Age, sex, and APOE ϵ4 effects on memory, brain structure, and β-Amyloid across the adult life Span

Clifford R. Jack, Heather J. Wiste, Stephen D. Weigand, David S. Knopman, Prashanthi Vemuri, Michelle M. Mielke, Val Lowe, Matthew L. Senjem, Jeffrey L. Gunter, Mary M. Machulda, Brian E. Gregg, V. Shane Pankratz, Walter A. Rocca, Ronald C. Petersen

Research output: Contribution to journalArticlepeer-review

188 Scopus citations


IMPORTANCE Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging. OBJECTIVE To compare age, sex, and APOE ϵ4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old. MAIN OUTCOMES AND MEASURES Memory, HVa, and amyloid PET. RESULTS Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ϵ4 status at any age. From age 70 years onward, APOE ϵ4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ϵ4 carriers and 64 years for noncarriers. CONCLUSIONS AND RELEVANCE Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ϵ4 is not. In contrast, APOE ϵ4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.

Original languageEnglish (US)
Pages (from-to)511-519
Number of pages9
JournalJAMA neurology
Issue number5
StatePublished - May 2015

ASJC Scopus subject areas

  • Clinical Neurology


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