Genetics of late-onset Alzheimer's disease: progress and prospect.

Genetic susceptibility factors for late-onset Alzheimer's disease remain largely elusive, with the exception of apolipoprotein E4 (APOE e4) as the only confirmed genetic risk factor. Numerous other putative risk markers have been proposed, although all suffer inconsistent replication. These results suggest that modest effect sizes are likely to be the norm for non-APOE-related factors. This unsettling situation has been similar to other complex diseases such as diabetes and cardiovascular diseases until very recently, when a spate of new, although weak, genetic markers has been convincingly linked to these conditions. If we assume that multiple weak factors, together with APOE e4, account for the genetic contribution to late-onset Alzheimer's disease risk, it will require the concerted efforts of the greater Alzheimer's genetics community to pool existing genetic resources and/or data to identify novel genetic risk factors that are genuine. Increased confidence in the disease-associated factors will provide the foundation to develop better diagnostic and prognostic tests, select new drug targets and, perhaps, elucidate pharmacogenetic markers that assist in making the best treatment decisions.