Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease
Main Article Content
Abstract
Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer’s disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals.
Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort.
Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status.
Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals.
Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.
Article Details
How to Cite
SS, Hoost et al.
Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease.
Medical Research Archives, [S.l.], v. 11, n. 9, oct. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4468>. Date accessed: 03 july 2024.
doi: https://doi.org/10.18103/mra.v11i9.4468.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia. 2018;14(4):535-562. doi:10.1016/j.jalz.2018.02.018
2. Brickman AM, Manly JJ, Honig LS, et al. Plasma p‐tau181, p‐tau217, and other blood‐based Alzheimer’s disease biomarkers in a multi‐ethnic, community study. Alzheimer’s & Dementia. 2021;17(8):1353-1364. doi:10.1002/alz.12301
3. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26(3):379-386. doi:10.1038/s41591-020-0755-1
4. Janelidze S, Berron D, Smith R, et al. Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease. JAMA Neurol. 2021;78(2):149-156. doi:10.1001/jamaneurol.2020.4201
5. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. The Lancet Neurology. 2022;21(1):66-77. doi:10.1016/S1474-4422(21)00361-6
6. Mielke MM, Dage JL, Frank RD, et al. Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med. Published online May 26, 2022. doi:10.1038/s41591-022-01822-2
7. Brickman AM, Manly JJ, Honig LS, et al. Correlation of plasma and neuroimaging biomarkers in Alzheimer’s disease. Annals of Clinical and Translational Neurology. 2022;9(5):756-761. doi:10.1002/acn3.51529
8. Kivimäki M, Luukkonen R, Batty GD, et al. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement. 2018;14(5):601-609. doi:10.1016/j.jalz.2017.09.016
9. Hohman TJ, Samuels LR, Liu D, et al. Stroke risk interacts with Alzheimer’s disease biomarkers on brain aging outcomes. Neurobiology of Aging. 2015;36(9):2501-2508. doi:10.1016/j.neurobiolaging.2015.05.021
10. Rabin JS, Schultz AP, Hedden T, et al. Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study. JAMA Neurology. 2018;75(9):1124-1131. doi:10.1001/jamaneurol.2018.1123
11. Vemuri P, Lesnick TG, Przybelski SA, et al. Age, Vascular Health, and Alzheimer’s disease Biomarkers in an Elderly Sample. Ann Neurol. 2017;82(5):706-718. doi:10.1002/ana.25071
12. Gu D, Ou S, Liu G. Traumatic Brain Injury and Risk of Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. NED. 2022;56(1):4-16. doi:10.1159/000520966
13. Bureau USC, Census of Population and Housing. Summary Population and Housing Characteristics. Bureau of the Census; 2001.
14. Ogino E, Manly JJ, Schupf N, Mayeux R, Gu Y. Current and past leisure time physical activity in relation to risk of Alzheimer’s disease in older adults. Alzheimers Dement. 2019;15(12):1603-1611. doi:10.1016/j.jalz.2019.07.013
15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944. doi:10.1212/wnl.34.7.939
16. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-2414. doi:10.1212/wnl.43.11.2412-a
17. Reitz C, Patel B, Tang MX, Manly J, Mayeux R, Luchsinger JA. Relation between vascular risk factors and neuropsychological test performance among elderly persons with Alzheimer’s disease. Journal of the Neurological Sciences. 2007;257(1):194-201. doi:10.1016/j.jns.2007.01.030
18. Luchsinger JA, Honig LS, Tang MX, Devanand DP. Depressive symptoms, vascular risk factors, and Alzheimer’s disease. Int J Geriatr Psychiatry. 2008;23(9):922-928. doi:10.1002/gps.2006
19. Lee AJ, Sanchez D, Reyes-Dumeyer D, et al. Reliability and Validity of self-reported Vascular Risk Factors in a Multi-Ethnic Community Based Study of Aging and Dementia. Published online April 17, 2023:2023.04.12.23288492. doi:10.1101/2023.04.12.23288492
20. Pedditzi E, Peters R, Beckett N. The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age Ageing. 2016;45(1):14-21. doi:10.1093/ageing/afv151
21. Buchman AS, Schneider JA, Wilson RS, Bienias JL, Bennett DA. Body mass index in older persons is associated with Alzheimer disease pathology. Neurology. 2006;67(11):1949-1954. doi:10.1212/01.wnl.0000247046.90574.0f
22. Huang SJ, Ma YH, Bi YL, et al. Metabolically healthy obesity and lipids may be protective factors for pathological changes of alzheimer’s disease in cognitively normal adults. Journal of Neurochemistry. 2021;157(3):834-845. doi:10.1111/jnc.15306
23. Ma LZ, Huang YY, Wang ZT, et al. Metabolically healthy obesity reduces the risk of Alzheimer’s disease in elders: a longitudinal study. Aging. 2019;11(23):10939-10951. doi:10.18632/aging.102496
24. Ewers M, Schmitz S, Hansson O, et al. Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer’s disease. Neurobiology of Aging. 2012;33(8):1599-1608. doi:10.1016/j.neurobiolaging.2011.05.005
25. Mathys J, Gholamrezaee M, Henry H, von Gunten A, Popp J. Decreasing body mass index is associated with cerebrospinal fluid markers of Alzheimer’s pathology in MCI and mild dementia. Experimental Gerontology. 2017;100:45-53. doi:10.1016/j.exger.2017.10.013
26. Pichet Binette A, Janelidze S, Cullen N, et al. Confounding factors of Alzheimer’s disease plasma biomarkers and their impact on clinical performance. Alzheimer’s & Dementia. 2022;n/a(n/a). doi:10.1002/alz.12787
27. Donini LM, Pinto A, Giusti AM, Lenzi A, Poggiogalle E. Obesity or BMI Paradox? Beneath the Tip of the Iceberg. Front Nutr. 2020;7:53. doi:10.3389/fnut.2020.00053
28. Kivimäki M, Luukkonen R, Batty GD, et al. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement. 2018;14(5):601-609. doi:10.1016/j.jalz.2017.09.016
29. Nordestgaard LT, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Body Mass Index and Risk of Alzheimer’s Disease: A Mendelian Randomization Study of 399,536 Individuals. J Clin Endocrinol Metab. 2017;102(7):2310-2320. doi:10.1210/jc.2017-00195
30. Gu Y, Scarmeas N, Short EE, et al. Alcohol intake and brain structure in a multiethnic elderly cohort. Clin Nutr. 2014;33(4):662-667. doi:10.1016/j.clnu.2013.08.004
31. Centers for Disease Control. What Is Dementia? cdc.gov. Published December 19, 2019. Accessed August 29, 2022. https://www.cdc.gov/aging/dementia/index.html
32. Sacuiu SF. Chapter 8 - Dementias. In: Aminoff MJ, Boller F, Swaab DF, eds. Handbook of Clinical Neurology. Vol 138. Neuroepidemiology. Elsevier; 2016:123-151. doi:10.1016/B978-0-12-802973-2.00008-2
33. World Health Organization. Dementia. who.int. Published September 2, 2021. Accessed August 29, 2022. https://www.who.int/news-room/fact-sheets/detail/dementia
34. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. The Lancet. 2001;357(9251):169-175. doi:10.1016/S0140-6736(00)03589-3
35. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197-2204. doi:10.1212/01.wnl.0000271090.28148.24
36. Feldman H, Levy AR, Hsiung GY, et al. A Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD): Study Methods and Baseline Results. NED. 2003;22(5):265-274. doi:10.1159/000071189
37. Hogan DB, Jetté N, Fiest KM, et al. The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review. Canadian Journal of Neurological Sciences. 2016;43(S1):S96-S109. doi:10.1017/cjn.2016.25
38. Jones SAV, O’Brien JT. The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychological Medicine. 2014;44(4):673-683. doi:10.1017/S0033291713000494
39. Chun MY, Jang H, Kim SJ, et al. Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer’s and concomitant cerebrovascular burdens. J Neurol Neurosurg Psychiatry. Published online August 9, 2023. doi:10.1136/jnnp-2023-331603
40. Winder Z, Sudduth TL, Anderson S, et al. Examining the association between blood-based biomarkers and human post mortem neuropathology in the University of Kentucky Alzheimer’s Disease Research Center autopsy cohort. Alzheimer’s & Dementia. 2023;19(1):67-78. doi:10.1002/alz.12639
41. Yu L, Boyle PA, Janelidze S, et al. Plasma p-tau181 and p-tau217 in discriminating PART, AD and other key neuropathologies in older adults. Acta Neuropathol. 2023;146(1):1-11. doi:10.1007/s00401-023-02570-4
42. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14(1):32. doi:10.1186/s13024-019-0333-5
43. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. The Lancet. 2001;357(9251):169-175. doi:10.1016/S0140-6736(00)03589-3
44. Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Annals of Neurology. 2007;62(1):59-66. doi:10.1002/ana.21142
45. Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013;136(9):2697-2706. doi:10.1093/brain/awt188
46. Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ. Effect of Infarcts on Dementia in the Baltimore Longitudinal Study of Aging. Ann Neurol. 2008;64(2):168-176. doi:10.1002/ana.21413
47. Song Y, Stampfer MJ, Liu S. Meta-Analysis: Apolipoprotein E Genotypes and Risk for Coronary Heart Disease. Ann Intern Med. 2004;141(2):137-147. doi:10.7326/0003-4819-141-2-200407200-00013
48. Brickman AM, Schupf N, Manly JJ, et al. APOE ε4 and risk for Alzheimer’s disease: do regionally distributed white matter hyperintensities play a role? Alzheimers Dement. 2014;10(6):619-629. doi:10.1016/j.jalz.2014.07.155
49. Gustavsson AM, van Westen D, Stomrud E, Engström G, Nägga K, Hansson O. Midlife Atherosclerosis and Development of Alzheimer or Vascular Dementia. Annals of Neurology. 2020;87(1):52-62. doi:10.1002/ana.25645
50. Lane CA, Barnes J, Nicholas JM, et al. Associations Between Vascular Risk Across Adulthood and Brain Pathology in Late Life: Evidence From a British Birth Cohort. JAMA Neurology. 2020;77(2):175-183. doi:10.1001/jamaneurol.2019.3774
51. Pettigrew C, Soldan A, Wang J, et al. Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline. Neurology. 2020;95(23):e3093-e3103. doi:10.1212/WNL.0000000000010946
52. Walters MJ, Sterling J, Quinn C, et al. Associations of lifestyle and vascular risk factors with Alzheimer’s brain biomarker changes during middle age: a 3-year longitudinal study in the broader New York City area. BMJ Open. 2018;8(11):e023664. doi:10.1136/bmjopen-2018-023664
53. Walsh P, Sudre CH, Fiford CM, et al. CSF amyloid is a consistent predictor of white matter hyperintensities across the disease course from aging to Alzheimer’s disease. Neurobiol Aging. 2020;91:5-14. doi:10.1016/j.neurobiolaging.2020.03.008
54. Graff-Radford J, Arenaza-Urquijo EM, Knopman DS, et al. White matter hyperintensities: relationship to amyloid and tau burden. Brain. 2019;142(8):2483-2491. doi:10.1093/brain/awz162
55. Mielke MM, Frank RD, Dage JL, et al. Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes. JAMA Neurol. 2021;78(9):1108-1117. doi:10.1001/jamaneurol.2021.2293
2. Brickman AM, Manly JJ, Honig LS, et al. Plasma p‐tau181, p‐tau217, and other blood‐based Alzheimer’s disease biomarkers in a multi‐ethnic, community study. Alzheimer’s & Dementia. 2021;17(8):1353-1364. doi:10.1002/alz.12301
3. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26(3):379-386. doi:10.1038/s41591-020-0755-1
4. Janelidze S, Berron D, Smith R, et al. Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease. JAMA Neurol. 2021;78(2):149-156. doi:10.1001/jamaneurol.2020.4201
5. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. The Lancet Neurology. 2022;21(1):66-77. doi:10.1016/S1474-4422(21)00361-6
6. Mielke MM, Dage JL, Frank RD, et al. Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med. Published online May 26, 2022. doi:10.1038/s41591-022-01822-2
7. Brickman AM, Manly JJ, Honig LS, et al. Correlation of plasma and neuroimaging biomarkers in Alzheimer’s disease. Annals of Clinical and Translational Neurology. 2022;9(5):756-761. doi:10.1002/acn3.51529
8. Kivimäki M, Luukkonen R, Batty GD, et al. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement. 2018;14(5):601-609. doi:10.1016/j.jalz.2017.09.016
9. Hohman TJ, Samuels LR, Liu D, et al. Stroke risk interacts with Alzheimer’s disease biomarkers on brain aging outcomes. Neurobiology of Aging. 2015;36(9):2501-2508. doi:10.1016/j.neurobiolaging.2015.05.021
10. Rabin JS, Schultz AP, Hedden T, et al. Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study. JAMA Neurology. 2018;75(9):1124-1131. doi:10.1001/jamaneurol.2018.1123
11. Vemuri P, Lesnick TG, Przybelski SA, et al. Age, Vascular Health, and Alzheimer’s disease Biomarkers in an Elderly Sample. Ann Neurol. 2017;82(5):706-718. doi:10.1002/ana.25071
12. Gu D, Ou S, Liu G. Traumatic Brain Injury and Risk of Dementia and Alzheimer’s Disease: A Systematic Review and Meta-Analysis. NED. 2022;56(1):4-16. doi:10.1159/000520966
13. Bureau USC, Census of Population and Housing. Summary Population and Housing Characteristics. Bureau of the Census; 2001.
14. Ogino E, Manly JJ, Schupf N, Mayeux R, Gu Y. Current and past leisure time physical activity in relation to risk of Alzheimer’s disease in older adults. Alzheimers Dement. 2019;15(12):1603-1611. doi:10.1016/j.jalz.2019.07.013
15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-944. doi:10.1212/wnl.34.7.939
16. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43(11):2412-2414. doi:10.1212/wnl.43.11.2412-a
17. Reitz C, Patel B, Tang MX, Manly J, Mayeux R, Luchsinger JA. Relation between vascular risk factors and neuropsychological test performance among elderly persons with Alzheimer’s disease. Journal of the Neurological Sciences. 2007;257(1):194-201. doi:10.1016/j.jns.2007.01.030
18. Luchsinger JA, Honig LS, Tang MX, Devanand DP. Depressive symptoms, vascular risk factors, and Alzheimer’s disease. Int J Geriatr Psychiatry. 2008;23(9):922-928. doi:10.1002/gps.2006
19. Lee AJ, Sanchez D, Reyes-Dumeyer D, et al. Reliability and Validity of self-reported Vascular Risk Factors in a Multi-Ethnic Community Based Study of Aging and Dementia. Published online April 17, 2023:2023.04.12.23288492. doi:10.1101/2023.04.12.23288492
20. Pedditzi E, Peters R, Beckett N. The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age Ageing. 2016;45(1):14-21. doi:10.1093/ageing/afv151
21. Buchman AS, Schneider JA, Wilson RS, Bienias JL, Bennett DA. Body mass index in older persons is associated with Alzheimer disease pathology. Neurology. 2006;67(11):1949-1954. doi:10.1212/01.wnl.0000247046.90574.0f
22. Huang SJ, Ma YH, Bi YL, et al. Metabolically healthy obesity and lipids may be protective factors for pathological changes of alzheimer’s disease in cognitively normal adults. Journal of Neurochemistry. 2021;157(3):834-845. doi:10.1111/jnc.15306
23. Ma LZ, Huang YY, Wang ZT, et al. Metabolically healthy obesity reduces the risk of Alzheimer’s disease in elders: a longitudinal study. Aging. 2019;11(23):10939-10951. doi:10.18632/aging.102496
24. Ewers M, Schmitz S, Hansson O, et al. Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer’s disease. Neurobiology of Aging. 2012;33(8):1599-1608. doi:10.1016/j.neurobiolaging.2011.05.005
25. Mathys J, Gholamrezaee M, Henry H, von Gunten A, Popp J. Decreasing body mass index is associated with cerebrospinal fluid markers of Alzheimer’s pathology in MCI and mild dementia. Experimental Gerontology. 2017;100:45-53. doi:10.1016/j.exger.2017.10.013
26. Pichet Binette A, Janelidze S, Cullen N, et al. Confounding factors of Alzheimer’s disease plasma biomarkers and their impact on clinical performance. Alzheimer’s & Dementia. 2022;n/a(n/a). doi:10.1002/alz.12787
27. Donini LM, Pinto A, Giusti AM, Lenzi A, Poggiogalle E. Obesity or BMI Paradox? Beneath the Tip of the Iceberg. Front Nutr. 2020;7:53. doi:10.3389/fnut.2020.00053
28. Kivimäki M, Luukkonen R, Batty GD, et al. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement. 2018;14(5):601-609. doi:10.1016/j.jalz.2017.09.016
29. Nordestgaard LT, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Body Mass Index and Risk of Alzheimer’s Disease: A Mendelian Randomization Study of 399,536 Individuals. J Clin Endocrinol Metab. 2017;102(7):2310-2320. doi:10.1210/jc.2017-00195
30. Gu Y, Scarmeas N, Short EE, et al. Alcohol intake and brain structure in a multiethnic elderly cohort. Clin Nutr. 2014;33(4):662-667. doi:10.1016/j.clnu.2013.08.004
31. Centers for Disease Control. What Is Dementia? cdc.gov. Published December 19, 2019. Accessed August 29, 2022. https://www.cdc.gov/aging/dementia/index.html
32. Sacuiu SF. Chapter 8 - Dementias. In: Aminoff MJ, Boller F, Swaab DF, eds. Handbook of Clinical Neurology. Vol 138. Neuroepidemiology. Elsevier; 2016:123-151. doi:10.1016/B978-0-12-802973-2.00008-2
33. World Health Organization. Dementia. who.int. Published September 2, 2021. Accessed August 29, 2022. https://www.who.int/news-room/fact-sheets/detail/dementia
34. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. The Lancet. 2001;357(9251):169-175. doi:10.1016/S0140-6736(00)03589-3
35. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197-2204. doi:10.1212/01.wnl.0000271090.28148.24
36. Feldman H, Levy AR, Hsiung GY, et al. A Canadian Cohort Study of Cognitive Impairment and Related Dementias (ACCORD): Study Methods and Baseline Results. NED. 2003;22(5):265-274. doi:10.1159/000071189
37. Hogan DB, Jetté N, Fiest KM, et al. The Prevalence and Incidence of Frontotemporal Dementia: a Systematic Review. Canadian Journal of Neurological Sciences. 2016;43(S1):S96-S109. doi:10.1017/cjn.2016.25
38. Jones SAV, O’Brien JT. The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies. Psychological Medicine. 2014;44(4):673-683. doi:10.1017/S0033291713000494
39. Chun MY, Jang H, Kim SJ, et al. Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer’s and concomitant cerebrovascular burdens. J Neurol Neurosurg Psychiatry. Published online August 9, 2023. doi:10.1136/jnnp-2023-331603
40. Winder Z, Sudduth TL, Anderson S, et al. Examining the association between blood-based biomarkers and human post mortem neuropathology in the University of Kentucky Alzheimer’s Disease Research Center autopsy cohort. Alzheimer’s & Dementia. 2023;19(1):67-78. doi:10.1002/alz.12639
41. Yu L, Boyle PA, Janelidze S, et al. Plasma p-tau181 and p-tau217 in discriminating PART, AD and other key neuropathologies in older adults. Acta Neuropathol. 2023;146(1):1-11. doi:10.1007/s00401-023-02570-4
42. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14(1):32. doi:10.1186/s13024-019-0333-5
43. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. The Lancet. 2001;357(9251):169-175. doi:10.1016/S0140-6736(00)03589-3
44. Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Annals of Neurology. 2007;62(1):59-66. doi:10.1002/ana.21142
45. Toledo JB, Arnold SE, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013;136(9):2697-2706. doi:10.1093/brain/awt188
46. Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ. Effect of Infarcts on Dementia in the Baltimore Longitudinal Study of Aging. Ann Neurol. 2008;64(2):168-176. doi:10.1002/ana.21413
47. Song Y, Stampfer MJ, Liu S. Meta-Analysis: Apolipoprotein E Genotypes and Risk for Coronary Heart Disease. Ann Intern Med. 2004;141(2):137-147. doi:10.7326/0003-4819-141-2-200407200-00013
48. Brickman AM, Schupf N, Manly JJ, et al. APOE ε4 and risk for Alzheimer’s disease: do regionally distributed white matter hyperintensities play a role? Alzheimers Dement. 2014;10(6):619-629. doi:10.1016/j.jalz.2014.07.155
49. Gustavsson AM, van Westen D, Stomrud E, Engström G, Nägga K, Hansson O. Midlife Atherosclerosis and Development of Alzheimer or Vascular Dementia. Annals of Neurology. 2020;87(1):52-62. doi:10.1002/ana.25645
50. Lane CA, Barnes J, Nicholas JM, et al. Associations Between Vascular Risk Across Adulthood and Brain Pathology in Late Life: Evidence From a British Birth Cohort. JAMA Neurology. 2020;77(2):175-183. doi:10.1001/jamaneurol.2019.3774
51. Pettigrew C, Soldan A, Wang J, et al. Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline. Neurology. 2020;95(23):e3093-e3103. doi:10.1212/WNL.0000000000010946
52. Walters MJ, Sterling J, Quinn C, et al. Associations of lifestyle and vascular risk factors with Alzheimer’s brain biomarker changes during middle age: a 3-year longitudinal study in the broader New York City area. BMJ Open. 2018;8(11):e023664. doi:10.1136/bmjopen-2018-023664
53. Walsh P, Sudre CH, Fiford CM, et al. CSF amyloid is a consistent predictor of white matter hyperintensities across the disease course from aging to Alzheimer’s disease. Neurobiol Aging. 2020;91:5-14. doi:10.1016/j.neurobiolaging.2020.03.008
54. Graff-Radford J, Arenaza-Urquijo EM, Knopman DS, et al. White matter hyperintensities: relationship to amyloid and tau burden. Brain. 2019;142(8):2483-2491. doi:10.1093/brain/awz162
55. Mielke MM, Frank RD, Dage JL, et al. Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes. JAMA Neurol. 2021;78(9):1108-1117. doi:10.1001/jamaneurol.2021.2293