Neurology -- Correspondence for Erten-Lyons et al., 72 (4) 354-360

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Correspondence published:

Factors associated with resistance to dementia despite high Alzheimer disease pathology: Majid Fotuhi, MD, PhD, Vladimir Hachinski, MD, FRCPC, DSc; Miia Kivipelto, MD, PhD; Peter Whitehouse, MD, PhD (21 May 2009)

Reply from the authors: Deniz Erten-Lyons, Jeffrey Kaye (21 May 2009)

Factors associated with resistance to dementia despite high Alzheimer disease pathology 21 May 2009

Majid Fotuhi, MD, PhD,
LifeBridge Health Brain & Spine Institute and Johns Hopkins University
5051 Greenspring Avenue, Baltimore MD 21209,
Vladimir Hachinski, MD, FRCPC, DSc; Miia Kivipelto, MD, PhD; Peter Whitehouse, MD, PhD
Send Correspondence to journal:
Re: Factors associated with resistance to dementia despite high Alzheimer disease pathology

mfotuhi{at}jhu.edu Majid Fotuhi, MD, PhD, et al.

Dr. Erten-Lyons et al. report an important observation that raises new questions regarding the accuracy of Alzheimer Disease (AD) diagnosis in 80+ elderly. [1] Other studies have shown that brains of the elderly contain mixed pathology in the presence or absence of dementia. [2] It should be considered whether the label “AD” should continue to be assigned to elderly who experience cognitive decline.
Most people in their 80s and 90s have varying degrees of plaques and tangles, just as they may have varying degrees of cerebrovascular damage, Lewy body disease, or white matter changes. [2] The combination of these factors, and not any single factor, determines the degree of their mental frailty. [2] Thus, is it accurate to assume, or even imply, that they have developed a single “disease” that accounts for their cognitive decline? In clinical trials, some patients with “AD” may have large loads of plaques and tangles, whereas control subjects may have just as many plaques and tangles. Could an unjustified focus on “AD” partly account for the failure of all disease-modifying drugs for dementia?
Diagnostic criteria for late-onset AD should be updated. An alternative framework for thinking about cognitive decline is necessary—one that is broader and views plaques and tangles only as players among a team of culprits, and not necessarily as the captains. Plaques and tangles may have some role in cognitive deterioration in 80+ elderly, but it accompanies at least a dozen other inter-related genetic and environmental factors (e.g., chronic hypertension, diabetes, obesity, obstructive sleep apnea, and head trauma as well as exposure to chronic stress or toxins such as lead and mercury). Therefore, we must stop over-diagnosing this population with AD. Perhaps a better and more respectful label would be mild, intermediate, and severe cognitive impairment (MCI, ICI, and SCI) “with mixed etiology.”
A strong link between factors that determine the amount of brain substrate and mental agility strengthens the new field of research toward finding ways to improve cognitive fitness. For example, MRI studies in adult humans have shown that 6 months of exercise or 3 months of rigorous cognitive stimulation increases brain volume. [3,4] Do effects of these interventions last for years? Omega-3 fatty acids lower risk of cognitive decline with aging. [5] Do they affect brain volume? Answers to these questions can help baby-boomers who are worried about “AD” make better decisions regarding methods to improve their brain health and longevity.
Isn’t it time for us to shift viewing the world of cognition through an AD lens and toward examining factors that impact size of cortex and hippocampus?
References
1. Erten-Lyons D, Woltjer RL, Dodge H, et al. Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology 2009;72:354-360.
2. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007;69:2197-2204.
3. Colcombe SJ, Erickson KI, Scalf PE, et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci 2006;61:1166-1170.
4. Draganski B, Gaser C, Kempermann G, et al. Temporal and spatial dynamics of brain structure changes during extensive learning. J Neurosci 2006;26:6314-6317.
5. Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Clin Pract Neurol 2009;5:140-152.
Disclosures
Dr. Hachinski has received honoraria for participating in symposia funded by the Ferrer Group and by Berringer-Ingelheim, receives research support from the Canadian Stroke Network, The Canadian Institutes of Health Research and The Alzheimer Association.
Dr. Whitehouse serves as consultant/speaker for Numico/Nutrica concerning nutritional products, serves as a consultant/speaker for Senior Bridge concerning care management in dementia. He does not consult for the pharmaceutical industry.
Dr. Kivipelto serves on the Pfizer steering committee, is on the advisory board for Elan Pharmaceuticals, serves as an editorial board member of Journal of Alzheimer’s Disease, and has served or serves on the speakers’ bureau of Pfizer, Novartis, and Jansen Pharmaceuticals.
Dr. Fotuhi reports no disclosures.

Reply from the authors 21 May 2009

Deniz Erten-Lyons,
Portland VA Medical Center & Oregon Health & Science University
3181 SW Sam Jackson Park Road, CR 131, Portland, Oregon 97239,
Jeffrey Kaye
Send Correspondence to journal:
Re: Reply from the authors

ertenlyo{at}ohsu.edu Deniz Erten-Lyons, et al.

We appreciate the comments by Dr. Fotuhi and colleagues who point out that while diverse neuropathology leads to dementia in older persons, [2] diverse amounts of the same kinds of neuropathology may be present in cognitively healthy older persons. [1] Thus, the effects of various neuropathological changes, alone or in combination, on the clinical phenotype commonly referred to as “Alzheimer disease” is not entirely clear.
We agree with Dr. Fotuhi et al. that better understanding of factors that mediate which neuropathological changes result in particular clinical syndromes will ultimately lead to interventions promoting healthy brain aging. In this quest, it will be important to identify genetic and environmental roles because, as we suggest, individuals may harbor similar amounts of pathology but without the same effects on the brain.
This phenomenon must be rooted in different life experiences or exposures as well as genetic endowments that modulate the relationship between pathology and clinical symptoms.
Disclosures: Dr. Erten-Lyons is funded by the Department of Veterans Affairs (VA) by a Career Development Award, provides clinical assessment and care for patients and receives reimbursement for these activities through Medicare or commercial insurance plans amounting to less than $2000/year. At the Portland VA Medical Center, she is salaried to see patients.
Dr. Kaye is funded for research by the Department of Veteran’s Affairs by a Merit Review grant, and National Institutes of Health (NIH) grants # AG008017, # AG024059, # AG024978, # AG026916, # AG024826, # AG010483, # AG024904, AG016976. The research centers he directs conducts research supported by NIH, Elan Corporation and Intel Corporation and previously by Myriad Pharmaceuticals. Dr. Kaye provides clinical assessment and care for patients and receives reimbursement for these activities through Medicare or commercial insurance plans amounting to less than $3000 per year. At the Portland VA Medical Center, he is salaried to see patients. Dr. Kaye serves as an unpaid Chair for the Work Group on Technology, for the National Alzheimer’s Association and as an unpaid Commissioner for the Center for Aging Services and Technologies based in Washington, DC. Dr. Kaye receives a royalty from sales of the book, Evidence-based Dementia Practice. Dr. Kaye serves on the editorial advisory board of the journal Alzheimer’s & Dementia.