This R01 application responds to FOA PA-18-061: Marijuana Use In Older Adults. Baby-
boomers who began using cannabis as young people, and who have continued cannabis use
for years, are now entering later life. The FOA prioritizes new evidence about the current risk
status of life-long cannabis users in relation to the aging process, and the aging brain, including
potential risk for Alzheimer’s disease and related disorders. How prepared are they for
successful aging and a long healthspan in late life? We propose to characterize midlife reserve
status of long-term cannabis users in the Dunedin Study, a cohort of 1037 infants born in one
city in 1972-73 and studied to age 45 in 2019, with 94% retention. There have been 8 waves of
in-depth clinical cannabis-use interviews from age 13 to age 45, a unique asset for defining the
users who are the target of this FOA. Our primary group of interest are the cohort members who
have used cannabis weekly-to-daily for the past 3 decades, three-quarters of whom have met
cannabis-dependence criteria. We will test whether such long-term cannabis users do or do not
show diminished reserve capacities in midlife, including accelerated biological aging.
Accelerated aging and diminished reserve pose risk for poor quality of life, brief health span,
and early mortality. The project’s novel conceptual framework extends the logic of “protective
cognitive reserve capacities” to a range of other life domains: we will study reserve in tested
cognitive abilities, but also reserve in neural structure and connectivity assessed through
neuroimaging, physical-health reserve assessed in clinical medical examinations, epigenetic-
maintenance reserve assessed as genome-wide DNA methylation, and financial reserves
assessed through interviews, credit ratings and tax records. In addition to analyses of
continuous dimensional measures, analyses will uniquely be able to compare long-term
cannabis users against 5 informative groups: lifelong non-users, midlife recreational users,
formerly cannabis-dependent quitters, cannabis-free long-term alcohol-abusers, and cannabis-
free long-term tobacco-smokers. For many of the project’s Aims, the Dunedin Study’s
prospective repeated measures allow the rare advantage of comparing long-term users against
themselves at a younger age, before prolonged cannabis exposure. Innovations are: (1)
cannabis-use histories validly defined with 4 decades of prospective assessments, (2) our
conceptual framework of “reserve” for future aging, (3) a comprehensive portrait of participants’
reserve status on aging-relevant measures across multiple disciplines, collected in the same
individuals.