Abstract There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of ...Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
IMPORTANCE: Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be ...included to assess brain imaging findings associated with typical aging. OBJECTIVE: To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume HVa), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old. MAIN OUTCOMES AND MEASURES: Memory, HVa, and amyloid PET. RESULTS: Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward, APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers. CONCLUSIONS AND RELEVANCE: Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.
OBJECTIVETo examine whether the use of sex-specific norms and cut scores to identify memory impairment improves diagnostic accuracy of amnestic mild cognitive impairment (aMCI) compared to ...non–sex-specific (typical) norms/cut scores given the female advantage in verbal memory.
METHODSWe calculated sex-specific and typical norms/cut scores (age and education specific) for impairment on the Rey Auditory Verbal Learning Test in the Mayo Clinic Study of Aging. Norms/cut scores were applied to 453 women and 532 men from the Alzheimerʼs Disease Neuroimaging Initiative. We compared sex differences in rates of aMCI (Jak/Bondi criteria) for sex-specific vs typical norms/cut scores. Using sex-specific cut scores as the true condition and typical cut scores as the predicted condition, we categorized participants as true positives (TPs), false positives (FPs), true negative (TNs), or false negative (FNs). In cross-sectional analyses within sex, we compared positivity rates of CSF hyperphosphorylated tau/β-amyloid (Aβ) and cortical Aβ deposition (FAV45 PET) and APOE ε4 frequency among diagnostic comparison groups.
RESULTSThe frequency of aMCI was higher in men when using typical norms/cut scores. Using sex-adjusted norms/cut scores led to the identification of 10% FNs (missed aMCI cases) among women and 10% FPs among men. Biomarker analyses supported the hypothesis that sex-specific diagnostic criteria improves diagnostic accuracy. Biomarkers rates were higher in FNs vs TNs and similar in FNs and TPs. Biomarker rates were lower in FPs vs TPs and similar between FPs and TNs.
CONCLUSIONResults suggest that non–sex-specific aMCI diagnostic criteria led to a 20% diagnostic error rate. Accounting for sex differences in verbal memory performance may improve aMCI classification.
Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess ...brain imaging findings associated with typical aging. To compare age, sex, and APOE e4 effects on memory, brain structure (adjusted hippocampal volume HVa), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old. Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old. Memory, HVa, and amyloid PET. Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE e4 status at any age. From age 70 years onward, APOE e4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE e4 carriers and 64 years for noncarriers. Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE e4 is not. In contrast, APOE e4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than beta -amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which beta -amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with beta -amyloid deposits.
IMPORTANCE: Aging is associated with excessive daytime sleepiness (EDS), which has been linked to cognitive decline in the elderly. However, whether EDS is associated with the pathologic processes of ...Alzheimer disease remains unclear. OBJECTIVE: To investigate whether EDS at baseline is associated with a longitudinal increase in regional β-amyloid (Aβ) accumulation in a cohort of elderly individuals without dementia. DESIGN, SETTING, AND PARTICIPANTS: This prospective analysis included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota. Of 2900 participants, 2172 (74.9%) agreed to undergo carbon 11–labeled Pittsburgh compound B positron emission tomography (PiB-PET). We included 283 participants 70 years or older without dementia who completed surveys assessing sleepiness at baseline and had at least 2 consecutive PiB-PET scans from January 1, 2009, through July 31, 2016, after excluding 45 (13.7%) who had a comorbid neurologic disorder. MAIN OUTCOMES AND MEASURES: Excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score of at least 10. The difference in Aβ levels between the 2 consecutive scans (ΔPiB) in Aβ-susceptible regions (prefrontal, anterior cingulate, posterior cingulate-precuneus, and parietal) was determined. Multiple linear regression models were fit to explore associations between baseline EDS and ΔPiB while adjusting for baseline age, sex, presence of the apolipoprotein E ε4 allele, educational level, baseline PiB uptake, global PiB positivity (standardized uptake value ratio ≥1.4), physical activity, cardiovascular comorbidities (obesity, hypertension, hyperlipidemia, and diabetes), reduced sleep duration, respiratory symptoms during sleep, depression, and interval between scans. RESULTS: Of the initial 283 participants, mean (SD) age was 77.1 (4.8) years; 204 (72.1%) were men and 79 (27.9%) were women. Sixty-three participants (22.3%) had EDS. Baseline EDS was significantly associated with increased regional Aβ accumulation in the anterior cingulate (B coefficient = 0.031; 95% CI, 0.001-0.061; P = .04), posterior cingulate-precuneus (B coefficient = 0.038; 95% CI, 0.006-0.069; P = .02), and parietal (B coefficient = 0.033; 95% CI, 0.001-0.065; P = .04) regions. Association of EDS with longitudinal Aβ accumulation was stronger in participants with baseline global PiB positivity in the anterior cingulate (B coefficient = 0.065; 95% CI, 0.010-0.118; P = .02) and cingulate-precuneus (B coefficient = 0.068; 95% CI, 0.009-0.126; P = .02) regions. CONCLUSIONS AND RELEVANCE: Baseline EDS was associated with increased longitudinal Aβ accumulation in elderly persons without dementia, suggesting that those with EDS may be more vulnerable to pathologic changes associated with Alzheimer disease. Further work is needed to elucidate whether EDS is a clinical marker of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers. Early identification of patients with EDS and treatment of underlying sleep disorders could reduce Aβ accumulation in this vulnerable group.
Abstract
Objectives
The present study builds on recent findings suggesting that the stress of institutional and interpersonal racism may contribute to African Americans’ elevated risk for dementia. ...We investigated the extent to which 2 consequences of racism—low socioeconomic status (SES) and discrimination—predict self-reported cognitive decline (SCD) 19 years later. Further, we examined potential mediating pathways that might link SES and discrimination to cognitive decline. Potential mediators included depression, accelerated biological aging, and onset of chronic illnesses.
Methods
Hypotheses were tested using a sample of 293 African American women. SCD was assessed using the Everyday Cognition Scale. Structural equation modeling was used to assess the effects of SES and racial discrimination, both measured in 2002, on SCD reported in 2021. Turning to the mediators, midlife depression was assessed in 2002, accelerated aging in 2019, and chronic illness in 2019. Age and prodrome depression were included as covariates.
Results
There were direct effects of SES and discrimination on SCD. In addition, these 2 stressors showed a significant indirect effect on SCD through depression. Finally, there was evidence for a more complex pathway where SES and discrimination accelerate biological aging, with accelerated aging, in turn leading to chronic illness, which then predicted SCD.
Discussion
Results of the present study add to a growing literature indicating that living in a racialized society is a central factor in explaining the high risk for dementia among Black Americans. Future research should continue to emphasize the various ways that exposure to racism over the life course effects cognition.
Levels of insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, and their ratio in the blood may be useful for monitoring those at risk of cognitive and functional decline. However, the ...association between IGF measures and functional and cognitive outcomes has been mixed, and the associations may vary by sex. The present study investigated the cross-sectional, sex-specific associations between serum measures total IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio, gait speed, and cognition in 1320 cognitively unimpaired participants aged 50–95 years enrolled in the Mayo Clinic Study of Aging. We used multivariable linear regression models to determine the association between IGF measures and gait speed or cognitive test performance by sex. IGF measures were not associated with cognitive or functional performance among men. Among women, higher levels of log total IGF-1 and IGFBP-3 were associated with better performance in attention, visuospatial, and global cognitive domains, independent of the gait speed. These findings suggest that among women, IGF measures are associated with cognition, and these associations are independent of function.
Sporadic Alzheimer’s disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic ...pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endothelin (ET-1), adrenomedullin (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, however, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysbalances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal pathologies in the AD brain.
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