Mixed pathologies and neural reserve: Implications of complexity for Alzheimer disease drug discovery

1. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;3;6 : 37.

2. White LR, Edland SD, Hemmy LS, Montine KS, Zarow C, Sonnen JA, et al. Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies. Neurology. 2016;86 : 1000–8. doi: 10.1212/WNL.0000000000002480 26888993

3. Montine TJ, Sonnen JA, Montine KS, Crane PK, Larson EB. Adult Changes in Thought study: dementia is an individually varying convergent syndrome with prevalent clinically silent diseases that may be modified by some commonly used therapeutics. Curr Alzheimer Res. 2012;9 : 718–23. 22471861

4. Grinberg LT, Nitrini R, Suemoto CK, et al. Prevalence of dementia subtypes in a developing country: a clinicopathological study. Clinics (Sao Paulo). 2013;68 : 1140–5.

5. Honda H, Sasaki K, Hamasaki H, et al. Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study. Neuropathology. 2016;36 : 383–7. doi: 10.1111/neup.12298 26989005

6. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C; Medical Research Council Cognitive Function and Ageing Study. Age, neuropathology, and dementia. N Engl J Med. 2009;360 : 2302–9. doi: 10.1056/NEJMoa0806142 19474427

7. Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA. Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol. 2016;15 : 934–43. doi: 10.1016/S1474-4422(16)30029-1 27312738

8. James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia. Brain. 2016;139 : 2983–2993.

9. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol. 2009;66 : 200–8. doi: 10.1002/ana.21706 19743450

10. Dodge HH, Zhu J, Woltjer R, et al; SMART data consortium. Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease. Alzheimers Dement. 2016. E-pub ahead of print.

11. Brookmeyer R, Kawas CH, Abdallah N, Paganini-Hill A, Kim RC, Corrada MM. Impact of interventions to reduce Alzheimer's disease pathology on the prevalence of dementia in the oldest-old. Alzheimers Dement. 2016;12 : 225–32. doi: 10.1016/j.jalz.2016.01.004 26900132

12. Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med. 2009;6:e1000180. doi: 10.1371/journal.pmed.1000180 19901977

13. Boyle PA, Wilson RS, Yu L, Barr AM, Honer WG, Schneider JA, Bennett DA. Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol. 2013;74 : 478–89. doi: 10.1002/ana.23964 23798485

14. Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, et al. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988;23 : 138–44. doi: 10.1002/ana.410230206 2897823

15. Sonnen JA, Santa Cruz K, Hemmy LS, Woltjer R, Leverenz JB, Montine KS, et al. Ecology of the aging human brain. Arch Neurol. 2011;68 : 1049–56. doi: 10.1001/archneurol.2011.157 21825242

16. Stephan BC, Matthews FE, et al. Alzheimer and vascular neuropathological changes associated with different cognitive States in a non-demented sample. J Alzheimers Dis. 2012;29(2):309–18. doi: 10.3233/JAD-2011-110518 22233761

17. Jack CR Jr, Wiste HJ, Weigand SD, Knopman DS, Vemuri P, Mielke MM, et al. Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span. JAMA Neurol. 2015;72 : 511–9. doi: 10.1001/jamaneurol.2014.4821 25775353

18. Yu L, Boyle PA, Segawa E, Leurgans S, Schneider JA, Wilson RS, Bennett DA. Residual decline in cognition after adjustment for common neuropathologic conditions. Neuropsychology. 2015;29 : 335–43. doi: 10.1037/neu0000159 25495832

19. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014;13 : 788–94. doi: 10.1016/S1474-4422(14)70136-X 25030513

20. Del Ser T, Hachinski V, Merskey H, Munoz DG. An autopsy-verified study of the effect of education on degenerative dementia. Brain 1999;122 : 2309–2319 10581224

21. EClipSE Collaborative Members., Brayne C, Ince PG, Keage HA, McKeith IG, Matthews FE, Polvikoski T, Sulkava R. Education, the brain and dementia: neuroprotection or compensation? Brain. 2010;133 : 2210–6. doi: 10.1093/brain/awq185 20826429

22. Farfel JM, Nitrini R, Suemoto CK, et al. Very low levels of education and cognitive reserve: a clinicopathologic study. Neurology. 2013;81 : 650–7 doi: 10.1212/WNL.0b013e3182a08f1b 23873971

23. Valenzuela MJ, Matthews FE, Brayne C, et al. Multiple biological pathways link cognitive lifestyle to protection from dementia. Biol Psychiatry. 2012;71 : 783–91. doi: 10.1016/j.biopsych.2011.07.036 22055015

24. Iacono D, Markesbery WR, Gross M, Pletnikova O, Rudow G, Zandi P, Troncoso JC. The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology. 2009 1;73 : 665–73. doi: 10.1212/WNL.0b013e3181b01077 19587326

25. Wilson RS, Nag S, Boyle PA, Hizel LP, Yu L, Buchman AS, Schneider JA, Bennett DA. Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology. 2013;80 : 1202–8. doi: 10.1212/WNL.0b013e3182897103 23486878

26. Buchman AS, Yu L, Boyle PA, Schneider JA, De Jager PL, Bennett DA. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology. 2016;86 : 735–41. doi: 10.1212/WNL.0000000000002387 26819457