A study published online today in JAMA Neurology that finds associations between reduced hippocampal volume (HVa) and being male, but not the gene APOE ɛ4, suggests that there are multiple factors contributing to cognitive decline throughout adulthood, according to an accompanying commentary by UC Davis Alzheimer's Disease Center Director Charles DeCarli.
The research, by Clifford R. Jack and colleagues at the Mayo Clinic and Foundation, compared age, sex and apolipoprotein E ɛ4 (APOE ɛ4) genotype effects on memory, brain structure and the amyloid brain plaques associated with Alzheimer disease, using positron emission tomography (PET) in 1,246 cognitively normal individuals between the ages of 30 and 95.
The study found:
- Overall memory worsened from age 30 through the 90s.
- HVa worsened gradually from age 30 to the mid-60s and more steeply after that with advancing age.
- Median amyloid accumulation seen on PET scans was low until age 70 but increased after that.
- Memory was worse in men than women overall, especially after 40.
- The HVa was lower in men than women overall, especially after 60.
- For both males and females, memory performance and HVa were not different by APOE ɛ4 carrier status at any age.
"If one ascribes religiously to the concept that a large proportion of cognitive differences with age are driven by incipient disease, then one might expect that memory performance — a cognitive ability that changes most dramatically with age and is common to Alzheimer's disease — would follow increasing levels of associated cerebral amyloid and be strongly associated with hippocampal atrophy. In their article Jack et al present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range," De Carli says in his editorial.
"Importantly, this work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 years to brain structure, amyloid accumulation and memory performance among cognitively normal individuals.”
DeCarli notes that "If one tenaciously holds to the notion that the insidious consequences of other diseases may be contributing to these earlier differences, vascular brain injury is an obvious candidate. Vascular risk factors, such as diabetes mellitus, are associated with subtle cognitive impairment among individuals aged 47 to 57 years and hypertension is associated with significantly greater cerebral atrophy among individuals 40 years on average."
Other contributing factors include genetic influences, which include sex differences and the "major effects" of APOE ɛ4 genotype on amyloid retention beyond age 70 years.
“Understanding the basic biology of these early processes is likely to substantially inform us about ways in which we can maintain cognitive health and optimize resistance to late-life dementia. However, such work requires the necessary motivation found by seminal work, such as that of Jack et al, which tell us where and when to investigate these processes. Establishing what is normal creates avenues for new research, increasing the likelihood of discovering novel therapeutics for late-life disease states, which is a laudable goal indeed,” De Carli says.