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Chapter 2 - Anatomic and Histological Changes of the Aging Brain

Published online by Cambridge University Press:  30 November 2019

Kenneth M. Heilman
University of Florida
Stephen E. Nadeau
University of Florida
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This chapter discusses the age-related microscopic changes affecting neurons and glia emphasizing the alterations seen in cognitively intact individuals, although some changes also occur in neurodegenerative diseases. Also reviewed are common histopathological correlates of white matter changes and small vessel cerebrovascular changes. One age-associated vascular lesion, brain arteriolosclerosis, was recently shown to be related to “hippocampal sclerosis of aging.” The two disease entities are now collectively called “cerebral age-related TDP43 and sclerosis.” Finally, amyloid accumulation without tau or other neuropathologies, termed “pathological aging,” is discussed with a review of current described conditions occurring during aging, e.g., “primary age-related tauopathy” and “aging-related tau astrogliopathy.”

Publisher: Cambridge University Press
Print publication year: 2019

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Tomlinson, BE, Blessed, G, Roth, M. Observations on the brains of demented old people. J Neurol Sci 1968;7:331356.CrossRefGoogle ScholarPubMed
Tomlinson, BE, Blessed, G, Roth, M. Observations on the brains of non-demented old people. J Neurol Sci 1970;11:205242.CrossRefGoogle Scholar
Dickson, DW. Senile cerebral amyloidosis (pathological aging) and cognitive status predictions: a neuropathology perspective. Neurobiol Aging 1996;17:936937.CrossRefGoogle ScholarPubMed
Dickson, DW, Crystal, HA, Mattice, LA, et al. Identification of normal and pathological aging in prospectively studied nondemented elderly individuals. Neurobiol Aging 1992;13:179189.CrossRefGoogle Scholar
Mufson, EJ, Malek-Ahmadi, M, Perez, S, et al. Braak staging, plaque pathology, and APOE status in elderly persons without cognitive impairment. Neurobiol Aging 2016;37:147153.CrossRefGoogle ScholarPubMed
Neltner, JH, Abner, E, Jicha, GA, et al. Brain pathologies in extreme old age. Neurobiol Aging 2016;37:111.CrossRefGoogle ScholarPubMed
Lowe, J. Ageing of the brain. In: Love, S, Budka, H, Ironside, JW, Perry, A, eds. Greenfield’s Neuropathology, 9th edition. CRC Press, Taylor & Francis Group, 2015; 849857.Google Scholar
Esiri, MM. Ageing and the brain. J Pathol 2007;211:181187.CrossRefGoogle Scholar
Allen, JS, Bruss, J, Brown, CK, Damasio, H. Normal neuroanatomical variation due to age: the major lobes and a parcellation of the temporal lobes. Neurobiol Aging 2005; 26:12451260.CrossRefGoogle Scholar
Fjell, AM, Walhovd, KB. Structural brain changes in aging: courses, causes and cognitive consequences. Rev Neurosci 2010;21:187221.CrossRefGoogle ScholarPubMed
Marner, L, Nyengaard, JR, Tang, Y, et al. Marked loss of myelinated nerve fibers in the human brain with age. J Comp Neurol 2003;462:144152.CrossRefGoogle ScholarPubMed
Peters, A, Morrison, JH, Rosene, DL, et al. Are neurons lost from the primate cerebral cortex during normal aging? Cereb Cortex 1998;8:295300.CrossRefGoogle ScholarPubMed
Simic, G, Kostovic, I, Winbld, B, et al. Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol 1997;379:482494.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
West, MJ, Coleman, PD, Flood, DG, et al. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 1994;344:769772.CrossRefGoogle ScholarPubMed
Ma, SY, Roytt, M, Collan, Y, et al. Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 1999;25:394399.CrossRefGoogle ScholarPubMed
Boldrini, M, Fulmore, CA, Tartt, AN, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell 2018;22:589599.CrossRefGoogle ScholarPubMed
Lodato, MA, Rodin, RE, Borhson, CL, et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 2018; 359:555559.CrossRefGoogle Scholar
Opris, I, Cassanova, MF. Prefrontal cortical minicolumn: from executive control to disrupted cognitive processing. Brain 2014;137:18631875.CrossRefGoogle ScholarPubMed
Opris, I. Inter-laminar microcircuits across the neocortex: repair and augmentation. Front Syst Neurosci 2013;7:8085.CrossRefGoogle ScholarPubMed
Van Veluw, SJ, Sawyer, EK, Clover, L, et al. Prefrontal cytoarchitecture in normal aging and Alzheimer’s disease: relationship with IQ. Brain Struct Funct 2012;217:797808.CrossRefGoogle ScholarPubMed
Chance, SA. Subtle changes in the aging human brain. Nutr Health 2006;18;20172224.CrossRefGoogle Scholar
Chance, SA, Casanova, MF, Switala, AE, et al. Minicolumn thinning in the temporal lobe association cortex but not in primary auditory cortex in normal aging. Acta Neuropathol 2006;111:459464.CrossRefGoogle ScholarPubMed
Brody, H. The deposition of aging pigment in the human cerebral cortex. J Gerontol 1960;15:258261.CrossRefGoogle ScholarPubMed
Braak, H. Spindle-shaped appendages of IIIab-pyramids filled with lipofuscin: a striking pathological change of the senescent human isocortex. Acta Neuropathol (Berl) 1979;46:197202.CrossRefGoogle ScholarPubMed
Keller, JN, Dimayuga, E, Chen, Q, et al. Autophagy, proteasomes, lipofuscin and oxidative stress in the aging brain. Int J Biochem Cell Biol 2004;36:23762391.CrossRefGoogle ScholarPubMed
Gray, DA, Woulfe, J. Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowledge Environ 2005;5:re1.Google Scholar
Hirano, A. Neurons and astrocytes. In: Davis, RL, Robertson, DM, eds. Textbook of Neuropathology, 3rd edition. Williams & Wilkins, 1997; 1109.Google Scholar
Mather, M, Harley, CW. The locus coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cogn Sci 2016;20:214226.CrossRefGoogle ScholarPubMed
Satoh, A, Iijima, KM. Roles of tau pathology in the locus coeruleus (LC) in age-associated pathophysiology and Alzheimer’s disease pathogenesis: potential strategies to protect the LC against aging. Brain Res. 2019;1702:1728.CrossRefGoogle ScholarPubMed
Crary, JF, Trojanowski, JQ, Schneider, JA, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 2014;128:755766.CrossRefGoogle ScholarPubMed
David, JP, Ghozali, F, Fallet-Bianco, C, et al. Glial reaction in the hippocampal formation is highly correlated with aging in the human brain. Neurosci Lett 1997;235:5356.CrossRefGoogle ScholarPubMed
Salminen, A, Ojala, J, Kaarniranta, K, et al. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 2011;34:311.CrossRefGoogle ScholarPubMed
Schultz, C, Ghebremedhin, E, Del Tredici, K, et al. High prevalence of thorn-shaped astrocytes in the aged human medial temporal lobe. Neurobiol Aging 2004;25:397405.CrossRefGoogle ScholarPubMed
Kovacs, GG, Ferrer, I, Grinberg, LT, et al. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 2016;131:87102.CrossRefGoogle ScholarPubMed
Kohler, W, Curiel, J, Vanderver, A. Adult leukodystrophies. Nat Rev Neurol 2018;14:94105.CrossRefGoogle Scholar
Peters, A, Sethares, C. Aging and the myelinated fibers in the prefrontal cortex and corpus callosum of the monkey. J Comp Neurol 2002;442:277291.CrossRefGoogle ScholarPubMed
Nasrabady, SE, Rizvi, B, Goldman, JE, et al. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropathol Commun 2018;6:2232.CrossRefGoogle ScholarPubMed
Von Bernhardi, R, Tichauer, JE, Eugenin, J. Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 2010;112:10991114.CrossRefGoogle ScholarPubMed
Conde, JR, Streit, WJ. Microglia in the aging brain. J Neuropathol Exp Neurol 2006;65:199203.CrossRefGoogle ScholarPubMed
Streit, WJ, Xue, QS. Human CNS immune senescence and neurodegeneration. Curr Opin Neurol 2014;29:9396.Google ScholarPubMed
Grimm, A, Eckert, A. Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem 2017;143:418431.CrossRefGoogle Scholar
Venkateshappa, C, Harish, G, Mahadevan, A, et al. Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: implications for neurodegeneration in Alzheimer’s disease. Neurochem Res 2012;37:16011614.CrossRefGoogle ScholarPubMed
Mandal, PK, Tripathy, M, Sugunan, S. Brain oxidative stress: detection and mapping of anti-oxidant marker “Glutathione” in different brain regions of healthy male/female, MCI and Alzheimer’s disease using non-invasive magnetic resonance spectroscopy. Biochem Biophys Res Commun 2012;417:4348.CrossRefGoogle ScholarPubMed
Schmidt, R, Schmidt, H, Haybaeck, J, et al. Heterogeneity in age-related white matter changes. Acta Neuropathol 2001;122:171185.CrossRefGoogle Scholar
Moody, DM, Brown, WR, Challa, VR, et al. Periventricular venous collagenosis: association with leukoaraiosis. Radiology 1995;194:469476.CrossRefGoogle ScholarPubMed
Popsecu, BO, Toescu, EC, Popescu, LM, et al. Blood–brain barrier alterations in ageing and dementia. J Neurol Sci 2009;283:99106.CrossRefGoogle Scholar
Abbott, NJ, Ronnback, L, Hansson, E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 2006;7:4153.CrossRefGoogle ScholarPubMed
Adelbert, R, Colman, MP. Axon pathology in age-related neurodegenerative disorders. Neuropathol Appl Neurobiol 2013;39:90108.CrossRefGoogle Scholar
Salvadores, N, Sanhueza, M, Manque, P, et al. Axonal degeneration during aging and its functional role in neurodegenerative disorders. Front Neurosci 2017;11:121.CrossRefGoogle ScholarPubMed
Pakkenberg, B, Gundersen, HJ. Neocortical number in humans: effect of sex and age. J Comp Neurol 1997;384:312320.3.0.CO;2-K>CrossRefGoogle ScholarPubMed
Ighodaro, ET, Abner, EL, Fardo, DW, et al. Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J Cereb Blood Flow Metab 2017;37:201216.CrossRefGoogle ScholarPubMed
Nelson, PT, Trojanowski, JQ, Abner, EL, et al. “New Old Pathologies”: AD, PART, and cerebral age-related TDP-43 with sclerosis (CARTS). J Neuropathol Exp Neurol 2016;75:482498.CrossRefGoogle Scholar
Nelson, PT, Jicha, GA, Wang, W-X, et al. ABCC9/SUR2 in the brain: implications for hippocampal sclerosis of aging and a potential therapeutic target. Ageing Res Rev. 2015;24:111125.CrossRefGoogle Scholar
Nelson, PT, Dickson, DW, Trojanowski, JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 2019;142:15031527.CrossRefGoogle ScholarPubMed
Brenowitz, WD, Monsell, SE, Schmitt, FA, et al. Hippocampal sclerosis of aging is a key Alzheimer’s disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer’s disease and non-tauopathic frontotemporal lobar degeneration. J Alzheimers Dis 2014;39:691702.CrossRefGoogle ScholarPubMed
Cykowski, MD, Powell, SZ, Schulz, PE, et al. Hippocampal sclerosis in older patients: practical examples and guidance with a focus on cerebral age-related TDP-43 with sclerosis. Arch Pathol Lab Med 2017;141:1131126.CrossRefGoogle ScholarPubMed
Cykowski, MD, Takei, H, Van Eldik, LJ, et al. Hippocampal sclerosis but not normal aging or Alzheimer disease is associated with TDP-43 pathology in the basal forebrain of aged persons. J Neuropathol Exp Neurol 2016;75:397407.CrossRefGoogle ScholarPubMed
Murray, ME, Dickson, DW. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer’s disease? Alzheimers Res Ther 2014;6:2428.CrossRefGoogle ScholarPubMed
Morris, JC, Storandt, M, McKeel, DW, et al. Cerebral amyloid deposition and diffuse plaques in “normal aging”: evidence for presymptomatic and very mild Alzheimer’s disease. Neurology 1996;46:707719.CrossRefGoogle ScholarPubMed
Braak, H, Alafuzoff, I, Arzberger, T, et al. Staging of Alzheimer’s disease-associated neurofibrillary pathology using paraffin sections and immunohistochemistry. Acta Neuropathol 2006;112:389404.CrossRefGoogle Scholar
Lowe, J, Kalaria, R. Dementia. In: Love, S, Budka, H, Ironside, JW, Perry, A, eds. Greenfield’s Neuropathology, 9th edition. CRC Press, Taylor & Francis Group, 2015;858973.Google Scholar
Kovacs, GG, Robinson, JL, Xie, SX, et al. Evaluating patterns of aging-related tau astrogliopathy unravels novel insights into brain aging and neurodegenerative disease. J Neuropathol Exp Neurol 2017;76:270288.CrossRefGoogle Scholar
Nishimura, M, Namba, Y, Ikeda, K, et al. Glial fibrillary tangles with straight tubules in the brains of patients with progressive supranuclear palsy. Neurosci Lett 1992;143:3538.CrossRefGoogle ScholarPubMed
McKee, AC, Cairns, NJ, Dickson, DW, et al. The first NINDS/NBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 2016;131:7586.CrossRefGoogle Scholar
Liu, AK, Goldfinger Questari, HE, et al. ARTAG in the basal forebrain: widening the constellation of astrocytic tau pathology. Acta Neuropathol Comm 2016;4:59.CrossRefGoogle ScholarPubMed

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