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Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life.

ABSTRACT: Background: Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer's disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (A?) pathology and AD-related neurodegeneration in non-demented older adults. Methods: Cross-sectional analyses of data collected between April 2014 and March 2016 from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort. In total, 321 community-dwelling, non-demented older adults were involved in this study. Cerebral A? deposition and A? positivity were measured using ¹¹C-Pittsburgh compound B (PiB)-positron emission tomography (PET). AD-signature region cerebral glucose metabolism (AD-CMglu) and AD-signature region neurodegeneration (AD-ND) positivity were measured using ¹⁸F-fluorodeoxyglucose (FDG)-PET. In addition, CA in early, mid, and late life was systematically evaluated using a structured questionnaire. Results: Of the 321 participants, 254 were cognitively normal (CN) and 67 had mild cognitive impairment (MCI). The mean age of participants was 69.6 years old [standard deviation (SD) = 8.0]. Higher early-life CA (CA_early) was associated with significantly increased AD-CMglu (B = 0.035, SE = 0.013, P = 0.009) and a decreasing trend of AD-ND positivity (OR = 0.65, 95% CI 0.43-0.98, P = 0.04) but was not associated with A? deposition or positivity. We observed no association between midlife CA (CA_mid) and any AD-related brain changes. Late-life CA (CA_late) showed an association with both global A? deposition and AD-CMglu, although it was not statistically significant. Sensitivity analyses controlling for current depression or conducted only for CN individuals revealed similar results. Conclusion: Our results suggest that CA in early life may be protective against late-life AD-related neurodegeneration, independently of cerebral A? pathology.

SUBMITTER: Ko K

PROVIDER: S-EPMC5875443 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life.

Ko Kang K Byun Min Soo MS Yi Dahyun D Lee Jun Ho JH Kim Chan Hyung CH Lee Dong Young DY

Frontiers in aging neuroscience 20180322

<b>Background:</b> Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer's disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (Aβ) pathology and AD-related neurodegeneration in non-demented o ...[more]

PMID: 29623037

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Project description:ImportanceThere are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)-negative (Aβ-) suspected non-Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts.ObjectiveTo examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts.Design, setting, and participantsA longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ- and neurodegeneration-positive [Aβ-N+]) subtypes and their Aβ+N+ counterparts.Main outcomes and measuresParticipants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]).ResultsThe study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were Aβ-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were Aβ+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their Aβ+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: Aβ-N+, 1.25 [0.11] vs Aβ+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ε4 (Aβ-N+, 18.7% vs Aβ+N+, 70.6%) and disproportionately high APOE ε2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (Aβ-N+, 6.5% vs Aβ+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their Aβ+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between Aβ-N+ and Aβ+N+ cases.Conclusions and relevanceIn MCI with SNAP, low APOE ε4 and high APOE ε2 carrier prevalence may account for differences in neurodegeneration patterns between Aβ-N+ and Aβ+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

Project description:ImportanceIndicators of early-life cognitive enrichment (ELCE) have been associated with slower cognitive decline and decreased dementia in late life. However, the mechanisms underlying this association have not been elucidated.ObjectiveTo examine the association of ELCE with late-life Alzheimer disease (AD) and other common dementia-related pathological changes.Design, setting, and participantsThis clinical-pathological community-based cohort study, the Rush Memory and Aging Project, followed up participants before death for a mean (SD) of 7.0 (3.8) years with annual cognitive and clinical assessments. From January 1, 1997, through June 30, 2019, 2044 participants enrolled, of whom 1018 died. Postmortem data were leveraged from 813 participants. Data were analyzed from April 12, 2019, to February 20, 2020.ExposuresFour indicators of ELCE (early-life socioeconomic status, availability of cognitive resources at 12 years of age, frequency of participation in cognitively stimulating activities, and early-life foreign language instruction) were obtained by self-report at the study baseline, from which a composite measure of ELCE was derived.Main outcomes and measuresA continuous global AD pathology score derived from counts of diffuse plaques, neuritic plaques, and neurofibrillary tangles.ResultsThe 813 participants included in the analysis had a mean (SD) age of 90.1 (6.3) years at the time of death, and 562 (69%) were women. In a linear regression model controlled for age at death, sex, and educational level, a higher level of ELCE was associated with a lower global AD pathology score (estimate, -0.057; standard error, 0.022; P = .01). However, ELCE was not associated with any other dementia-related pathological changes. In addition, a higher level of ELCE was associated with less cognitive decline (mean [SD], -0.13 [0.19] units per year; range, -1.74 to 0.85). An indirect effect through AD pathological changes constituted 20% of the association between ELCE and the rate of late-life cognitive decline, and 80% was a direct association.Conclusions and relevanceThese findings suggest that ELCE was associated with better late-life cognitive health, in part through an association with fewer AD pathological changes.

Project description:ImportanceLow early-life cognitive ability is a potential early marker of dementia risk in later life. Previous studies use only global measures of general intelligence and/or study this relationship in gender-specific samples. The contribution of early-life performance on specific cognitive abilities, such as language, reasoning, and visualization aptitudes, to indicating future dementia risk is unknown.ObjectivesTo investigate the association between adolescent cognitive ability and Medicare-recorded Alzheimer disease and related disorders (ADRD) using both general and specific measures of cognitive ability and to explore these associations separately in men and women.Design, setting, and participantsPopulation-based cohort study from the Project Talent-Medicare linked data set, a linkage of adolescent sociobehavioral data collected from high school students in 1960 to participants' 2012 to 2013 Medicare Claims and expenditures data. The association between adolescent cognitive ability and risk of ADRD in later life was assessed in a diverse sample of 43 014 men and 42 749 women aged 66 to 73 years using a series of logistic regressions stratified by sex, accounting for demographic characteristics, adolescent socioeconomic status, and regional effects. Data analysis was conducted from November 2017 to March 2018.Main outcomes and measuresPresence of Medicare-reported ADRD.ResultsOverall, 1239 men (2.9%) and 1416 women (3.3%) developed ADRD. Lower mechanical reasoning was associated with increased odds of ADRD in men (odds ratio, 1.17; 95% CI, 1.05-1.29), and lower memory for words in adolescence was associated with increased odds of ADRD in women (odds ratio, 1.16; 95% CI, 1.05-1.28). Lower performance on several other language, reasoning, visualization, and mathematic aptitudes in adolescence showed prominent, but weaker, associations with odds of ADRD.Conclusions and relevanceThis work contributes to the understanding of early-life origins of ADRD risk. The results suggest specific measures of cognitive ability may contribute to very early identification of at-risk subgroups who may benefit from prevention or intervention efforts.

Project description:The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease, infarcts, and Lewy bodies, account for ∼40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline [e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions]. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n = 1164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer's disease, non- Alzheimer's disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, P < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P < 0.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer's disease-related indices accounted for 30-36% of the variation, non-Alzheimer's disease neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

Dataset Information

Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life.

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Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life.

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