Alzheimer’s biomarkers present decades before symptoms

July, 2012

People with a strong genetic risk of early-onset Alzheimer’s have revealed a progression of brain changes that begin 25 years before symptoms are evident.

A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.

The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.

The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Family members without the risky genes showed none of these changes.

The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).

The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.

The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.

It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.

The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.

Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.

Reference: 

[2997] Bateman, R. J., Xiong C., Benzinger T. L. S., Fagan A. M., Goate A., Fox N. C., et al.
(2012).  Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease.
New England Journal of Medicine. 120723122607004 - 120723122607004.

Related News

Analysis of 40 spinal marrow samples, 20 of which belonged to Alzheimer’s patients, has identified six

Data from 848 adults of all ages has found that brain volume in the default mode network declined in both healthy and pathological aging, but the greatest decline occurred in Alzheimer’s patients and in those who progressed from mild cognitive impairment to Alzheimer’s disease.

New research supports the classification system for preclinical Alzheimer’s proposed two years ago. The classification system divides preclinical Alzheimer's into three stages:

Initial findings from an analysis of cerebrospinal fluid taken between 1995 and 2005 from 265 middle-aged healthy volunteers, of whom 75% had a close family member wi

Cognitive testing for dementia has a problem in that low scores on some tests may simply reflect a person's weakness in some cognitive areas, or the presence of a relatively benign form of mild cognitive impairment (one that is not going to progress to dementia).

A French study has predicted with 90% accuracy which patients with mild cognitive impairment would receive a clinical diagnosis of Alzheimer's disease within the following two years.

Studies linking head trauma with increased risk and earlier age of onset for Alzheimer's disease have yielded contradictory results.

A survey of 7,072 older adults in six provinces across China, with one rural and one urban community in each province, has identified 359 older adults with dementia and 328 with depression.

A survey of 7796 older adults (65+) living in three geographic areas in England has allowed us to compare dementia rates over time, with an identical survey having been taken between 1989 and 1994. The overall prevalence of dementia fell significantly, from 8.3% to 6.5%.

A large Danish study comparing two groups of nonagenarians born 10 years apart has found that not only were people born in 1915 nearly a third (32%) more likely to reach the age of 95 than those in the 1905 cohort, but members of the group born in 1915 performed significantly better on tests of

Pages

Subscribe to Latest newsSubscribe to Latest newsSubscribe to Latest health newsSubscribe to Latest news