Acta Neuropathologica

, Volume 121, Issue 5, pp 571–587 | Cite as

Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

  • Peter T. NelsonEmail author
  • Elizabeth Head
  • Frederick A. Schmitt
  • Paulina R. Davis
  • Janna H. Neltner
  • Gregory A. Jicha
  • Erin L. Abner
  • Charles D. Smith
  • Linda J. Van Eldik
  • Richard J. Kryscio
  • Stephen W. Scheff


Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.


Dementia Amyloid Precursor Protein Cerebral Amyloid Angiopathy Hippocampal Sclerosis Werner Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are deeply grateful to all of the study participants. We also thank Leslie Phillips, MS and Sarah Monsell, MS for help with NACC data. Brain tissue from the DS autopsy case was obtained from NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, was under contract HHSN275200900011C, reference number N01-HD-9-0011. Corresponding author: Dr. Nelson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

This study was supported by NIH grants R01 NS061933, K08 NS050110, P30 AG028383, and U01 AG016976.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Peter T. Nelson
    • 1
    • 4
    Email author
  • Elizabeth Head
    • 4
    • 5
  • Frederick A. Schmitt
    • 2
    • 4
  • Paulina R. Davis
    • 4
    • 5
  • Janna H. Neltner
    • 1
  • Gregory A. Jicha
    • 2
    • 4
  • Erin L. Abner
    • 4
  • Charles D. Smith
    • 2
    • 4
  • Linda J. Van Eldik
    • 4
    • 5
  • Richard J. Kryscio
    • 3
    • 4
  • Stephen W. Scheff
    • 4
    • 5
  1. 1.Department of PathologyUniversity of KentuckyLexingtonUSA
  2. 2.Division of Neuropathology, Department of NeurologyUniversity of KentuckyLexingtonUSA
  3. 3.Department of StatisticsUniversity of KentuckyLexingtonUSA
  4. 4.Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  5. 5.Department of Anatomy and NeurobiologyUniversity of KentuckyLexingtonUSA

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