'Normal' Memory Loss Worse in Men Than Women

March 26, 2015

A new study has found that being male is associated with worse memory and lower hippocampal volume throughout middle and old age in cognitively normal individuals.

Other findings suggest that memory loss and brain shrinkage seen in middle-age is not related to early manifestation of Alzheimer's disease and that the APOE ε4 gene, which is a risk factor for Alzheimer's disease, is not predictive of normal memory and brain loss in middle or older age.

The study, published online March 16 in JAMA Neurology, was conducted by a team led by Clifford Jack Jr, MD, Mayo Clinic and Foundation, Rochester, Minnesota.

"Our results paint a different picture than is presented in much of the recent imaging literature, which has focused great attention on the effect of APOE ε4 but little on the effect of sex on brain structure and function," the authors conclude.

Dr Jack commented to Medscape Medical News: "Our major findings show that memory performance and hippocampal volume track together and both decrease steadily from age 30. Amyloid levels do not start to appear until much later — in the 70s."

"We would conclude therefore that the decline in memory and brain volume seen in middle age is not due to amyloid plaques, and is not representative of the first stages of Alzheimer's It is rather just a consequence of normal aging, which may exacerbated by cerebrovascular disease."

Dr Jack explained that for many years people have attributed memory decline in middle age to the early manifestation of Alzheimer's. "But we show clearly that brain volume and memory starts to reduce decades before Alzheimer's biomarkers appear."

"Just because you may experience memory loss in middle age doesn't mean you are going to develop Alzheimer's in the vast majority of people. This is normal. It happens to everyone. The brain is like any other organ system in the body — it doesn't function as well aged 90 as it does aged 30. The memory decline we experience from middle age is just the inescapable nature of aging."

This has been seen before but it has largely been ignored; gender has been treated as a nuisance variable. I think that is a big mistake. We need to focus on this difference. Dr. Clifford Jack

But the research does suggest that being male is a strong risk factor for memory loss and hippocampal volume reduction. Dr Jack noted: "In men, brain volume and memory decline quicker from age 40 onwards than it does in women. This has been seen before but it has largely been ignored; gender has been treated as a nuisance variable. I think that is a big mistake. We need to focus on this difference."

The researchers postulate that the higher risk in men is probably due to their higher burden of vascular risk factors, such as diabetes, hypertension, and high cholesterol.

"This will affect brain volume," Dr Jack says. "And men lack the protective effect of estrogen on vascular risk. Women have 4 decades of estrogen protection." But he adds that these vascular risk factors are modifiable by lifestyle choices, and this should be the priority target in the battle against memory loss.

The study did not show a significant effect of the APOE ε4 gene on memory loss and brain volume throughout the age range. "While the APOE 4 gene has large effect on predicting preclinical Alzheimer's disease, it does not seem to affect normal memory and brain volume loss in cognitively normal people," Dr Jack said.

What Is Normal?

In an accompanying editorial, Charles DeCarli, MD, UC Davis Alzheimer's Disease Center, says the study "challenges the notion that amyloid accumulation explains memory performance across the entire age range."

"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," he adds.

"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," Dr De Carli concludes.

The cross-sectional observational study included 1246 cognitively normal individuals aged 30 to 95 years who underwent memory testing protocols (including the Auditory Verbal Learning Test), hippocampal volume measurement on MRI, and amyloid positron emission tomography.

Overall, memory worsened from age 30 years through the 90s. Hippocampal volume worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET level 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 hippocampal volume 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 hippocampal volume 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. The ages at which 10% of the population was amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers.

The researchers conclude: "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."

This study was supported by grants from the National Institute on Aging and by the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation. Dr Jack provides consulting services for Eli Lilly and receives research funding from the National Institutes of Health and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation. Dr DeCarli has disclosed no relevant financial relationships.

JAMA Neurol. Published online March 16, 2015. Abstract Editorial


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