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When Does Alzheimer Disease Start?

Summary and Comment |
July 31, 2012

When Does Alzheimer Disease Start?

  1. Brandy R. Matthews, MD and
  2. Jonathan Silver, MD

A study of familial AD suggests the disease starts more than 20 years before clinical symptoms develop.

  1. Brandy R. Matthews, MD and
  2. Jonathan Silver, MD

The pathological process of Alzheimer disease (AD) begins before the clinical symptoms manifest. To identify the timing and stages of this process, researchers examined biological markers of AD in 128 individuals who had a parent with dominantly inherited AD (carriers of the APP, PSEN1, or PSEN2 gene mutation). The researchers tested the participants for carrier status of the relevant gene. Using the affected parent's age at onset and the participant's age at assessment, the researchers estimated the years to symptom onset and identified correlations with biological and clinical AD parameters.

Of the 128 participants, 88 were AD gene carriers (mean age at assessment, 39). Levels of amyloid-beta (Aβ)42 in the cerebrospinal fluid (CSF) appeared to decline in carriers compared with noncarriers 25 years before estimated symptom onset and were significantly different starting 10 years before estimated onset. Compared with noncarriers, carriers had significantly greater Aβ deposition in the precuneus (measured by positron emission tomography), significantly higher CSF tau levels, and hippocampal atrophy 15 years before estimated onset. Carriers also had cerebral hypometabolism in the precuneus 10 years before estimated onset and significantly more global cognitive impairment and logical memory impairment than noncarriers 5 years before estimated onset. The diagnosis of AD was made in 44 participants (43 carriers) an average of 3 years after estimated onset.

Comment

This study shows that AD, including amnestic mild cognitive impairment, may be diagnosed up to 2 decades after the biological process has begun. It is unsurprising that treatments have been unimpressive. The findings suggest that our standards for diagnosing clinical dementia must be refined substantially, so that future disease-modifying therapies can target neuropathology early.

Developing new treatments would have high financial and psychological costs. We would need to screen numerous asymptomatic individuals in their 30s and 40s, to establish a theoretical risk and expose them to potential disease-modifying drugs. As the authors note, longitudinal data are needed to validate this model in dominantly inherited AD, and it may not apply to the more common “sporadic” AD. At present, this information does not warrant a significant change to routine clinical practice, but it highlights the importance of obtaining an accurate family history and encouraging research participation by patients with neurodegenerative illnesses.

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