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July 8, 2019

Preclinical Alzheimer Disease—Early Diagnosis or Overdiagnosis?

Author Affiliations
  • 1Division of General Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
  • 2Institute for Social Research, University of Michigan, Ann Arbor
  • 3Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan
  • 4Institute of Gerontology, University of Michigan, Ann Arbor
  • 5Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor
  • 6Department of Neurology, University of Michigan, Ann Arbor
JAMA Intern Med. 2019;179(9):1161-1162. doi:10.1001/jamainternmed.2019.2629

The results of clinical trials of new treatments for Alzheimer disease (AD) have been consistently disappointing. Treatment failures for symptomatic individuals with mild cognitive impairment (MCI) or dementia due to AD combined with growing evidence of a perhaps decades long presymptomatic stage of AD1 have led to a focus on preventive treatments for high-risk individuals prior to any symptom onset. The hope is that treatment of preclinical AD, which is defined as the presence of AD brain pathology without evidence of cognitive impairment,2 will be the breakthrough that keeps older adults’ memories and independence intact.

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    3 Comments for this article
    Is preclinical Alzheimer disease a "diagnosis"?
    Robert Wang, Ph.D., M.D. | Private Practice
    Given the lack of certainty about the pathophysiology of AD, the actual contribution of amyloid deposition to the pathophysiology, and what other factors - environmental, vascular, or genetic - might be contributing to the syndrome of AD, make a "diagnosis of preclinical AD" seem a misnomer.

    The syndrome of preclinical AD seems to encompass radiologic or biomarker findings consistent with "above normal" levels of amyloid deposition in the brain. Although this finding may be useful as a risk factor for subsequent development in a dementing illness, it would seem to have no more meaning as a diagnosis -
    meaning a pathophysiological explanation for clinical findings - than the level of education of the patient in question.

    Application of pharmacologic therapy in such a situation, where the full neurologic effects of the therapy are poorly understood, and the efficacy is very limited, would have validity similar to the late night infomercial supplements which are sold so successfully.

    The risks of pharmacologic intervention should be apparent, given recent studies suggesting long-term anticholinergic therapy - widely used as bladder "relaxants" or to manage intestinal dysmotility - may increase risks of AD. Additionally, the studies regarding antidepressant withdrawal illustrate that neuron receptor modification may have long lasting effects beyond the treatment target.

    Practice of medicine should reflect a more scientifically informed approach than what public whim dictates, otherwise, only the infomercial physicians will survive.
    Agree with caution
    Mark Mc Connell, M.D. | Private practice
    Excellent, logical work in an emotionally laden field. With all sensitivity to individuals and families (including my own) impacted by this ravaging disease, I fully support the caution advised by the authors. Until and unless we have effective treatment, more "screening" seems to violate well established criteria for screening and would seem to offer far more harms than benefits.
    Preclinical Alzheimers-it's a bigger problem than just overdiagnosis
    Peter Whitehouse, MD-PhD | Case Western Reserve University
    Langer and Burke do a great service by credibly and diplomatically pointing out the dangers of overdiagnosis in the field of dementia, but their critique can and should extend further. Social science studies have demonstrated that diagnoses like MCI are not well understood by lay people (in part because the conceptual framework of preclinical diagnostic categories is not fully grasped by experts), and that genetic (ApoE) and imaging biomarkers are similarly confusing because they affect risk in poorly understood ways and are not definitive. Claims of being able to find a single diagnostic test (or a potential expensive panel) and an associated cure for age-related heterogenous syndromes like “Alzheimer’s”—which are borne of this new preclinical research paradigm—are often irresponsible and unethical. For example, the Alzheimer Association and its allied “dementia experts” are now promoting a new diagnostic category, Subjective Cognitive Impairment (SCI), in public health educational programs. So too have they published allegedly ethical “appropriate use guidelines” for biomarkers in which some patients who only subjectively complain of their memory worsening (i.e. SCI) with no objective clinical measures are recommended to have amyloid imaging and other tests. Through these actions, the field has created fear and anguish, fostered stigma, exaggerated statistics, not fulfilled countless promises, and produced false hope. The real regret is that evidence shows that we could address the individual and social challenges of dementia more effectively if we designed better public health and community-level interventions, like food, exercise, and environmental quality, and reflected more deeply on the science and ethics in the field.

    Peter Whitehouse MD-PhD and Danny George PhD