Major depressive disorder (MDD) and diabetes mellitus (DM) have reciprocal relationship and share common pathophysiological mechanisms in the central nervous system. Depression and diabetes negatively affect cognitive function and are independent risk factors for mild cognitive impairment and Alzheimer‟s disease (AD). It has been hypothesized that alterations in the production and processing of amyloid beta (Aβ) may be the principal pathological process in AD. Furthermore, it has been increasingly demonstrated that a long preclinical course precedes AD. A derivative of this observation is the hypothesis that a convergent pathophysiological substrate subserving MDD and DM may promote beta amyloid (Aβ) deposition. The present paper will review evidence linking MDD and DM to Aβ accumulation, with a particular emphasis on original reports that report on levels of Aβ40, Aβ42 and the Aβ40/42 ratio in plasma, serum, or cerebrospinal fluid of individuals with MDD and DM. The overarching goal herein is to press the point that MDD and DM are amyloidogenic and consequently represent modifiable risk factors for AD in later life. The prognostic intervention and prevention opportunity suggested by this notion is that: 1) increased rates of mood disorders and DM in an aging population will increase the population attributable risk for AD ascribed to these conditions, 2) improved outcomes in mood disorders and DM by effective "treating to target" may exert a salutary influence on underlying dementia promoting processes, 3) novel and repurposed medications that are capable of normalizing pathophysiological processes in MDD and DM could decrease the vulnerability towards AD.