Previous studies of autosomal dominant Alzheimer’s disease have showed hippocampal atrophy,27
and biochemical abnormalities in the CSF.29
With the establishment of DIAN, a worldwide network of autosomal dominant Alzheimer’s disease centers, we have estimated the timing and order of changes in autosomal dominant Alzheimer’s disease in a large cohort with the disease. Changes begin in the brain at least two decades before the estimated onset of clinical symptoms. With the use of estimates of years from expected symptom onset, the order and magnitude of changes indicate that genetic mutations cause increased Aβ42
, which is followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism. After these biologic changes, cognitive impairment can be detected, which culminates in clinical impairment and eventually dementia. These findings suggest that the diagnosis of clinical dementia is made late in the course of the biologic cascade of autosomal dominant Alzheimer’s disease.
The estimated year from expected symptom onset normalizes the stage of disease on the basis of the parental age of onset. Our findings suggest that once initiated, Alzheimer’s disease processes are likely independent of absolute age but rather depend on the start of processes such as Aβ misfolding and other modulating factors. Furthermore, other findings suggest that amyloid deposition probably occurs years or decades before dementia symptoms are manifest in sporadic Alzheimer’s disease.24
Previous cross-sectional studies in sporadic Alzheimer’s disease have suggested a series of changes that lead to clinical disease.2
Our results support the hypothesis of a pathophysiological cascade and suggest the possibility of a common pathophysiology between autosomal dominant Alzheimer’s disease and the much more common “sporadic” form.
A strength of this study is that it shows relative changes in Alzheimer’s disease processes that occur over a period of four decades. However, interpretations of the results are not certain, because the current analyses are based on cross-sectional data, which do not represent individual longitudinal changes. In addition, although many of our findings in autosomal dominant Alzheimer’s disease are similar to findings in sporadic Alzheimer’s disease, there were some differences. For example, trends for increased levels of Aβ42
in the CSF have not been reported in sporadic Alzheimer’s disease or autosomal dominant Alzheimer’s disease, although this trend was predicted in autosomal dominant Alzheimer’s disease, because familial Alzheimer’s disease mutations cause increased Aβ or Aβ42
Furthermore, unlike sporadic Alzheimer’s disease, autosomal dominant Alzheimer’s disease typically presents with early and pronounced PIB-PET signaling in the neostriatum.28
Although the findings of this study were largely based on PSEN1
mutations, a comparison with PSEN2
mutations (Table S2 in the Supplementary Appendix
) suggests no differences in results among the mutation gene types. Owing to the younger age of the cohort, the prevalence of confounders such as vascular risk factors was low (<15%) in this cohort and not significantly different between carriers and noncarriers. Although the clinical and pathologic phenotypes of dominantly inherited Alzheimer’s disease are similar to those of sporadic Alzheimer’s disease, the generalizability of the nature and sequence of brain changes in autosomal dominant Alzheimer’s disease remains to be determined for sporadic Alzheimer’s disease.
The definition of the timing and magnitude of pathophysiological changes associated with Alzheimer’s disease has implications for the development and implementation of diagnostic and predictive tests and the design of prevention trials. 31
For example, our data suggest that amyloid deposition will develop and be detectable in all persons with a mutation while still asymptomatic, whereas no noncarriers had positive scans for amyloid deposition. If autosomal dominant Alzheimer’s disease is similar to late-onset Alzheimer’s disease, this finding suggests that Alzheimer’s dementia will eventually develop in persons with positive scans for amyloid deposition. These findings suggest that the targeting of Aβ earlier in the course of the disease may provide better clinical outcomes than the treatment of mild to moderate dementia after substantial neuronal and synaptic loss has occurred.32
In summary, our findings indicate that the Alzheimer’s disease process begins more than 20 years before the clinical onset of dementia. Treatment and prevention trials can incorporate these pathophysiological changes to gauge the likelihood of future clinical success. Secondary prevention trials that are designed to prevent or delay cognitive and clinical impairment may ultimately test the amyloid hypothesis, just as the cholesterol hypothesis of heart disease was tested three decades ago.33