Insular Alzheimer disease pathology and the psychometric correlates of mortality

Author and Disclosure Information


Right hemisphere dysfunction is associated with mortality in Alzheimer's disease (AD) and other neurologic conditions. These associations may be mediated by insular pathology, as insular lesions result in demonstrable changes in cardiovascular and autonomic control. AD affects the insulae at a preclinical stage, and insular AD pathology may be present in up to 40% of nondemented septuagenarians and octogenarians. This pathology can affect in vivo cardiac conduction and thereby dispose to cardiac arrhythmias and sudden death. Thus, AD pathology should be considered as a possible explanation for autonomic morbidity and mortality in nondemented elderly persons.



Only a few brain structures have been implicated in the autonomic control of blood pressure and heart rate. Among them are heteromodal association areas in the cortex, especially the insular cortex. Insular infarction has been associated with both cardiac arrhythmias and mortality. However, stroke may not be the only insular pathology with the potential to disrupt autonomic function. Alzheimer disease (AD) is associated with both insular pathology and autonomic dysfunction.

This article presents the hypothesis that autonomic dysfunction reflects subclinical stages of AD pathology affecting the insular cortex and discusses the resulting clinical implications.


Braak and Braak have demonstrated a hierarchical progression of AD pathology that includes the insular cortex.1 This may explain why AD has effects on blood pressure and central autonomic cardioregulatory functions. However, AD reaches the insular cortex at a “preclinical” stage in the Braak and Braak sequence (before “dementia” can be diagnosed). Thus, AD pathology should also be considered as a possible explanation for autonomic morbidity and mortality in nondemented elderly persons.2

Suggestive evidence

The following observations support this possibility:

  • Clinical AD is associated with a wide range of dysautonomic phenomena. These can already be demonstrated at the initial diagnosis, which suggests a preclinical onset.
  • Only a limited set of brain regions are capable of affecting autonomic control. The insulae are affected at a preclinical stage in the sequence of Braak and Braak (ie, stage III of VI).
  • Neurofibrillary tangle (NFT) counts inside the insulae moderate the association between the heart rate–corrected QT interval (QTc) and survival. This has been demonstrated by my colleagues and I in collaboration with the Honolulu-Asia Aging Study, which is examining the association between insular pathology at autopsy and the slope of premorbid change in the QTc.

Implications of AD-mediated autonomic dysfunction

AD-mediated autonomic dysfunction could have important clinical implications:

  • The prevalence of preclinical AD is likely to be higher than the number of demented cases. Many apparently well elderly persons may be affected solely on the basis of subclinical AD pathology.
  • Autonomic functions have widespread effects; many cardiac and noncardiac “age-related” changes may actually be related to AD.
  • Pharmacologic therapies for AD are known to delay the progression of symptoms and to reduce mortality; these medications may also impact AD-related autonomic problems.
  • Conversely, the association between other medications and cardiac arrhythmias/sudden death may be mediated via effects on insular function.


AD has been associated with a wide variety of dys-autonomic phenomena, including increased pupillary dilation, altered skin conductivity, blunted autonomic response to noxious stimuli, diminished heart rate variability, depressed baroreflex sensitivity, and orthostasis. Autonomic instability has yet to be sought in mild cognitive impairment or even earlier preclinical stages of AD. However, nondemented subjects with mild cognitive impairment and early AD do experience more frequent falls and more gait and balance problems than do age-matched controls.


The insulae have been specifically implicated in the cortical control of autonomic function.3 The vulnerability of the insular cortex to AD is easy to understand. NFTs appear to spread retrogradely along cortico-cortical and cortico-subcortical connections.4 The insulae are mesiotemporal structures with direct connections to the hippocampus and entorhinal cortex.

Insular lesions result in changes in cardiovascular and autonomic control that are readily detectable by a variety of measures and procedures, including blood pressure, tilt table, balance platform, and electrocardiogram. The electrocardiographic effects of insular pathology include diminished heart rate variability, determined in either the time domain or the frequency domain. Diminished heart rate variability has been associated with increased mortality in cardiovascular disease and type 2 diabetes. It is important to note, however, that the effects of diminished heart rate variability are statistically independent of disease severity in these disorders, and that they can be demonstrated in the absence of clinically significant cardiovascular disease.5

Next Article: