n engl j med
348;25
www.nejm.org
june
19, 2003
perspective
2489
Use It or Lose It — Do Effortful Mental
Activities Protect against Dementia?
Joseph T. Coyle, M.D.
The past 15 years, since the cloning of the gene for
amyloid precursor protein, have witnessed breath-
taking advances in our understanding of the patho-
physiology of Alzheimer’s disease, the most com-
mon cause of dementia. Most findings point to a
final common pathway involving the accumulation
in the brain of the toxic
b
-amyloid peptide, a degra-
dation product of amyloid precursor protein, result-
ing in progressive neuronal damage and concom-
itant cognitive deterioration. Notably, the border
between Alzheimer’s disease and vascular dementia
has become increasingly blurred as shared patho-
logic processes have been identified.
Against this background comes the study by
Verghese et al. in this issue of the
Journal
(pages
2508–2516), which suggests that participation in
cognitively demanding leisure activities in late life
may provide protection against dementia. How can
the molecular determinism of Alzheimer’s disease
be trumped by elderly people’s card playing? To
begin to answer this question, it is important to
understand the limitations of our current knowl-
edge about Alzheimer’s disease. First, the molec-
ular mechanisms proposed for Alzheimer’s disease
are based largely on findings related to mutations
of genes associated with the autosomal dominant
forms of the disorder. These forms of Alzheimer’s
disease are rare, accounting for only a small per-
centage of cases. The precise mechanisms respon-
sible for pathologic disposition of
b
-amyloid pep-
tide in the majority of cases of Alzheimer’s disease
remain rather speculative. Second, with regard to
the much more common, late-onset form of Alzhei-
mer’s disease, studies reveal complex interactions
between genes conferring a risk, such as the alleles
of apoenzyme E, and environmental factors. Com-
pelling epidemiologic studies have shown, for ex-
ample, th