Authors: Lennon, Matthew J. | Makkar, Steve R. | Crawford, John D. | Sachdev, Perminder S.
Article Type: Research Article
Abstract: Background: Hypertension is an established risk factor for stroke and vascular dementia but recent meta-analyses examining the association between Alzheimer’s disease (AD) and hypertension have found no significant association. These meta-analyses included short term studies starting in late life which may have obscured the real effect of midlife hypertension. Objective: To examine the association of AD with midlife hypertension, by including only studies with a sufficiently long follow up duration. Methods: Relevant studies were found by searches of MEDLINE, EMBASE, and PubMed. Study outcomes were grouped by measures of blood pressure and definition of hypertension (e.g., systolic hypertension > 140 mmHg or > 160 …mmHg). We assessed pooled effect estimates using random effects models and heterogeneity of pooled estimates through the I2 statistic. Results: Literature search found 3,426 publications of which 7 were eligible studies. There was a significant association between systolic hypertension (>160 mm Hg) and AD (HR 1.25, 95CI 1.06 – 1.47, p = 0.0065). Similarly, for systolic hypertension > 140 mm Hg, there was a smaller but still significant association (HR 1.18, 95CI 1.02 – 1.35, p = 0.021). For diastolic hypertension, all four studies found no significant associations between diastolic hypertension and AD, and these data could not be pooled due to heterogeneity in reporting. Conclusions: Our study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension. It is likely that assertive control of systolic hypertension starting in midlife is important to preventing AD. Show more
Keywords: Alzheimer’s disease, dementia, hypertension, meta-analysis, midlife
DOI: 10.3233/JAD-190474
Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 307-316, 2019
Authors: Kaur, Gurjeet | Poljak, Anne | Braidy, Nady | Crawford, John D. | Lo, Jessica | Sachdev, Perminder S.
Article Type: Research Article
Abstract: Background: Numerous studies have reported on cerebrospinal fluid (CSF) and blood biomarkers of Alzheimer’s disease (AD); however, to date, none has compared biomarker patterns across the early-onset subtypes, i.e., early onset sporadic AD (EOsAD) and autosomal dominant AD (ADAD), qualitatively and quantitatively. Objective: To compare the fluid biomarker patterns in early-onset subtypes of AD; EOsAD and ADAD. Methods: Six scientific databases were searched for peer-reviewed research publications. The total number of individuals used in all the meta-analysis were 2,427, comprised of 1,337 patients and 1,090 controls. Results: In the subset of EOsAD cases without APP , PSEN1 /PSEN2 mutations, CSF …Aβ42 and tau levels were higher when compared to the EOsAD group as a whole. Prevalence of the APOE ɛ 4 allele was more elevated in EOsAD relative to controls, and not significantly elevated in ADAD cases. Conclusion: Established CSF biomarkers confirmed quantitative differences between variants of EOAD. EOsAD is enriched with APOE ɛ 4, but the level is not higher than generally reported in late-onset AD. The results prompt further exploration of the etiopathogenesis of EOsAD, which accounts for ∼4–10% of all AD cases, but the reasons for the early onset remain poorly understood. Show more
Keywords: Amyloid-β42, APOE ɛ4, APP/PSEN, early onset Alzheimer’s disease, neurodegeneration biomarkers, tau
DOI: 10.3233/JAD-200052
Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 827-843, 2020
Authors: Koncz, Rebecca | Wen, Wei | Makkar, Steve R. | Lam, Ben C.P. | Crawford, John D. | Rowe, Christopher C. | Sachdev, Perminder | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: Cerebral small vessel disease (SVD) and Alzheimer’s disease pathology, namely amyloid-β (Aβ) deposition, commonly co-occur. Exactly how they interact remains uncertain. Objective: Using participants from the Alzheimer’s Disease Neuroimaging Initiative (n = 216; mean age 73.29±7.08 years, 91 (42.1%) females), we examined whether the presence of vascular risk factors and/or baseline cerebral SVD was related to a greater burden of Aβ cross-sectionally, and at 24 months follow-up. Method: Amyloid burden, assessed using 18 F-florbetapir PET, was quantified as the global standardized uptake value ratio (SUVR). Multimodal imaging was used to strengthen the quantification of baseline SVD as a composite variable, …which included white matter hyperintensity volume using MRI, and peak width of skeletonized mean diffusivity using diffusion tensor imaging. Structural equation modeling was used to analyze the associations between demographic factors, Apolipoprotein E ɛ4 carrier status, vascular risk factors, SVD burden and cerebral amyloid. Results: SVD burden had a direct association with Aβ burden cross-sectionally (coeff. = 0.229, p = 0.004), and an indirect effect over time (indirect coeff. = 0.235, p = 0.004). Of the vascular risk factors, a history of hypertension (coeff. = 0.094, p = 0.032) and a lower fasting glucose at baseline (coeff. = –0.027, p = 0.014) had a direct effect on Aβ burden at 24 months, but only the direct effect of glucose persisted after regularization. Conclusion: While Aβ and SVD burden have an association cross-sectionally, SVD does not appear to directly influence the accumulation of Aβ longitudinally. Glucose regulation may be an important modifiable risk factor for Aβ accrual over time. Show more
Keywords: Amyloid, cerebral small vessel disease, hypertension, peak width of skeletonized mean diffusivity, positron emission tomography, white matter hyperintensities
DOI: 10.3233/JAD-210358
Citation: Journal of Alzheimer's Disease, vol. 86, no. 4, pp. 1617-1628, 2022
Authors: Hyun, Jinshil | Hall, Charles B. | Katz, Mindy J. | Derby, Carol A. | Lipnicki, Darren M. | Crawford, John D. | Guaita, Antonio | Vaccaro, Roberta | Davin, Annalisa | Kim, Ki Woong | Han, Ji Won | Bae, Jong Bin | Röhr, Susanne | Riedel-Heller, Steffi | Ganguli, Mary | Jacobsen, Erin | Hughes, Tiffany F. | Brodaty, Henry | Kochan, Nicole A. | Trollor, Julian | Lobo, Antonio | Santabarbara, Javier | Lopez-Anton, Raul | Sachdev, Perminder S. | Lipton, Richard B. | for Cohort Studies of Memory in an International Consortium (COSMIC)
Article Type: Research Article
Abstract: Background: Education and occupational complexity are main sources of mental engagement during early life and adulthood respectively, but research findings are not conclusive regarding protective effects of these factors against late-life dementia. Objective: This project aimed to examine the unique contributions of education and occupational complexity to incident dementia, and to assess the mediating effects of occupational complexity on the association between education and dementia across diverse cohorts. Method: We used data from 10,195 participants (median baseline age = 74.1, range = 58∼103), representing 9 international datasets from 6 countries over 4 continents. Using a coordinated analysis approach, the accelerated failure time model was …applied to each dataset, followed by meta-analysis. In addition, causal mediation analyses were performed. Result: The meta-analytic results indicated that both education and occupational complexity were independently associated with increased dementia-free survival time, with 28%of the effect of education mediated by occupational complexity. There was evidence of threshold effects for education, with increased dementia-free survival time associated with ‘high school completion’ or ‘above high school’ compared to ‘middle school completion or below’. Conclusion: Using datasets from a wide range of geographical regions, we found that both early life education and adulthood occupational complexity were independently predictive of dementia. Education and occupational experiences occur during early life and adulthood respectively, and dementia prevention efforts could thus be made at different stages of the life course. Show more
Keywords: Cognitive reserve, coordinated analysis, education, occupational complexity
DOI: 10.3233/JAD-210627
Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 179-196, 2022