Onset of Memory Loss in Alzheimer's Tied to APOE Status

A divergence in the age-related memory performance of individuals according to their apolipoprotein e4 allele status begins around the age of 55-60 years in neuropsychologic testing, according to a longitudinal analysis of 815 individuals.

The divergence in memory performance may “date the onset of cognitive decline due to Alzheimer's disease for the first time,” said Dr. Richard J. Caselli, who reported the findings with his colleagues in the July 16 issue of the New England Journal of Medicine.

“We're following people before they're changing and have captured the change point,” said Dr. Caselli of the Mayo Clinic, Scottsdale, Ariz., noting that one might be able to detect Alzheimer's disease–related changes even earlier with imaging or at a pathologic, microscopic level.

Dr. Caselli and his associates followed 498 noncarriers of the apolipoprotein e4 (APOE e4) allele and 79 homozygous APOE e4 and 238 heterozygous APOE e4 carriers during a period of about 5 years in either the Arizona APOE cohort or the Arizona Alzheimer's Disease Center cohort. The patients' ages ranged from 21 to 97 years. All of the e4 heterozygotes carried an APOE e3 allele, rather than an e2 allele, which is known to be protective against Alzheimer's disease (N. Engl. J. Med. 2009;361:255-63).

In analyses that isolated the longitudinal aspect of age on cognitive measures in cross-sectional and longitudinal data, the researchers found that APOE e4 carriers had significantly greater predicted decline on the Auditory-Verbal Learning Test–the primary end point of the study–beginning in their 50s, compared with the predicted annual decline of noncarriers beginning in their 70s. This decline in memory performance was significantly correlated with a trend in APOE e4 allele dose on the Auditory-Verbal Learning Test, although the test results were only directly significant for the comparison between APOE e4 homozygotes and noncarriers.

“Our findings suggest that the APOE e4 allele affects age-related memory performance prior to the symptomatic presentation of mild cognitive impairment and dementia. That memory rather than another measure shows the earliest decline suggests that accelerated memory decline among persons with the APOE e4 allele may be caused by subclinical Alzheimer's disease,” Dr. Caselli said in an interview. “Also consistent with this possibility was the observation that visuospatial function subsequently decreased in homozygous carriers of the APOE e4 allele.”

A previous study by this group of investigators that was led by Dr. Eric Reiman of the Banner Alzheimer's Institute and the Translational Genomics Research Institute, Phoenix, showed that amyloid levels in the brain correlated with an individual's dose of the APOE e4 allele. The frontotemporal region of the brain was the most heavily affected by amyloid deposition, and it was the site of the greatest correlation with APOE e4 dose. But medial temporal regions–the sites of memory loss–were much less affected.

Dr. Caselli reported receiving consulting fees from Myriad Pharmaceuticals and Medication, as well as having an equity interest in Pfizer Inc.

'We're following people before they're changing and have captured the change point.'

Source Dr. Caselli

A divergence in the age-related memory performance of individuals according to their apolipoprotein e4 allele status begins around the age of 55-60 years in neuropsychologic testing, according to a longitudinal analysis of 815 individuals.

The divergence in memory performance may “date the onset of cognitive decline due to Alzheimer's disease for the first time,” said Dr. Richard J. Caselli, who reported the findings with his colleagues in the July 16 issue of the New England Journal of Medicine.

“We're following people before they're changing and have captured the change point,” said Dr. Caselli of the Mayo Clinic, Scottsdale, Ariz., noting that one might be able to detect Alzheimer's disease–related changes even earlier with imaging or at a pathologic, microscopic level.

Dr. Caselli and his associates followed 498 noncarriers of the apolipoprotein e4 (APOE e4) allele and 79 homozygous APOE e4 and 238 heterozygous APOE e4 carriers during a period of about 5 years in either the Arizona APOE cohort or the Arizona Alzheimer's Disease Center cohort. The patients' ages ranged from 21 to 97 years. All of the e4 heterozygotes carried an APOE e3 allele, rather than an e2 allele, which is known to be protective against Alzheimer's disease (N. Engl. J. Med. 2009;361:255-63).

In analyses that isolated the longitudinal aspect of age on cognitive measures in cross-sectional and longitudinal data, the researchers found that APOE e4 carriers had significantly greater predicted decline on the Auditory-Verbal Learning Test–the primary end point of the study–beginning in their 50s, compared with the predicted annual decline of noncarriers beginning in their 70s. This decline in memory performance was significantly correlated with a trend in APOE e4 allele dose on the Auditory-Verbal Learning Test, although the test results were only directly significant for the comparison between APOE e4 homozygotes and noncarriers.

“Our findings suggest that the APOE e4 allele affects age-related memory performance prior to the symptomatic presentation of mild cognitive impairment and dementia. That memory rather than another measure shows the earliest decline suggests that accelerated memory decline among persons with the APOE e4 allele may be caused by subclinical Alzheimer's disease,” Dr. Caselli said in an interview. “Also consistent with this possibility was the observation that visuospatial function subsequently decreased in homozygous carriers of the APOE e4 allele.”

A previous study by this group of investigators that was led by Dr. Eric Reiman of the Banner Alzheimer's Institute and the Translational Genomics Research Institute, Phoenix, showed that amyloid levels in the brain correlated with an individual's dose of the APOE e4 allele. The frontotemporal region of the brain was the most heavily affected by amyloid deposition, and it was the site of the greatest correlation with APOE e4 dose. But medial temporal regions–the sites of memory loss–were much less affected.

Dr. Caselli reported receiving consulting fees from Myriad Pharmaceuticals and Medication, as well as having an equity interest in Pfizer Inc.

'We're following people before they're changing and have captured the change point.'

Source Dr. Caselli

A divergence in the age-related memory performance of individuals according to their apolipoprotein e4 allele status begins around the age of 55-60 years in neuropsychologic testing, according to a longitudinal analysis of 815 individuals.

The divergence in memory performance may “date the onset of cognitive decline due to Alzheimer's disease for the first time,” said Dr. Richard J. Caselli, who reported the findings with his colleagues in the July 16 issue of the New England Journal of Medicine.

“We're following people before they're changing and have captured the change point,” said Dr. Caselli of the Mayo Clinic, Scottsdale, Ariz., noting that one might be able to detect Alzheimer's disease–related changes even earlier with imaging or at a pathologic, microscopic level.

Dr. Caselli and his associates followed 498 noncarriers of the apolipoprotein e4 (APOE e4) allele and 79 homozygous APOE e4 and 238 heterozygous APOE e4 carriers during a period of about 5 years in either the Arizona APOE cohort or the Arizona Alzheimer's Disease Center cohort. The patients' ages ranged from 21 to 97 years. All of the e4 heterozygotes carried an APOE e3 allele, rather than an e2 allele, which is known to be protective against Alzheimer's disease (N. Engl. J. Med. 2009;361:255-63).

In analyses that isolated the longitudinal aspect of age on cognitive measures in cross-sectional and longitudinal data, the researchers found that APOE e4 carriers had significantly greater predicted decline on the Auditory-Verbal Learning Test–the primary end point of the study–beginning in their 50s, compared with the predicted annual decline of noncarriers beginning in their 70s. This decline in memory performance was significantly correlated with a trend in APOE e4 allele dose on the Auditory-Verbal Learning Test, although the test results were only directly significant for the comparison between APOE e4 homozygotes and noncarriers.

“Our findings suggest that the APOE e4 allele affects age-related memory performance prior to the symptomatic presentation of mild cognitive impairment and dementia. That memory rather than another measure shows the earliest decline suggests that accelerated memory decline among persons with the APOE e4 allele may be caused by subclinical Alzheimer's disease,” Dr. Caselli said in an interview. “Also consistent with this possibility was the observation that visuospatial function subsequently decreased in homozygous carriers of the APOE e4 allele.”

A previous study by this group of investigators that was led by Dr. Eric Reiman of the Banner Alzheimer's Institute and the Translational Genomics Research Institute, Phoenix, showed that amyloid levels in the brain correlated with an individual's dose of the APOE e4 allele. The frontotemporal region of the brain was the most heavily affected by amyloid deposition, and it was the site of the greatest correlation with APOE e4 dose. But medial temporal regions–the sites of memory loss–were much less affected.

Dr. Caselli reported receiving consulting fees from Myriad Pharmaceuticals and Medication, as well as having an equity interest in Pfizer Inc.

'We're following people before they're changing and have captured the change point.'

Source Dr. Caselli