examined between November 29, 2004, and June 5, 2018. Data were analyzed between February 19, 2018, and March 26, 2019. MAIN OUTCOMES AND MEASURES: The sex- and age-specific prevalence of the following 3 biologically defined diagnostic entities was estimated: Alzheimer continuum (abnormal amyloid regardless of tau status), Alzheimer pathologic change (abnormal amyloid but normal tau), and Alzheimer disease (abnormal amyloid and tau). These were compared with the prevalence of 3 clinically defined diagnostic groups (mild cognitive impairment or dementia, dementia, and clinically defined probable Alzheimer disease). RESULTS: The median (interquartile range) age was 77 (72-83) years in the clinical cohort (n = 5213 participants), 77 (70-83) years in the amyloid PET cohort (n = 1524 participants), and 77 (69-83) years in the tau PET cohort (n = 576 participants). There were roughly equal numbers of women and men. The prevalence of all diagnostic entities (biological and clinical) increased rapidly with age, with the exception of Alzheimer pathologic change. The prevalence of biological Alzheimer disease was greater than clinically defined probable Alzheimer disease for women and men. Among women, these values were 10% (95% CI, 6%-14%) vs 1% (95% CI, 1%-1%) at age 70 years and 33% (95% CI, 25%-41%) vs 10% (95% CI, 9%-12%) at age 85 years (P < .001). Among men, these values were 9% (95% CI, 5%-12%) vs 1% (95% CI, 0%-1%) at age 70 years and 31% (95% CI, 24%-38%) vs 9% (95% CI, 8%-11%) at age 85 years (P < .001). The only notable difference by sex was a greater prevalence of the mild cognitive impairment or dementia clinical category among men than women. CONCLUSIONS AND RELEVANCE: Results of this study suggest that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men. This difference is mostly driven by asymptomatic individuals with biological Alzheimer disease. These findings illustrate the magnitude of the consequences on public health that potentially exist by intervening with disease-specific treatments to prevent symptom onset.
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