Alzheimer's Disease has the Look of a Condition Built of Multiple Causes

As a companion piece to the news of amyloid clearance in Alzheimer's patients from earlier this week, in which the outcome was not enough of an improvement to suggest that amyloid accumulation is the only issue, this article looks at a range of recent evidence for Alzheimer's disease to be a condition with multiple significant causes, some of which may be fairly independent of one another.

When pursuing an elusive beast, hunters look for the traces it leaves behind as clues to its whereabouts. Geneticists are employing a similar method to hunt variants linked to Alzheimer's disease (AD), with changes in the brain representing the variants' traces. By correlating biomarker changes with genetic factors, researchers gain clues to the mechanism of action of these genes. A common theme emerged when various groups reported finding distinct sets of factors that influenced amyloidosis versus tau degeneration. The findings imply that these processes have different underlying causes. Other research homed in on specific genes involved in atrophy, in some cases analyzing known AD genes for associations. To many researchers, the data reinforce that to prevent the progression of AD it will be important to treat not only factors that affect amyloid, but also those that affect neurodegeneration.

Previous data have long identified a disconnect between amyloid and atrophy. The regions affected by each form distinct, though overlapping, patterns in the brain. In addition, many older people have brain atrophy without amyloid accumulation. Researchers wondered if amyloid and atrophy might involve distinct risk and protective factors. To test this idea, they analyzed data from Mayo Clinic Study of Aging participants aged 70-90. The cohort comprised 713 cognitively healthy controls, 148 people with mild cognitive impairment, and 12 with AD dementia. For amyloidosis, as expected, older age and the presence of an ApoE4 allele heightened risk. Being a man, or having ApoE2, protected against plaques. However, little else affected amyloid deposition. In contrast, many factors contributed to atrophy. Lifestyle choices such as smoking associated with brain shrinkage, as did numerous chronic diseases of aging, such as hypertension and diabetes.

The data argue that Alzheimer's progression is more complex than simply amyloidosis driving tangles that in turn drive atrophy. Instead, different factors affect each process. The researchers tweaked the common AD analogy that amyloid acts as the gun and tau the bullet by saying that amyloid is the gun and degeneration the bullet. The speed of the bullet varies, they believe, based on risk factors that have nothing to do with amyloid. How do tau tangles fit in? Neurodegeneration has often been thought of as synonymous with tangles, but tau PET imaging data has now made clear that the brain can shrink without any tangles present. To specifically compare risk factors for amyloidosis, for tangles, and for atrophy, researchers analyzed a smaller cohort of 326 cognitively normal participants who had undergone tau imaging. They found that amyloidosis was the main factor driving tau pathology, in agreement with recent imaging studies. In turn, tangles drove some atrophy. However, here, too, the researchers calculated that many other factors affected neurodegeneration independently of amyloid or tau deposits.


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