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Wednesday, October 07, 2020

What are your odds of getting Alzheimer's disease?

Latest research shows that risk of late-onset Alzheimer's disease is 75% genetic

T he one question I get asked all the time is whether someone is getting Alzheimer's disease. Sometimes they say it as a joke when they forget a name or a word. But people are clearly worried about it.

The simple answer I always give is that unless someone in your family died of Alzheimer's disease before age 40, any memory loss before age 65 is almost certainly not Alzheimer's.

Estimating the risk is not easy, because Alzheimer's disease (AD) is a diagnosis of exclusion: your doctor must rule out B12 deficiency, vascular dementia, depression and other factors, all of which cause memory loss, then make a probabilistic judgment based on a cognitive test such as the Montreal test or the MMSE that prioritizes memory. A definitive diagnosis is currently only possible after death, and even though 79% of dementia is caused by AD, there are many other types of dementia besides AD that could strike at a younger age.

The CDC has a table showing the overall death rates. From this table it can be seen that your rate goes up exponentially with age and it is relatively rare for people younger than 75.

Age Group   Death rate per 100,000   Annual risk   Total risk*  
65–74 19.80.0198%0.198%
75–84184.50.184 %1.84 %
>85 987.10.987 %19.7 %
* Probability of dying from AD while within the specified age bracket. >85 bracket is taken as 85–105

However, these numbers may be somewhat misleading because death may occur ten years after the patient gets AD. What patients want to know is not the death rate, but the incidence rate. It is also misleading because genetic factors dramatically change the incidence. If a patient has a parent who died from early-onset AD, which is a genetic form of AD that strikes between 25 and 45, their risk could be 50%. Fortunately, although devastating to the families afflicted by it, early-onset AD is uncommon: only 5% of AD patients are in this group.

For late-onset AD, which is also called sporadic AD, the rate varies by sex (women have a 30% higher risk than men) and geographical location, as shown in this map of death rates in US states from the CDC. The rate in Hawaii is 10.5 per 100,000 while the rate in Washington State is 43.6 per 100,000.

CDC map of death rates from Alzheimer's disease by state
CDC map of death rates from Alzheimer's disease by state

Many people don't realize that late-onset AD is also mostly genetic. A person with one ApoE4 allele has a 3-fold increased risk. A person with two ApoE4 alleles has a 12- to 15-fold increased risk. ApoE mutations account for about 20–25% of AD cases.[3] There are many other genes that increase the risk to a lesser extent, but their cumulative effect is such that it's been estimated that even late-onset AD is 75% heritable.[1]

A lot of effort has gone into stratifying the AD risk predictions. The primary tool researchers use is logistic regression, which is a way of fitting yes/no binary data to an S-shaped probability curve. This is similar to the Kaplan-Meier curve, where we plot the percentage surviving as a function of time.

About 1/4 of the heritability comes from ApoE, but it is estimated that there are between 40 and 100 other mutations, which we call SNPs (single-nucleotide polymorphisms, pronounced “snips”) that are statistically associated with late-onset AD. This is much lower than the huge number of SNPs associated with schizophrenia (184,879) and depression (172,735). For this reason, the authors in a recent Nat Commun article call AD “oligogenic.”[1]

The accuracy of these predictions is still far too low (on the order of 20% at best) to provide guidance to any individual. These marginal genes have functions in cellular repair and resistance to oxidants, so it's also a stretch to say they cause the disease, but they provide useful clues to scientists. Even the question of whether ApoE4 causes a loss of ApoE's repair function, or whether ApoE4 is inherently toxic, or both, is not yet known.

Alzheimer incidence rates by age for various genetic profiles
Alzheimer incidence rates by age for various genetic profiles. Redrawn from Desikan et al., Fig. 4.[2]. PHS score is a statistic derived from their genetic makeup that the authors say predicts the age at which they are likely to get Alzheimer's disease. The gray line shows the actual rates in the general US population, based on Brookmeyer's paper [4].

A good example of logistic regression can be found in a paper in PLOS Medicine [2] where the authors took data from 70,000 patients to calculate a polygenic hazard score to estimate age at onset for 6,409 AD patients and 9,386 aged controls. They created a graph, which is shown at right.

This graph tells us what we really want to know, and the gray line, which represents the average person, generally agrees with the public health estimates of Brookmeyer et al.[4] who said that a cognitively normal 60-year-old has a 0.08% chance of getting AD by that year, an average 65-year-old has a 0.17% chance, an 85-year-old has a 2.92% chance, while a 95-year-old has a 12.1% chance.[4] They estimated that the incidence rate increases exponentially, doubling every 4.9 years. Their calculation, still useful today, used the following equation:

Incidence (% per year) = 0.084 × e0.142(t−60)

where t = age in years. There is limited information for patients over 95, so the equation doesn't apply for them.

Brookmeyer is also the source for the commonly cited figure that 68% of individuals with AD are female. This is not just due to lower death rates by other causes; the reasons for it are not known.

The dashed red line in Desikan's graph shows that an ApoE4 carrier has a 35% risk by age 95, while a non-carrier has a 7% risk. By contrast, a person with a high polygenic hazard score, or PHS, as they define it, has a much earlier expected incidence of AD. This is why a reasonable goal is to delay AD if we can't cure it.

It should be emphasized again that these statistics are from research and could change dramatically as new information becomes known. No one should run out and have their DNA tested: it would merely create anxiety. And there is some evidence that stress and anxiety increase your risk [5–7]. This means if everyone got tested, it would screw up all these statistics, and the authors would have to do all those calculations all over again.

1. Zhang Q, Sidorenko J, Couvy-Duchesne B, Marioni RE, Wright MJ, Goate AM, Marcora E, Huang KL, Porter T, Laws SM; Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Sachdev PS, Mather KA, Armstrong NJ, Thalamuthu A, Brodaty H, Yengo L, Yang J, Wray NR, McRae AF, Visscher PM. Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture. Nat Commun. 2020 Sep 23;11(1):4799. doi: 10.1038/s41467-020-18534-1. PMID: 32968074.

2. Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, Thompson WK, Besser L, Kukull WA, Holland D, Chen CH, Brewer JB, Karow DS, Kauppi K, Witoelar A, Karch CM, Bonham LW, Yokoyama JS, Rosen HJ, Miller BL, Dillon WP, Wilson DM, Hess CP, Pericak-Vance M, Haines JL, Farrer LA, Mayeux R, Hardy J, Goate AM, Hyman BT, Schellenberg GD, McEvoy LK, Andreassen OA, Dale AM (2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS Med. Mar 21;14(3):e1002258. doi: 10.1371/journal.pmed.1002258. Erratum in: PLoS Med. 2017 Mar 28;14 (3):e1002289. PMID: 28323831; PMCID: PMC5360219.

3. Karch CM, Cruchaga C, Goate AM. Alzheimer's disease genetics: from the bench to the clinic. Neuron 2014; 83:11–26. doi: 10.1016/j.neuron.2014.05.041 PMID: 24991952

4. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998; 88:1337–1342. PMID: 9736873

5. Stuart KE, Padgett C (2020). A Systematic Review of the Association Between Psychological Stress and Dementia Risk in Humans. J Alzheimers Dis. Sep 25. doi: 10.3233/JAD-191096.PMID: 33016901

6. Liew TM (2020). Subjective cognitive decline, anxiety symptoms, and the risk of mild cognitive impairment and dementia.Alzheimers Res Ther. Sep 11;12(1):107. doi: 10.1186/s13195-020-00673-8. PMID: 32917264 PMCID: PMC7488541

7. Santabárbara J, Lipnicki DM, Bueno-Notivol J, Olaya-Guzmán B, Villagrasa B, Ló;pez-Antón R (2020). Updating the evidence for an association between anxiety and risk of Alzheimer's disease: A meta-analysis of prospective cohort studies. J Affect Disord. Feb 1;262:397–404. doi: 10.1016/j.jad.2019.11.065. PMID: 31744742

oct 07 2020, 7:41 am

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