Memory Complaints Linked to Alzheimer's Biomarkers

Pauline Anderson

July 16, 2015

Emerging research provides compelling new evidence that patients who report memory problems and carry the apolipoprotein E (APOE) 4 allele may be at heightened risk for Alzheimer's disease (AD).

Older adults in the study who reported mentally slipping in recent months or years who still tested normally on cognitive tests had several markers for AD. For example, they had increased cerebral amyloid deposition and changes in tau.

The study was published online May 7 in Alzheimer's & Dementia.

Don't Dismiss Memory Problems

According to the investigators, it's important to identify individuals who are likely to develop AD as soon as possible to minimize such progression. Patients with subjective memory problems are at risk for more severe cognitive impairment, and future therapeutic approaches will likely focus on prevention.

"Doctors should not to ignore older adults with subjective memory complaints even if they test as normal on cognitive tests because they could be at higher risk" for AD, lead author Shannon Risacher, PhD, assistant professor, radiology and imaging sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, told Medscape Medical News.

"Don't dismiss their claim that they're slipping, in the absence of an objective decline."

The study used data from the Alzheimer's Disease Neuroimaging Initiative, a global public-private collaborative project that is collecting long-term AD-related data from volunteers ranging from the cognitively normal to patients diagnosed with AD.

In this analysis of 594 participants, study participants were CN or had significant memory concerns (SMCs) or early mild cognitive impairment (EMCI).

CN participants (n = 185) had no subjective or informant-based report of memory decline and had normal cognitive performance, adjusted for education level, on the Wechsler Logical Memory Delayed Recall (LM-delayed), and on the Mini-Mental State Examination (MMSE).

Participants with EMCI (n = 305) had a memory concern reported by the participant, informant, or clinician; memory function of about 1 standard deviation below normative performance adjusted for education level on the LM-delayed; an MMSE total score greater than 24; and preserved daily functioning such that AD couldn't be diagnosed.

Participants with SMCs (n = 104) had memory concerns as assessed by using the Cognitive Change Index, no informant-based report of memory impairment or decline, and normal cognitive performance on the LM-delayed recall and MMSE.

Researchers divided these diagnostic groups according to APOE ε4 carrier status. APOE ε4, the best-known genetic variant linked to AD, is found in about 25% of the population. Patients with AD who also have this allele tend to exhibit symptoms at an earlier age.

AD Biomarkers

The study showed that APOE 4–positive participants with SMCs had increased amyloid deposition — a hallmark of AD — throughout the cortex relative to participants with SMCs who were not APOE ε4 carriers. The CN and EMCI groups had similar patterns of increased amyloid deposition relative to the presence of an APOE 4 allele.

Cerebral spinal fluid (CSF) levels of amyloid β 1-42, a major component of amyloid plaques, were significantly lower in participants with SMCs who were APOE ε4 positive relative to those who were not carriers of APOE ε4. This suggests that this protein is being recruited to the brain.

Participants with SMCs positive for APOE ε4 also had increased CSF tau phosphorylated at threonine 181 (p-tau), and there was a trend for increased CSF total tau (t-tau) relative to APOE ε4 noncarriers. Tau is another protein linked to AD.

The greatest CSF amyloid and tau abnormalities were in participants with SMCs who were both APOE ε4 carriers and positive for cerebral amyloid on [18F] florbetapir positron emission tomography.

The study showed that glucose metabolism and medial temporal lobe neurodegeneration were not associated with APOE carrier status in those with SMCs but were associated with the presence of mild memory impairment, for example, EMCI.

While changes in amyloid and tau might occur 10 or 15 years before cognitive symptoms, alterations in glucose metabolism and brain atrophy may occur closer to the actual cognitive changes, said Dr Risacher. "The study suggests that they are later markers" of AD, he noted.

There was a trend for people with SMCs to have more glucose metabolism.

"So it's possible that there is some compensatory activity in people with amyloid deposition. Maybe the brain has to work harder to do a cognitive task."

But she stressed that experts don't know the exact course of AD biomarkers. "We don't know what comes first or second or third, and whether one leads to another."

Some AD biomarkers — for example, white matter degeneration and functional MRI — were not evaluated in the study. However, Dr Risacher noted that the biomarkers that were measured are the most commonly used.

Doctors should inquire of older patients whether they're experiencing memory decline, said Dr Risacher.

"They should ask patients if they feel that they've had a change in memory in the last 5 years and how they feel about it."

She added that evidence suggests that patients who are worried about their cognitive decline have worse outcomes.

In these patients, sometimes referred to as the "worried well," doctors should recommend lifestyle changes, for example, increased physical activity and a healthy diet. There's evidence that the Mediterranean diet, which is rich in olive oil and features unrefined cereals, legumes, fresh fruits, vegetables, fish, and a moderate amount of wine, helps preserve cognition, said Dr Risacher.

As well, such patients may benefit from "cognitive training," which involves using practice exercises and other tools and techniques to improve cognition and memory, she said.

Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative, which is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering and through contributions from several groups, including the Alzheimer's Association and numerous pharmaceutical companies.

Alzheimer Dementia. Published online May 7, 2015. Abstract

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